The purposes of this study were to (1) determine beliefs in the health benefits of dietary fiber, an under-consumed nutrient of public health concern, and (2) determine the relationship between beliefs about dietary fiber and consideration of fiber when making food choices. We conducted a nationally representative within-subject randomized online survey of 42,018 US primary shoppers in May–June 2021. Participants selected health benefits they believed were associated with consumption of fiber from a list of six benefits recognized by the Food and Drug Administration (FDA), one indirect benefit, and one unrelated benefit. Respondents then indicated which nutrients, if any, they considered when making food choices. Respondents selected 1.77 (95% CI = 1.76–1.77) FDA-recognized benefits out of a total six; half (50.6%) of respondents identified zero or one FDA-recognized benefit. The most-cited benefit was “improving bowel movements” (64.4%). Older participants perceived significantly more FDA-recognized fiber benefits. Identification of FDA-recognized benefits increased odds ratios for consideration of fiber during food choice (relative to zero benefits) from 3.0 for one benefit (95% CI = 2.8–3.3) to 14.3 for six benefits (95% CI = 12.4–16.6). Consumers are largely unaware of the many health benefits of dietary fiber, which dramatically decreases the likelihood that they consider this important, under-consumed nutrient during food choice. Low quality diet, which contributes to heart disease, certain cancers, and type-2 diabetes, is the leading risk factor for premature morbidity and mortality, and chronic disability, in the United States (US) ,2. The hThe Dietary Guidelines for Americans (DGA), a document compiled by the US Department of Agriculture and the Department of Health and Human Services, provides guidance for healthy dietary patterns . In addiAmong these nutrients, dietary fiber may be particularly valuable for reducing many of the diet-related diseases that plague modern society. Indeed, dietary fiber is associated with reduced risk of coronary heart disease and type-2 diabetes, which ranked first and eighth, respectively, among all causes of mortality in the United States in 2019 and 2020 ,9.Since their inception, the US Dietary Guidelines have emphasized the importance of a high fiber diet. Yet, after more than four decades, less than 3% of men and 6% of women consume the recommended 14 g dietary fiber/1000 kcal ,12,13. BA recent qualitative study on dietary fiber in Australia showed that while many people understood that experts recommend consuming high-fiber foods, they reported being largely unaware of the health benefits of dietary fiber consumption . This isThe US Food and Drug Administration (FDA) has established a list of recognized health benefits of dietary fiber . These FIn addition to these FDA-recognized health benefits, recent research has established that fermentation by the microbiome is critical for bringing about many of the health benefits of dietary fibers ,17. AccoWe hypothesized that many individuals are unaware of the numerous and diverse health benefits of dietary fiber. Further, given that nutritional knowledge is an important driver of consumption of healthy foods , we hypoIn this research, we examined knowledge of FDA-recognized health benefits of fiber and consideration of fiber during food choice among 42,018 US participants in the National Consumer Panel Omnibus Survey . This is a bi-monthly survey of members of a nationwide consumer panel fielded by IRi, with half of the panel completing the survey each month. In the May–June 2021 survey cycle, we included questions about health benefits of dietary fiber consumption and consideration of fiber during food choice. This study was conducted according to the guidelines outlined in the Declaration of Helsinki, and all procedures involving research study participants were approved by the University of Nebraska–Lincoln’s Institutional Review Board (IRB protocol #20201020721EX). All participants provided electronic informed consent before participating in the research.Respondents selected health benefits they believed were associated with consumption of dietary fiber from a list of eight potential benefits, which were presented in a random order . The lisThe responses to the questions about fiber health beliefs were used in combination with respondent-specific population weights, which were provided with the data by the survey firm. We used the responses and weights to calculate weighted means and 95% confidence intervals of participants’ beliefs of the health benefits of dietary fiber, using the “weighted.mean” and “weighted.sd” commands in RStudio.We conducted a multivariate ordinal logistic regression of the number of FDA-recognized health benefits that participants selected on gender and age to examine associations between demographic characteristics and fiber beliefs. Finally, we conducted a multivariate binary logistic regression of consideration of dietary fiber when making food choices on the number of FDA-recognized fiber health benefits a participant identified and demographic variables to examine the relationship between the number of health benefits selected and the likelihood that an individual incorporates information about dietary fiber into food choice. In the ordinal logistic regression, the variable “number of FDA-recognized health benefits” was treated as an ordered categorical variable. Data were analyzed and visualized using R and R Studio using the “radiant.data,” “nnet”, “MASS”, “ggplot2”, and “cowplot” packages ,28,29,30Inasmuch as the purposes of this study were to gather information about consumer beliefs about the health benefits of dietary fiber and to determine associations between these beliefs and food choice, we gathered data from a population-weighted consumer panel of US primary shoppers. The panel consisted of primary household shoppers and thus reflects a primarily female and older demographic , which iThe most frequently perceived FDA-recognized health benefit of dietary fiber was increased frequency of bowel movements . All othIn the IRi survey, respondents selected only 1.77 (95% CI = 1.76–1.77) FDA-recognized benefits out of a total of six. More than 1 in 5 participants selected none of the FDA-recognized health benefits and over 50% of respondents selected zero or only one recognized benefit . Only 2.The ordinal logistic regression analysis of FDA-recognized benefits on demographic characteristics showed that age had the largest impact on the number of FDA-recognized dietary fiber benefits selected . RelativNext, we examined how beliefs in the health benefits of dietary fiber affected the likelihood that an individual considered dietary fiber content during food choice. Overall, 12,278 respondents (29.2%) indicated that they considered fiber when making food choices. The multivariate binary logistic regression of consideration of dietary fiber during food choice on the number of FDA-recognized fiber health benefits selected and demographic characteristics showed that the number of health benefits a person believed stemmed from dietary fiber was highly important in determining whether dietary fiber was considered during food choice. Relative to an individual who acknowledged zero FDA-recognized benefits, individuals who recognized 1 to 6 benefits were between 3 and 14 times more likely to report considering dietary fiber when making food choices . In factBy comparison, demographic variables were also significantly associated with consideration of fiber during food choice, but the magnitude of the effects were far smaller than the number of benefits of fiber believed . Female Given the widespread media attention to the microbiome and the extensive recognition of the microbiome as a potential health benefit of dietary fiber, we repeated the analysis of the relationship between number of fiber health benefits—with the addition of the “supporting healthy gut bacteria” to the six FDA-recognized benefits—and consideration of dietary fiber during food choice. The results suggest that the belief that dietary fiber supports healthy gut bacteria strongly motivates consideration of fiber during choice, increasing the range of odds ratios for perceiving 1–7 benefits to 3.90 (for 1 benefit) to 24.32 (7 benefits). We report the odds ratios and 95% CI for both regressions in The results support our hypotheses that many people are unaware of the multiple health benefits of dietary fiber and that awareness of health benefits is an important motivator for considering fiber while making food choices. While a majority of respondents believed improving bowel movements was a benefit of dietary fiber, each of the other five FDA-recognized health benefits was identified by fewer than 40% of respondents in the population-weighted IRi survey. Moreover, the most widely recognized benefit—promoting bowel movements—may be perceived as less important, particularly for individuals who do not regularly experience constipation, and therefore not a motivating factor for increasing fiber intake. However, it is important to note that belief in any health benefit markedly increased the likelihood of considering dietary fiber during food choice.Our findings, combined with previous research reporting positive correlations between nutrition knowledge and healthy diets, suggest that limited knowledge about the health benefits of fiber may limit the amount of fiber in people’s diets . In factInterestingly, while not recognized by the FDA, a majority of respondents identified promoting healthy gut bacteria as a benefit of dietary fiber. The influence of dietary fiber on the gut microbiome is not only an active area of research, but also a popular topic in mainstream books and websites ,20. Our Reducing energy intake was the least recognized benefit of dietary fiber—even less so than improving skin complexion, which has no known relationship to fiber intake. We speculate that this was a misunderstood benefit and if the wording were changed, for example to “promotes satiety,” more respondents would have identified this benefit, though given low levels of awareness of most health benefits, it would still likely be under-recognized. Future research could examine the best terminology to tailor messages that will meet the needs of consumers in general and for specific demographics .Another important outcome of the analysis is the disparity in beliefs in the benefits of fiber by age group, with young adults selecting significantly fewer health benefits of dietary fiber than older adults. This is perhaps not surprising because many of the health benefits of fiber, such as reduced cholesterol and blood glucose, are long-term benefits that become more relevant as one ages . PreviouAlthough being older or female was associated with greater likelihood of consideration of fiber during food choice compared with being younger or not female, our results clearly show that consideration of dietary fiber during choice is predominantly explained by the number of benefits respondents believed resulted from dietary fiber consumption. The effect size of identifying any benefit was markedly larger than being in the oldest age category or being female. Therefore, identification of the positive impacts of fiber consumption on health may provide motivation for individuals to seek out high-fiber foods.A strength of our study is our large sample size of population-weighted responses from US shoppers. However, this is also a limitation. Due to the cost of adding questions to the survey and limitations to the structure of added questions imposed by the survey firm that conducted this survey, we were unable to include detailed demographic and probing questions to determine the underlying reasons for the differences in beliefs in fiber benefits among consumers. Despite this, we show a strong relationship between the number of benefits consumers believed resulted from fiber consumption and consideration of fiber during food choice, which suggests the importance of awareness in helping consumers to make better food choices.We were also unable to ask multi-part questions. We evaluated beliefs about the health benefits of fiber using a check-all-that-apply question format where a great majority of the response options were in fact established or actively researched benefits (6 or 7 out of 8). Previous research has shown that multi-part questions such as check-all-statements questions where consumers must answer yes or no to each item in a list rather than the check-all-that-apply setup that we used affects the number of agree responses ,41. If aAnother limitation to our study is that we only have data on self-reported consideration of dietary fiber during food choice rather than data on individuals’ real-world food choices. Real-world choices would provide more powerful evidence of the linkages between beliefs about the health benefits of fiber and the fiber content of foods purchased. However, previous research has shown that people with greater general nutrition knowledge select healthier foods and have lower incidence of diet-related diseases . Based oAdditionally, there may be underlying individual characteristics, such as a general health motivation, that drive both beliefs about individual nutrients, such as dietary fiber, and the choice of healthier foods ,44. In tThis study confirmed our hypothesis that many individuals are unaware of the numerous and diverse health benefits of dietary fiber. Indeed, a majority of respondents identified no benefits or only one FDA-recognized benefit of dietary fiber. This study also revealed that belief in the health benefits is critical to considering healthier foods, as individuals that identified all six FDA-recognized benefits of dietary fiber were 14 times more likely to consider the fiber content of foods when making food choices than those who recognized no benefits of fiber. Although respondents across all demographic categories did not recognize many of the benefits of fiber, younger adults identified the lowest number of health benefits of fiber.These findings suggest that education and messaging focused on the less well-known, but highly important, health benefits of dietary fiber—especially targeted at younger adults—may promote higher levels of dietary fiber consumption and ultimately improve public health. Our finding that a majority of consumers identified “supporting healthy gut bacteria” as a consumer-perceived benefit of fiber is encouraging. Although not an FDA-recognized benefit of fiber, consumers consider this a relatively new indirect benefit of fiber that has been discussed widely in popular media, including news articles and books. Thus, similar messaging used to promote healthy gut bacteria could be used to promote the lesser-known benefits of fiber.


Histone modification is an important epigenetic alteration, and histone deacetylases are involved in the occurrence and development of various respiratory diseases. Sirtuins (SIRTs) have been demonstrated to play an important role in the formation and progression of chronic inflammatory diseases of the respiratory tract. SIRTs participate in the regulation of oxidative stress and inflammation and are related to cell structure and cellular localization. This paper summarizes the roles and mechanisms of SIRTs in airway inflammation and describes the latest research on SIRT modulators, aiming to provide a theoretical basis for the study of potential epigenetic alteration-inducing drug targets. Chronic inflammation is characterized by the presence of several pro-inflammatory mediators, primarily produced by activated macrophages, such as interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) which persist in inflammation . InflammEpigenetic modifications are heritable changes that do not involve changes in gene expression levels or alterations in DNA sequences. Abnormal epigenetic modifications can cause structural and functional changes in the body and cause disease . EpigeneDue to the complexity of inflammatory cells, the pathogenesis of respiratory system diseases is multifaceted. Some researchers believe that those blood-based molecular parameters and other metabolites, such as DNA methylation markers, cell-free DNA mutation markers, and microRNAs, are attractive future biomarkers for diagnosing inflammatory diseases . Thus, tRespiratory diseases are highly heterogeneous, with complex etiologies and unclear pathogeneses. Even diseases within the same clinical classification exhibit large differences in intrinsic cellular and molecular pathological mechanisms. Despite the dramatic increase in the use of new therapeutics for respiratory diseases, they are infrequently discovered; therefore, few new classes of therapeutics have been developed to regulate or treat airway inflammatory diseases. In summary, methods of reestablishing regulatory mechanisms that attenuate this chronic inflammation are urgently needed . HoweverMembers of the HDAC family contain a highly conserved deacetylase domain and are critical for maintaining the balance of histone lysine acetylation and deacetylation . The deaSaccharomyces cerevisiae, silent information regulator 2 (Sir2), and SIRTS were subsequently found in other species, including mammals, in which they play essential roles in epigenetic regulation  and tyrosine residues (Tyr102) in SIRT5’s acyl bags explains the preference for succinyl and malonyl groups. Several mammalian proteins with succinyl or malonyl lysine modifications were identified by mass spectrometry. Deletion of Sirt5 in mice appears to increase succinylation of carbamoyl phosphytase 1, a known target for SIRT5. Thus, protein lysine succinylation may represent a posttranslational modification that can be reversed by SIRT5 in vivo  activity. One study showed that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 complementary DNA (cDNA), triggering a strong type I interferon response via activation of cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS) and promoting pathological inflammation . There iSIRT7 is located in the nucleoli and functions in association with active ribosomal RNA (rRNA) genes. SIRT7 and rRNA interact closely with RNA polymerase I (Pol I) . SIRT7 iBA is one of the most common chronic inflammatory disorders. Asthma severely limits airflow in the lungs . This liSIRT1 plays a role in maintaining the Th2 cell balance and preventing sustained cellular differentiation toward a Th2 phenotype . In someCRS is characterized by mucosal inflammation in the sinuses and paranasal sinuses and mucosal changes, including inflammatory thickening and nasal polyp formation. The formation of nasal polyps is related to hypoxic factors and Th2-type immune responses; that is, a hypoxic environment can affect nasal mucosal inflammation and epithelial cell remodeling and promote the formation of nasal polyps . StudiesCOPD, a leading cause of mortality and morbidity, has become a major health problem worldwide. COPD affects approximately 10% of people over 45 years of age . MelatonOxidative and carbonyl stress occur in the lungs of patients with chronic obstructive pulmonary disease and smokers, as well as in rodents exposed to cigarette smoke (CS) . HoweverStudies have revealed severe inflammation in the airway of COPD mouse models, along with alveolar space enlargement and mitochondrial damage. SIRT3 may inhibit mitochondrial oxidative stress in the airway epithelium by regulating MnSOD, thereby promoting the pathogenesis of COPD . SIRT4 eALI and ARDS are characterized by the activation of macrophages and neutrophils and the disruption or edema of the alveolar capillary membrane barrier, all of which can lead to respiratory failure . One stuGiven the critical role of SIRTs in a variety of human respiratory diseases, including BA, CRS, COPD, ALI, and ARDS, the use of small-molecule modulators to modulate the activity of SIRTs may provide therapeutic benefits for blocking the initiation and progression of these diseases .Although understanding of this family of broad-spectrum protein lysine deacylases has increased dramatically in recent years, many questions remain. The search for heterospecific modulators (including SIRT activators (SIRTas) and inhibitors (SIRTis)) is still in its infancy. Therefore, many relevant SIRT modulators have been described in the literature and in patents. For example, dietary SRT1720 (SIRT1a) improves insulin sensitivity and glucose tolerance in genetically obese mice, leading to beneficial effects on lipid metabolism and weight loss . UBCS039The lack of well-described pharmacological characteristics of these small-molecule compounds has hindered their translation from the laboratory to clinical use . In the SIRT1 is the most studied isotype to date, followed by SIRT2 and SIRT3. Thus, a few small-molecule modulators targeting the other isotopes have been developed, and most of the regulators evaluated in clinical trials target SIRT1. Resveratrol (RSV) is a mediator of the cardioprotective effects of wine, sparking interest in RSV as a potential therapeutic agent . This coFurther study needs to be done on the application of SIRT modulators in inflammatory diseases of the respiratory system . RSV treThis review provides an up-to-date overview of the most relevant biometrics of SIRT enzymes and SIRT formulations reported in the scientific literature. These small-molecule modulators are inhibitory compounds, and their selectivity regarding other SIRTs has not yet been fully evaluated. Future rational inhibitor design and direct high-throughput screening of all SIRTs, especially mammalian homologs, will undoubtedly lead to the development of highly selective and powerful inhibitors that will provide the necessary tools for elucidating the cellular function of these enzymes and may lead to the development of treatments targeted toward individual SIRTs. SIRT-targeting drugs are promising therapeutics, and advances in the respiratory field will accelerate the development of small-molecule drug candidates. If additional SIRT modulators are translated to the clinic, a surprising amount of progress will be made in targeted precision therapy for otolaryngology and pneumology.


NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the  NOTCH3 gene mutation. Granular osmiophilic material (GOM) deposition in the small arteries is the classical pathology of CADASIL. White matter hyperintensity (WMH), especially that in the anterior temporal lobes and external capsule, has been identified as a typical neuroimaging feature of CADASIL. Currently, many mechanisms are reported to be linked to WMH, including cerebral hypoperfusion, impaired cerebral vascular reactivity, and blood-brain barrier impairment. Among them, cerebral hypoperfusion is an early feature of the disease and its relationship with WMH has been clearly investigated by many groups. Collectively, these studies provide strong evidence demonstrating that cerebral hypoperfusion is an early event and may play a key role in the CADASIL pathophysiological cascade. In this review, we summarize the possible pathophysiology of hypoperfusion in CADASIL.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a common pure form of subcortical vascular dementia, which is caused by NOTCH3 gene mutation causes arteriolar dysfunction has not been clearly studied. The mature Notch3 receptor consists of the 210-kDa Notch3 extracellular domain (Notch3ECD) and the 97-kDa Notch3 transmembrane intracellular domain (Notch3TICD). Signal activation of Notch3 requires the Notch3 receptor to undergo a series of proteolytic cleavages for division into Notch3ECD and Notch3TICD. Notch3 protein is mainly expressed in mural cells, including vascular smooth muscle cells (VSMCs) and pericytes. Therefore, it can be speculated that abnormal vascular mural cells may be an important reason for the dysfunction of arterioles in CADASIL.Although there is sufficient evidence confirmed the existence of cerebral hemodynamic abnormalities and cerebral arteriolar dysfunction in CADASIL patients, how ECD is one of the earliest detectable pathological features in CADASIL patients and mouse models, suggesting that Notch3ECD accumulation is an early event in CADASIL. NOTCH3 mutations lead to an odd number of cysteine residues in Notch3ECD, consequently resulting in abnormal degradation of Notch3ECD on the surface of mural cells. Joutel A. is the first to put forward the Notch3ECD cascade hypothesis for CADASIL: early Notch3ECD deposition abnormally recruits the other extracellular matrix (ECM) proteins, thus leading to the accumulation and formation of the so-called GOM, which can be observed under the transmission electron microscope. Notch3ECD along with other ECM proteins causes dysfunction in the small vessels of the brain. This hypothesis provides an alternate understanding of the pathogenesis of CADASIL. Postmortem studies have found a series of ECM proteins that are components of GOM, including clusterin, tissue inhibitor of metalloproteinases 3 (TIMP3), vitronectin, latency in TGF-β binding protein 1 (LTBP-1), high-temperature requirement protein A1 (HTRA1), and other ECM proteins. Abnormal deposition of these proteins can affect the normal structure and function of arterioles. TIMP3 is a tissue inhibitor of matrix metalloproteinase, which helps maintain tissue microenvironment homeostasis. Studies have shown that the increase of TIMP3 is associated with abnormal small artery function and decreased cerebral blood flow (CBF) in mouse models. Abnormal TIMP3 accumulation inactivates the metalloprotease ADAM17, which results in the inactivation of HB-EGF-ErbB1/ErbB4 signaling and endocytic dysfunction of the voltage-dependent potassium channels (Kv). Increased Kv channel activity in the VSMCs membrane leads to compromised cerebral arterial tone and CBF responses, which can be restored by exogenous addition of ADAM17 or HB-EGF. Besides, an autophagy-lysosomal defect was detected in human CADASIL VSMCsR133C, aggravating the accumulation of intracellular and extracellular proteins. Abnormal aggregation and deposition of proteins can further lead to endoplasmic reticulum oxidative stress, apoptosis and cell dysfunction.Accumulation of Notch3. Given its critical role in vascular integrity, dysregulation of Notch3 signaling may be associated with cerebrovascular dysfunction in individuals with NOTCH3 gene mutations. Severe cerebrovascular abnormalities have been detected in NOTCH3 gene knockout mice, including VSMC loss, blood-brain barrier leakage, and arterial myogenic tone changes. Interestingly, cerebrovascular abnormalities reported in NOTCH3 knockout mice were consistent with those observed in CADASIL mutant mice (TgNotch3C455R). However, except for mutations in the binding region of Notch3 receptor, the Notch3 pathway activity is not significantly affected–17. Besides, increased Notch3 activity and the impairment of maximal vasodilator capacity were found in CADASIL mutant mice (TgNotch3R169C), which can be prevented by conditionally reducing Notch3 activity and mimicked by conditionally activating Notch3 in VSMCs. Therefore, different NOTCH3 mutations may have different effects on Notch3 signaling, and contribute to reductions in CBF through different mechanisms.Notch3 signaling plays an important role in arterial maturation, maintenance, and function. In 2010, Brennan-Krohn T et al reported that astrocytic-associated molecular abnormalities are restricted to the regions of WMH and contribute to vascular degeneration in brain tissues in patients with CADASIL. Furthermore, in 2018, Hase Y et al demonstrated the activation of normal-appearing astrocytes and their transformation into clasmatodendritic astrocytes in the deep white matter in CADASIL . Immunohistochemical analyses have shown that clasmatodendritic astrocytes are abundant in the anterior temporal pole and that aquaporin 4 (AQP4) is displaced in these astrocytes, indicating that the gliovascular unit of the deep white matter is severely impaired in CADASIL . Next, we tried to understand the pathology of neurovascular dysfunction and WMH in light of astrocytopathy in CADASIL.In addition to mural cells, Notch3 receptor is also expressed in astrocytes. Being a part of the cellular composition of the neurovascular unit (NVU), astrocytes contribute to the regulation of small vessel tone and CBF responses2+ levels in astrocyte endfeet result in arteriolar vasodilation. A study has reported the astrocyte-regulated vascular tone in VSMC through the phospholipase A2-arachidonic acid pathway . Whether astrocytopathy-mediated VSMC dysfunction is the cause of CBF reduction in CADASIL remains unknown.Astrocyte endfeet show close apposition around VSMCs and pericytes. Increased intracellular Ca . The function of the perivascular glymphatic pathway is primarily dependent on AQP4 water channels, which are highly expressed in the astrocyte endfeet. The glymphatic system not only facilitates the elimination of excess fluid and interstitial waste in the brain parenchyma but also plays an important role in the fluid exchange between cerebrospinal fluid (CSF) and brain parenchyma interstitial fluid (ISF). Waste clearance and fluid exchange are critical for brain homeostasis maintenance. WMH represents local fluid accumulation in the white matter. Decreased glymphatic activity probably results in waste and fluid accumulation and further initiates the loss of mature oligodendrocytes and WMH in patients with CADASIL . WMH is not only the hallmark of CADASIL, but also the characteristic pathological change in other small-vessel diseases (SVDs). The stroke-prone spontaneously hypertensive rat (SHRSP) is a rodent model of human sporadic SVD. Studies show that total CSF flux is significantly reduced in the SHRSP rats than in controls. The glymphatic flux is also significantly reduced in SHRSP rats than in controls. Altered perivascular AQP4 expression is also observed in SHRSP. Diabetes is a cardiovascular risk factor for SVD. Dysfunctional CSF flow dynamics and glymphatic transport occur in the streptozotocin-induced type 2 diabetes rat model.Astrocyte endfeet also form a unique network of interconnected perivascular tunnels called the glymphatic systemNOTCH3 gene mutations cause abnormal Notch3 deposition and signaling, leading to mural cell dysfunction and degeneration. However, whether severe astrocytopathy is the main cause of vascular degeneration or it is secondary to VSMC- and pericyte-mediated vascular pathology in the deep white matter of CADASIL remains to be elucidated. Much more work is needed to elucidate the relationship between NOTCH3 mutations and decreased CBF in order to seek therapeutic targets and clinical translations.Recent studies have demonstrated that CBF hemodynamic deficit occurs in the early stage of CADASIL and plays an important role in brain parenchymal injury formation. As the component of NVU, endothelial cell, VSMC, pericyte, astrocyte and ECM all participate in CBF regulation. We reviewed the possible pathophysiology of hypoperfusion in CADASIL from the aspects of mural cells and glial cells.


Cancer is a complex phenomenon that encompasses over 200 different diseases that are the consequence of accumulation of genetic alterations . DespiteLigusticum chuanxiong Hort is shown to be effective against different cancers at preclinical stages . Another example of a such paradigm was discussed by Li et al., where they have reported the anticancer potential of gracillin, a steroidal saponin compound found in different medicinal plants such as Rhizoma paridis, Pairs polyphylla, Dioscorea villosa, Acontum carmichaeli, Solanum incanum, and Solanum xanthocarpum against non-small cell lung cancer (NSCLC) cells. Their research indicated that gracillin possesses anti-NSCLC activity through promoting autophagy of cancer that was regulated via the mTOR signaling pathway. Similarly, Chen et al. showed that α-hederin, a monodesmosidic triterpenoid saponin extracted from Fructus akebiae enhanced apoptosis while inhibiting the proliferation of hepatocellular carcinoma (HCC) cells through the alteration of Hippo/YAP protein signaling pathway. It was observed that the treatment of α-hederin treatment led to the increased level of proteins and genes associated with the Hippo signaling pathway. Moreover, their treatment also caused decreased nuclear YAP levels that consequently inhibited the proliferation while increasing the apoptosis of HCC cells.Interestingly, the single treatment of natural product such as tetramethylpyrazine (TMP) isolated from Cho et al.). A triple-regimen of vemurafenib that targets BRAFV600E, a topoisomerase I inhibitor (irinotecan), and cetuximab  resulted in a complete response to the therapy. EGFRi can initiate many side effects and natural products in the therapeutic regimen can alleviate these challenges , in overcoming resistance to receptor tyrosine kinase (RTK)-EGFRi in non small cell lung cancer (NSCLC) models. The authors have shown that the combination of Brucein H in the therapy increased the gefinitib response by suppressing Notch3, EGFR activation and β-catenin expression. Remarkably, the combination of Brucein H and gefinitib also induced Foxo3a, whose expression correlates with better response to EGFR inhibitors and better overall survival in NSLCC patients. Similar to this study, the comparative proteomic analysis by Cai et al. demonstrated the chemosensitizing effect of cryptotanshinone (CTS), a bioactive component of Salvia miltiorrhiza against gefitinib-resistant EGFR-mutant lung cancer cells. Lately, three proteins namely, catalase (CAT), heme oxygenase 1 (HMOX1), and stearoyl-CoA desaturase (SCD) identified through a proteomic analysis were validated as the important target of CTS and suggested to be a potential therapeutic target in lung cancers.Many researches over the past decades have suggested that the cancer cells develop resistance to the drugs and that can this can be circumvented by the combination of multiple drugs, acting on redundant signaling nodes. Such an effective combination approach has been studied in a case report of BRAFV600E-mutant colorectal cancer (CRC)  can sensitize the sorafenib-resistant hepatocellular carcinoma (HCC) cells through the inhibition of AKT kinase protein phosphorylation. Interestingly, the past literatures have indicated the importance of AKT kinase involvement in different types of cancers, and through in silico analysis it was also shown that it can potentially be targeted by natural products . Mechanistically, it was suggested that it induces its sensitization effect through the induction of inducing phenotypic differentiation of CSCs and it was due to the change in the notch signaling pathway and stem cell pathway.It is now well established that the cancer cells become resistant to certain kinds of therapy through the alterations of various signaling pathway . In accoproducts . In addiYu et al. have shown that TP5 can directly inhibit the stemness of colon cancer cells HCT116 as evident by reduced surface molecular markers associated with stemness such as CD133, CD44, and CD24 in addition to stemness-related genes like ALDH1, SOX2, Oct-4, and Nanog. These stemness-related changes thereby caused altered Wnt/β-catenin signaling that resulted in enhanced oxaliplatin (OXA) cytotoxicity against HCT116 cells. Also, Ragone et al.highlight the effectiveness of combination therapy of gemcitabine (Gem) and AdipoRon (AdipoR) in combating pancreatic ductal adenocarcinoma (PDAC) resistance to Gem. AdipoR is known to be the first synthetic orally active adiponectin receptor agonist suggested having an antitumorigenic effect against different types of cancers including PDAC. They have proposed that their combination halts the cell cycle progression in cancer cells effectively and p44/42 MAPK pathway involvement in the improved treatment outcomes.Apart from natural resources derived by plants, recent years have witnessed a plethora of research that has emphasized the application of compounds derived by other natural sources or natural product-inspired synthesized molecule in cancer therapy . One sucOverall, the present Research Topic received a range of remarkable original and review articles that can improve the understanding of the chemosensitizing properties of natural products. Moreover, natural products other than plant sources such as biomolecules, toxins, venoms, ligands etc. obtained/inspired from microorganisms and animal sources also open new avenues for exploration to unravel nature’s treasure for drug discovery. However, the lack of articles in context to immunotherapy and clinical trials highlights the ample opportunity available in this area to fill the void in our understanding. Recent research by


First, I congratulate the authors for theirinvaluable contribution to the literature. On the other hand, I would like to point outsome information about the scores and preoperative estimating in intensive carestay.We interestingly read the article by Zarrizi et al.. Additionally,we showed that the CHA2DS2-VASc and anticoagulation and risk factors in atrialfibrillation (ATRIA) scores were useful in detecting postoperative atrial fibrillationafter coronary artery bypass grafting and that these scores are related to intensivecare unit length of stay. I believethat it would be useful if the authors provided data about these easy scoring systems onintensive care unit length of stay.The authors in that article developed a scoring system including number of chest tubes,development of atrial fibrillation, and atelectasis. Accordingly, they showed that thisscoring system was useful in predicting the length of stay in intensive care unit aftercoronary artery bypass grafting. Although the results of this study were useful forclinical practice, they do not provide additional information on the duration ofintensive care unit length of stay before coronary artery bypass grafting. In a previousarticle, we showed that the CHA2DS2-VASc - congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke or transient ischemic attack, vasculardisease, age 65 to 74 years, sex category - score correlates with coronary care unitlength of stay and new-onset atrial fibrillation in patients with ST elevationmyocardial infarction[4,. It has been showed that these scorespredicted several anatomical and clinical diseases in cardiovascular practice[6-. Because of that, these scoring systems may be used to assessrisk and estimate length of stay in intensive care in patients undergoing coronaryartery bypass grafting.The CHA2DS2-VASc and ATRIA risk scores are cheap and easy scoring systems that are usedto predict the risk of thromboembolism in non-valvular atrial fibrillationpatients


The innate immune response constitutes the cell’s first line of defense against viruses and culminates in the expression of type I interferon (IFN) and IFN-stimulated genes, inducing an antiviral state in infected and neighboring cells. Efficient signal transduction is a key factor for strong but controlled type I IFN expression and depends on the compartmentalization of different steps of the signaling cascade and dynamic events between the involved compartments or organelles. This compartmentalization of the innate immune players not only relies on their association with membranous organelles but also includes the formation of supramolecular organizing centers (SMOCs) and effector concentration by liquid–liquid phase separation. For their successful replication, viruses need to evade innate defenses and evolve a multitude of strategies to impair type I IFN induction, one of which is the disruption of spatial immune signaling dynamics. This review focuses on the role of compartmentalization in ensuring an adequate innate immune response to viral pathogens, drawing attention to crucial translocation events occurring downstream of pattern recognition and leading to the expression of type I IFN. Furthermore, it intends to highlight concise examples of viral countermeasures interfering with this spatial organization to alleviate the innate immune response. Compartmentalization subtends most biological processes at the cellular level. While subcellular organization in distinct compartments is particularly refined in eukaryotes, even prokaryotes are now accepted to segregate functions in protein- or membrane-bound organelles . A compaThe type I interferon (IFN) system belongs to the first line of defense protecting all nucleated cells against viral infections and can be divided into two signaling cascades, IFN induction and IFN response . IFN indViral infection often results in a turmoil in the cell, hijacking resources and reprogramming the host for their own benefit. Strikingly, many viruses organize their replication organelle by remodeling host cell membranes or forming membrane-less condensates, again highlighting the functional importance of subcellular compartmentalization . In an eThis review concentrates on the subcellular compartmentalization of type I IFN induction in response to viral infection. It also describes how viruses can block IFN induction by disrupting this spatial organization by sequestrating, retargeting, or even repurposing innate immune factors. For clarity, it focuses on the main innate immune sensors, adaptors, and effectors and highlights selected examples of cellular compartmentalization and viral antagonism. Therefore, it does not have the presumption to provide an exhaustive picture of the molecular pathways leading to IFN production or of the many viral evasion strategies. Rather, it intends to emphasize common themes and concepts in innate immune compartmentalization while encompassing the newly acknowledged complexity in subcellular architecture and dynamics.A key feature for rapid recognition of PAMPs is the strategic localization of PRRs within the cell and on the cell surface. This allows immediate access to the ligand at the site where it first becomes accessible. While highly conserved structures displayed on the surface of bacteria and fungi can be detected by Toll-like receptors (TLRs) on the cell surface , recogniThe cytoplasmic RNA receptors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation gene 5 (MDA5), as well as the signaling incompetent laboratory of genetics and physiology 2 (LGP2), constitute the RIG-I-like receptor (RLR) protein family . To prevBesides RNA, viral DNA is also a common PAMP detected by PRRs in the cytoplasm. One very prominent receptor for viral dsDNA in the cytoplasm is the cyclic GMP-AMP synthase (cGAS), which synthesizes the second messenger cGAMP, a non-canonical 2′-5′-linked cyclic dinucleotide  Figure B. HoweveDepending on the virus entry or elicitation mechanism, viral nucleic acids are also released within endosomes, where they are detected by different TLRs C. TLRs aRestricted localization of TLRs to the endosomes rather than the plasma membrane is likely essential to preferentially sense non-self nucleic acids. Indeed, self nucleic acids in the extracellular space are usually degraded before reaching the endosomal compartment and therefore do not trigger the endosomal TLRs. On the contrary, foreign nucleic acids are typically protected, for instance, by the viral capsid, and only able to be sensed once released after enzymatic digestion of the virion in the endosomal pathway . The end+ LAMP2− endosomes. There it is cleaved for activation and mediates NFκB signaling resulting in the expression of pro-inflammatory cytokines. For type I IFN production, TLR9 needs to journey on to LAMP2+ lysosome-related organelles (LROs), which exhibit some lysosomal characteristics but are overall distinct from lysosomes. Targeting to LROs is AP-3 dependent and enables IRF7 activation and subsequent type I IFN production. The dependency on TLR9 relocation to LROs is conferred by the restricted localization of TNF receptor-associated factor (TRAF) 3. This signaling constraint can be bypassed by targeting TRAF3 from LROs to early VAMP3+ LAMP2− endosomes, thus enabling IRF7 activation from NFκB endosomes [In addition to the general spatial distribution between plasma membrane and endosomes as described above, signaling from TLRs is highly dependent on cell type and further layers of compartmentalization. Plasmacytoid dendritic cells (pDC) constitute a specialized cell population that selectively expresses TLR7 and TLR9 and secretes high amounts of type I IFN in response to immune stimulation . The firndosomes . In vivondosomes . Likewisndosomes ,33 but hOther immune cells with unique receptor utilization are inflammatory macrophages. TLR2 is a cell surface receptor for viral and bacterial ligands and induces the expression of tumor necrosis factor (TNF) in response to both. In addition, inflammatory macrophages possess the inimitable ability to produce type I IFN in response to viral TRL2 stimuli in a process dependent on internalization of the receptor and myeloid differentiation primary response 88 (MyD88) mediated signal transduction. Inhibition of endocytosis and, consequently, receptor re-localization results in a loss of type I IFN but not TNF production , demonstApart from immune cells, also polarized cells such as intestinal epithelial cells (IECs) activate diverse signaling pathways depending on PRR localization. IECs possess an apical membrane that faces the gut lumen and a basolateral membrane facing the lamina propria . While iThe spectrum of PRRs matches the diversity of pathogens to detect, and their subcellular distribution allows surveying the most relevant pathogen entry sites. However, while initiated in different cell compartments, innate immune signaling converges to a limited number of transcription factors, in particular IRF3 and IRF7, to initiate the type I IFN production and NFκB to induce a panel of inflammatory cytokines. These transcription factors are sequestered in the cytosol until immune stimulation induces a range of posttranslational modifications that enable their nuclear translocation. Once in the nucleus, IRF3 and IRF7 bind to the type I IFN promoters and other promoters of a subset of ISGs and thus induce an antiviral state  Figure .A common feature of all these signaling pathways activated by PAMP sensing is the spatial separation of pattern recognition and signal transduction. This might serve as a safety mechanism to regulate immune activation and highlights the importance of adaptor proteins . TherefoThe CARD-containing MAVS protein constitutes the signaling adaptor for the RLRs RIG-I and MDA5  Figure A. BesideMAVS localization and its relevance for signaling outcome, as is the case with TLR localization, is still a matter of debate. Nevertheless, mitochondria association seems to be of great relevance for MAVS-mediated signal transduction since successful signaling is highly dependent on mitochondrial dynamics . MitochoSome publications support the presumption that peroxisomal MAVS fulfills unique functions ,55, whilOn top of that, the perception that mitochondria as standalone organelles provide the platform for MAVS signalosome formation was thoroughly questioned recently . Esser-NSTING plays a pivotal role in transducing signals in response to cytoplasmic viral DNA  Figure B. In the2+-sensitive protein, directly interacts with STING at the ER. STIM1 localization is controlled by the ER Ca2+ concentration. It is distributed throughout the ER when the Ca2+ concentration is high but exits the complex with STING and travels to ER-plasma membrane junctions when the concentration is low [In the absence of a stimulus, several mechanisms apply to prevent STING activation and trafficking. Stromal interaction molecule 1 (STIM1), a Can is low ,63. Lossn is low . Addition is low  and assen is low . STING an is low .Recently, viperin was described to be a further component of the STING enhanceosome, elevating type I IFN production . Upon stIn addition to these adaptor protein complexes required for signal transduction, activation by cGAMP causes the formation of another higher-order STING assembly at the ER, the so-called STING phase-separator . It is aLast but not least, SMOC formation is also observed downstream of TLR signaling pathways  Figure C. While MyD88 and TRIF are presumably distributed throughout the cytosol and recruited to the TLR signaling complexes upon immune stimulation . In the MyD88 comprises two domains essential for its adaptor protein function in connecting the two sections of this signaling pathway. The C-terminal TIR domain of MyD88 interacts with the TIR domains of activated TLRs and TIRAP, while the N-terminal death domain (DD) recruits members of the DD containing interleukin-1 receptor-associated kinase (IRAK) family. Consistently, the myddosome was initially defined as an ordered complex consisting of 7-8  or 6 MyDIn contrast to the myddosome, the signalosome surrounding TRIF is not well studied. Nevertheless, higher-order assemblies nucleated by TRIF are known to exist. Upon TLR3 activation, TRIF transiently co-localizes with the receptor and then proceeds to form speckle-like signalosomes in the cytoplasm that contain TBK1 . In addiA prerequisite for viral replication is the inhibition of a strong antiviral immune response by evasion from immune recognition or disruption of signal transduction. Successfully replicating viruses relyon a plethora of strategies to dampen the antiviral immune response, including shielding of viral genomes to prevent PRR sensing, cleavage or degradation of signaling molecules, and inhibition of posttranslational modifications required for signal transduction ,81. In tReplication of many viruses induces the formation of specialized subcellular compartments, called viral factories. These viral factories often concentrate viral replication factors, provide platforms for replication and assembly, and shield PAMPs from immune recognition. They can either be associated with membranes, as is the case for many positive-sense ssRNA viruses or be membrane-less . MembranOther strategies to impair RNA recognition by cytoplasmic PRRs are disruption of stress granules, which contain MDA5 and RIG-I, by encephalomyocarditis virus and poliovirus ,88 or inFor DNA viruses, recognition of the viral genomes by cGAS and activation of the associated signaling cascade pose a major threat. Therefore, herpesviruses express a highly conserved tegument protein ,91 whichAdditionally, some viruses have evolved not only to re-localize PRRs but also to simultaneously exploit them by utilization of non-canonical, pro-viral functions. Rabies virus (RABV) infection induces the formation of cytoplasmic aggregates, resembling IBs, which are called Negri bodies C. IntereWhile sensing of viral genomes can be mediated by a variety of different proteins, not all of which are mentioned in this review, the signaling cascades converge at the level of signaling adaptors. Therefore, interference with adaptor localization or manipulation of signaling relevant organelle integrity is a strategy often applied by viruses to impair signal transduction.2+ levels and induces the release of STING from STIM1 [STING is the adaptor of the cGAS-associated signaling pathway and thus links cGAS DNA sensing to the activation of the transcription factor IRF3 via phosphorylation by TBK1. As already explained previously, the trafficking of STING from ER to the ERGIC/Golgi compartment is essential for successful signal transduction. Therefore, this process poses a potential target for viral immune evasion strategies. The HCMV tegument protein pUL82 was shown to interfere with STING intracellular trafficking, resulting in inhibition of STING signaling complex assembly. This impairs the phosphorylation of TBK1 and IRF3 and consequently dampens IFN-β expression  Figure B. HCMV fom STIM1 . In addiom STIM1 . Althougom STIM1 , in otheMitochondria are highly dynamic organelles and are still widely accepted as the site of MAVS localization. As explained previously, mitochondrial fission and fusion events have a direct impact on innate immune signaling via MAVS. However, dynamic fission and fusion between mitochondria and constant mixing of mitochondrial content require preservation of mitochondrial fitness by extraction of partially defective mitochondria from the pool. Mitochondrial fitness is maintained by mitophagy, which constitutes a specific form of autophagy. Mitophagy is either receptor- or ubiquitin-mediated, for example, by the E3 ubiquitin ligase Parkin, induces the formation of autophagosomes around mitochondria, and culminates in delivery to and fusion with lysosomes for degradation. In addition to the regulation of inflammatory responses, mitophagy also plays a role in other essential cellular processes . A multiMeasles virus (MeV) induces mitophagy, as attested by the engulfment of mitochondria in autophagosomes and the drastic reduction in mitochondrial mass in infected cells. SiRNA targeting of essential autophagy effectors in this infection setting resulted in higher expression levels of IFN-β and, therefore, stronger elicitation of the innate immune response. Additionally, autophagy effector KO cells had higher MAVS expression in response to MeV infection than wildtype , emphasiWhile all previous examples focused on virus-induced fragmentation of mitochondria, eventually resulting in mitophagy to suppress MAVS activation, DENV and ZIKV pose a very interesting exception to that common theme. DENV virus infection induces major membrane alterations and the formation of an ER-derived membraneous compartment consisting of several substructures, one of which is convoluted membranes (CMs) . InsteadOne of the very last opportunities for a virus to circumvent immune activation is interfering with the translocation of transcription factors into the nucleus D. Thus, Targeting the nucleocytoplasmic transport machinery is a further option to prevent the nuclear translocation of the IRF3 and IRF7 transcription factors. Macromolecule exchange across the nuclear envelope takes place at the nuclear pore complex and is mediated by nuclear transport receptors, also called importins or karyopherins (KPNAs). This process is manipulated by DNA viruses and some RNA viruses to access their nuclear replication compartment, but also by viruses of distinct families to counteract innate immune signaling . Among tIn conclusion, the cellular innate immune response upon encounter with pathogens is highly organized in time and space. Signal transduction from the pathogen detection sites to the promoters of antiviral genes involves intracellular membranes to concentrate the adaptor platforms and spans multiple organelles and membrane-less compartments. Several of the involved players also shuttle between signaling and repository sites. In addition to innate immune players, which might change location during the elicitation of the defense mechanisms, whole organelles can be remodeled, as seen, for instance, with the mitochondrial elongation observed upon RLR activation . The cel


Advancements in our knowledge base surrounding the type 2 immune response, production of IgE and maintenance of immunological memory has led the field to explore targeted intervention of allergic pathways using monoclonal antibodies (mAbs). Intervention at various stages of the allergic cascade offers the opportunity to prevent initiation and/or maintenance of the type 2 immune response and effectively provide therapeutic benefit to patients. Furthermore, a better understanding of the protective mechanisms involved in allergen specific immunotherapy (AIT) has led us to appreciate the interplay of immunoglobulins in the allergic response, specifically the benefit in shifting the IgG:IgE ratio in favor of functionally relevant blocking IgG. Thus, treatments that lower IgE or boost IgG with the ability to outcompete IgE binding to allergen also present a favorable approach in the treatment of allergy. In this short review we discuss and highlight recent advances in the use of biologics to treat severe allergy, highlighting the key challenges but also the significant opportunities and advances to date.Over the last 4 decades there has been a significant global increase in the incidence and prevalence of IgE-mediated allergy. Although much progress has been made in the management of allergy  Over the last 4 decades there has been a significant increase in the incidence and prevalence of allergy across the globe creating a significant burden on patients, healthcare providers and society. It was recently estimated that allergic rhinitis (AR) alone affects 10%–30% of the population worldwide, with rates as high as 50% in some countries . Althoug+ T helper type 2 cells (Th2) results in recruitment of inflammatory effector cells , goblet cell hyperplasia, mucus secretion and antibody class switch in favor of IgE production -25, thymic stromal lymphopoietin (TSLP), and IL-33 that are released at sites of initial allergen exposure as well as downstream production of IL-4, IL-13, IL-5 and IL-9. Subsequent differentiation of CD4oduction , 9. Acutoduction , 11.via pharmacotherapeutics targeting symptom control  and humoral response . In a sePassive immunotherapy with antibodies against antigens is a treatment approach that has long been utilized in various settings. Its utility has extended to targeted treatment and prevention of viral infection using purified monoclonal antibodies (mAbs) with the advent of Palivizumab, a single mAb treatment for respiratory syncytial virus  and, morThe concept of passive administration of allergen specific blocking mAbs for the treatment of allergy was first validated in a small proof of mechanism study in cat allergic individuals and extended to a study in birch allergic individuals shortly thereafter , 18. SpeNotably, vaccines for the treatment of allergy also rely largely on the induction of blocking IgG, as do emerging AIT approaches aiming to achieve protective effects whilst limiting the risk of IgE-mediated side effects through the use of allergen components or allergoids modified to reduce allergenicity yet maintain an ability to mount humoral responses towards functional blocking IgG –60. AlthFundamental to this is approach is a robust understanding of the structural basis of allergens and allergen antibody interactions. Multiple epitopes of an allergen likely need to be blocked to achieve robust inhibition of allergic effector cell activation. Although it has been shown that maximal coverage of an allergen is not necessary to achieve blockade of the IgE mediated response , 55 defiOther approaches target cytokines involved in the development and/or maintenance of allergy. Of particular interest are type 2 cytokines, such as IL-4, IL-13 and IL-5 and the epithelial cell-derived cytokines IL-25, TSLP, and IL-33 that are released at sites of initial allergen exposure .α) inhibits signaling of both IL-4 and IL-13 and is approved for the treatment of atopic dermatitis, asthma, chronic sinusitis with nasal polyps and eosinophilic esophagitis , patients received 52 weeks of treatment followed by 52 weeks of observation off therapy. As tolerance induction was the goal, the primary endpoint of the study was defined as a significant reduction in TNSS in response to NAC in the cat-SCIT with tezepelumab group as compared to cat-SCIT alone at week 104 following completion of 52 weeks on therapy and 52 weeks with no treatment. Although those who received cat SCIT with tezepelumab did achieve a significant reduction in TNSS in response to NAC as compared to cat SCIT alone during treatment week 25 and 52), the effect was not sustained following completion of therapy (week 104) and thus the study did not meet its primary endpoint , short study duration, high dropout rate and an imbalance in baseline characteristics warrants a more comprehensive interrogation to determine a role for IL-33 in food allergy. Itepekimab is an additional fully human IL-33 neutralizing monoclonal antibody under clinical development. Although not yet evaluated for the treatment of allergy, it was shown to affect a lower incidence of loss of asthma control vs. placebo and improved lung function in a ph2 study for moderate to severe asthma  in comparison to placebo (0% at day 15 and 45). Reported differences in select biomarkers further suggest etokimab may interfere with downstream allergic pathways  . While pe asthma , 66 as we asthma  patientsWe have more to learn about the role of type 2 and epithelial cytokines as the drivers of established disease especially in the context of AIT. These studies have only begun to scratch the surface of our understanding with several additional clinical trials actively ongoing, evaluating various treatment regimens as well as interventions at the point of prevention in high-risk individuals (AD patients/genetic risk factors).IgE is the immunoglobulin subclass that plays the central role in acute allergic hypersensitivity therefore presenting as an overt target for the treatment of allergy . OmalizuMore recently, studies have focused on using omalizumab in combination with immunotherapy to enhance efficacy and safety of such tolerizing approaches. AIT in combination with omalizumab for the treatment of AR was first evaluated in 2002 in a randomized double blind placebo controlled (DBPC) study of 221 children with birch and/or grass pollen allergy. Omalizumab in combination with SCIT reduced symptoms by 48% over 2 pollen seasons when compared with SCIT alone . AdditioClinical trials evaluating Omalizumab as an add on to oral immunotherapy (OIT) for food allergy have also been conducted with a primary focus on milk, peanut and more recently multifood OIT . Early sThe next generation anti-IgE molecule, ligelizumab, a humanized monoclonal IgG1 mAb recognizing an IgE-epitope distinct from that of omalizumab, is also in clinical development for the treatment of allergic disease . Ligelizα, inhibits IL-4 and IL-13 signalling and inhibits class switching to IgE shows approximately a 70 percent reduction in IgE after one year (While anti-IgE therapy shows promise as a potential treatment option for patients with severe food allergies, identifying and targeting the source of IgE also offers promise. Clinical observations support the concept that such a source exists that maintains levels of circulating allergen specific IgE. For example, allergy can be transferred during a bone marrow transplant and persists long term , 78. It one year . These fone year . This fiTargeted intervention in the prevention, initiation, or maintenance of the type 2 immune response holds the potential to effectively provide therapeutic benefit to patients. Understanding the interplay of immunoglobulins in the allergic response and effectively shifting the IgG:IgE ratio in favor of functionally relevant blocking IgG with the ability to outcompete IgE binding to allergen presents one favorable approach to provide protection. To treat allergy more broadly, directly targeting IgE or allergic pathways and cytokines involved in its production and maintenance offers promise. Overall, these studies highlight key mechanistic similarities and differences driving the allergic response and collectively emphasize the need for more studies in this space.


Placental bands on T2-weighted magnetic resonance imaging (MRI) are a known imaging finding in placenta accreta spectrum (PAS). It is believed that these linear T2 hypo-intensities may reflect increased fibrin deposition in the setting of placental hemorrhage or infarct. However, to date there is little published data regarding histopathologic analysis of placental parenchyma at the site of identified bands. We report the case of a 34-year-old female with a single placental band demonstrated on preoperative MRI which was evaluated postoperatively and found to represent a placental infarct. MRI is an important tool in the diagnosis of placenta accreta spectrum (PAS), with key imaging features consisting of heterogeneous placental signal intensity, placental bands on T2-weighted imaging, abnormal placental contour and/or bulging, and direct visualization of myometrial invasion –3. To daA 34-year-old woman, G4P3003, presented at 30-weeks’ gestation for consultation regarding high concern for PAS on prenatal ultrasound. She had a history of one prior cesarean section and 2 prior vaginal deliveries. This was not an IVF pregnancy, and she had no history of additional uterine surgeries or instrumentation. Ultrasound demonstrated placenta previa with multiple placental lacunae, loss of the normal retroplacental hypoechoic space, and increased vascularity with uterine wall invasion noted by color Doppler , highly To further characterize the placenta, non-contrast MRI of the abdomen and pelvis was performed. MRI findings included complete placenta previa, lobulated placental contour, and a prominent T2 hypointense band in the anteroinferior placenta , all conA plan was made to deliver the fetus at 34-weeks’ gestation via cesarean hysterectomy. Bilateral uterine artery embolization was performed by interventional radiology intraoperatively after the cesarean section and before the hysterectomy. Intraoperative findings were consistent with placenta percreta with placenta visualized protruding through to the uterine serosa in the left lower uterine segment with confirmation of bladder invasion. The case had an estimated blood loss of 4500 mL, and she received 5 units of packed red blood cell, 3 units of fresh frozen plasma, and 2 units of cryoprecipitate. Although there was placental invasion into the detrusor, there was no invasion of the bladder mucosa and cystotomy was avoided. The patient progressed well and was discharged home on postoperative day 5. There were no neonatal complications outside of iatrogenic prematurity and both mother and baby were doing well at 6-week postpartum exam.Hysterectomy specimens including the morbidly adherent placenta were sent to pathology following the procedure for formal evaluation of the myometrial-placental interface, as well as the site of the placental band noted on MRI. The placental parenchyma was noted to be dark red brown with focal tan-white discoloration, measuring up to 2 cm. Areas of fibrosis concerning for infarct were noted and can be seen in PAS is typically diagnosed in the second or third trimester of pregnancy via ultrasound imaging, with MRI serving as an adjunctive tool in diagnosis and surgical planning The current standard management for patients with PAS is a planned fundal cesarean hysterectomy at 32-24 weeks, with the surgical approach influenced by the degree of vascular recruitment or structural invasion In summary, this case describes a patient with complete placenta previa and suspected PAS who presented for cesarean hysterectomy. MR imaging demonstrated features of placenta accreta spectrum including the presence of a singular placental band on T2-weighted images, which was found to represent a dense region of fibrous tissue consistent with placental infarct at pathological evaluation. This finding can help build upon the current hypothesis that placental bands represent areas of fibrous tissue due to increased fibrin deposition. Abnormal placentation has been previously associated with placental infarction, which could occur following pathologic development of the uteroplacental vasculature The patient reported in the manuscript signed the informed consent/authorization for participation in research which includes the permission to use data collected in future research projects including presented case details and images used in this manuscript.


Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP).  The melanocortin system of the brain regulates feeding behavior, energy balance and body weight, and investigating its development is helping researchers understand and explore treatments for chronic diseases, including obesity and type-2 diabetes. Sebastien Bouret at the University of Lille, France, reviews research into the role of the melanocortin system’s development in health and disease. The system consists of nerve cells that produce the precursor of peptide hormones called pro-opiomelanocortins, protein receptor molecules that interact with melanocortins, and peptide molecules that counteract and regulate melanocortin effects. The review discusses the major steps in the developmental programming of the melanocortin system and the hormonal, molecular, cellular, and nutritional factors influencing the nerve cells involved. Some chronic diseases may originate from disruption of the melanocortin system’s development in the embryo and soon after birth. More recently, neuron- and gene-specific genetic studies have shown the importance of POMC neurons in mediating the physiological actions of metabolic hormones, such as leptin and insulin3. Opto- and chemogenetic experiments further indicated that although arcuate POMC neurons appear to be more involved in integrating long-term adiposity signals, the contribution of hindbrain POMC neurons seems to be more specific to the integration of short-term satiety signals5. In contrast, optogenetic stimulation of AgRP neurons rapidly evokes feeding4, whereas genetic ablation of AgRP neurons in adult animals causes starvation7.The melanocortin system is a critical component of brain pathways that regulate feeding behavior and energy homeostasis. The brain’s melanocortin system consists of pro-opiomelanocortin (POMC) neurons and neurons that produce agouti-related peptide (AgRP), an endogenous inverse agonist of melanocortins. There are two anatomically distinct POMC neuronal populations in the brain. The largest population of POMC neurons resides in the arcuate nucleus of the hypothalamus (ARH). A discrete population of POMC neurons is also found in the nucleus of the solitary tract (NTS) in the brainstem. In contrast, AgRP neurons are exclusively located in the ARH and coexpress neuropeptide Y (NPY). Pharmacological approaches revealed more than three decades ago that melanocortins have a potent and long-lasting inhibitory effect on feeding10. Target neurons expressing MC4Rs include neurons producing oxytocin, thyrotropin-releasing hormone, and corticotrophin-releasing hormone in the paraventricular nucleus of the hypothalamus (PVH)11. The melanocortin system is universal and common to all mammals, including humans, nonhuman primates, and rodents, and mutations in the MC4R gene are the most common monogenic disorders that cause obesity in humans12.The POMC-derived peptide alpha-melanocyte-stimulating hormone (αMSH) and AgRP modulate the activity of the melanocortin 4 receptor (MC4R). αMSH activates MC4R, while AgRP acts as an endogenous inverse agonist of MC4R, meaning that it suppresses constitutive MC4R activity and simultaneously antagonizes the effects of αMSH. The highest expression of MC4Rs is found in the hypothalamus and the brainstemIn this review, we will first describe the major steps of melanocortin system development. We will also discuss the hormonal, molecular, cellular, and nutritional factors influencing the development of POMC and AgRP neurons.13 . These observations are consistent with the early determination of Pomc cell fate. Intriguingly, genetic cell lineage tracing studies revealed that approximately half of the Pomc-expressing precursors acquire a non-POMC fate in adult mice, and nearly one-quarter of the mature NPY neurons in the ARH share a common progenitor with POMC cells15. These data show the unique property of Pomc-expressing progenitors with respect to giving rise to antagonistic neuronal populations. Differentiated neurons then send out axonal processes to other target nuclei to convey neuronal information and control behavior. The majority of arcuate POMC and AgRP neurons have relatively short axons and connect primarily to neurons within the hypothalamus16. Axonal projections from the arcuate nucleus develop postnatally and provide inputs to the PVH between postnatal day (P) 8 and P10 in mice16 , and its expression peaks at E16 (ref. 19). These findings are particularly interesting because, as described above, it is known that neurons that compose various hypothalamic nuclei in adults are primarily derived from precursors that originate from this proliferative zone, raising the possibility that MC4R could be involved in hypothalamic neurogenesis. However, further studies are needed to determine the developmental stage during which MC4R becomes functional. Nevertheless, the observation that peripheral injection of the melanocortin agonist melanotan II (MTII) reduces milk intake and body weight as early as during the first 2 weeks of postnatal life suggests that MC4R receptors are present and functional in the hypothalamus at least soon after birth20. Consistent with this idea, in situ hybridization analysis showed that Mc4r mRNA is abundant in the hypothalamus, especially in the PVH at P10. Peripheral injection of MTII induces strong induction of cFos immunoreactivity  in the PVH at P5–P15, further supporting the functionality of MC4R in the PVH during early postnatal life20. Moreover, Melnick et al.21 showed an age-dependent increase in the electrophysiological response of specific sets of PVH neurons to melanocortins, with a maximal response observed at P28–P35, suggesting that synapses between POMC and AgRP axons and PVH MC4R+ target neurons continue to build until puberty  100. Although only a few AgRP/NPY fibers and no POMC fibers were detected in the PVH at this age, the density of AgRP/NPY fibers innervating the PVH markedly increased at G130 and G170, and POMC fibers were found in the PVH at G17022. In human fetuses, NPY-immunoreactive fibers are detected in the ARH and the PVH as early as 21 weeks of gestation23.The marked differences in the normal ontogeny of hypothalamic development between rodents and human and nonhuman primates warrant attention. First, the regional development of the rodent hypothalamus proceeds on a timeline of days in rodents versus weeks to months in human and nonhuman primates. Second, although rodents exhibit considerable postnatal hypothalamic development, human and nonhuman primates undergo considerably more prenatal maturation of hypothalamic circuits. For example, although the hypothalamus is not mature until after weaning in rodents, hypothalamic neurogenesis and axon growth occur primarily during intrauterine life in nonhuman primates, including humans. Hypothalamic development has been studied in detail by Grove and collaborators in Japanese macaques. They reported that 26. In 1994, Friedman et al.24 used positional cloning and found that the ob gene encodes the hormone leptin, which is secreted by adipose tissue in proportion to its mass. Subsequently, other groups reported that leptin administration reduces body weight and food intake in leptin-deficient mice and humans29. A few years later, Ahima and colleagues reported that circulating leptin levels exhibit a distinct surge between P8 and P12 in mice30, yet exogenous leptin does modulate food intake, growth, or energy expenditure at this developmental stage34. Instead of acutely regulating food intake and body weight, neonatal leptin appears to be an important neurodevelopmental factor that influences the wiring of hypothalamic circuits  mice35. The site of action for the developmental effects of leptin includes at least a direct action on ARH neurons because leptin induces neurite extension from isolated organotypic explants of the ARH ex vivo35. Remarkably, leptin appears to exert its developmental action on POMC neural projections during a discrete developmental critical period: exogenous leptin treatment up to P28 rescues AgRP projections in ob/ob mice36. In contrast, leptin treatment of ob/ob mice after P28 is relatively ineffective because it did not increase the density of either POMC or AgRP fibers in the PVH to levels that are characteristic of wild-type mice36. Together, these observations suggest the existence of a critical period for the neurotrophic effect of leptin on POMC and AgRP circuits that closes around puberty. More in-depth studies have examined leptin receptor signaling pathways that mediate the axonotrophic effect of leptin. The leptin receptor exists in several alternatively spliced isoforms, of which only the long form (LepRb) associates with Janus kinase 2 to mediate intracellular signaling. LepRb initiates multiple intracellular signal transduction pathways upon leptin binding that result in the activation of STAT family transcription factors, extracellular signal-regulated kinases (ERKs), and phosphoinositol-3 kinase/Akt. Developing POMC and AgRP neurons express LepRb37, and leptin administration in mouse neonates results in the activation of major LepRb signaling pathways, including STAT3, ERK, and Akt38. The disruption of POMC and AgRP axonal projections is observed in mice or rats that lack functional LepRb signaling 39. Moreover, a lack of functional LepRb→STAT3 signaling in vivo (s/s mice) or in vitro results in a reduced density of POMC fibers without altering the development of AgRP projections, showing the importance of this signaling pathway, specifically, in the development of POMC neural projections38. However, not all LepRb signaling pathways play a role in the formation of ARH projections. For example, mice that lack LepRb→ERK signaling (l/l mice) display densities of POMC and AgRP axons in the PVH that are comparable to those of wild-type mice38.The discovery of leptin led to a paradigm shift in understanding how food intake and body weight can be powerfully and dynamically regulated by hormonal signals41. Although the marked orexigenic effect of ghrelin is not yet present before weaning in mice or rats43, ghrelin in early postnatal life does have a lasting developmental effect on the hypothalamic circuits involved in energy homeostasis43 . It is one of the most potent orexigenic signals that exerts its action on food intake by stimulating AgRP/NPY neurons, which in turn inhibit POMC neurons44. Based on the documented finding that ghrelin influences hypothalamic development and can interact with leptin receptor signaling43, it is not surprising that the deletion of the growth hormone receptor in Leprb-expressing cells also alters the development of POMC and AgRP neuronal circuits45. In addition, selective loss of the growth hormone receptor in AgRP neurons affects AgRP axonal projections without affecting POMC circuits45, demonstrating a cell-autonomous effect of growth hormone on AgRP neuronal development.Ghrelin is a potent stimulator of growth hormone secretion46. The administration of the GLP1-R agonist exendin-4 during the first week of postnatal life decreases the density of NPY fibers innervating the PVH and has a protective effect against both age-related and diet-induced obesity47. Moreover, genetic deletion of Glp1r in Sim1 neurons of the PVH reduces AgRP/NPY projections, while it increases POMC projections to the PVH47.The incretin hormone glucagon-like peptide 1 (GLP1) is secreted postprandially by intestinal enteroendocrine cells to promote satiety and glucose-induced insulin release48 , which heterodimerizes with one or several receptor activity-modifying proteins RAMP-1, -2, and -3). The primary role of amylin in adults is to reduce food intake by promoting meal-ending satiation and maintaining glucose homeostasis. During development, amylin is detected in the blood circulation of embryos, where it appears to act through RMAP1-3 to influence the neurogenesis of POMC neurons, and -3.Otp), Nkx2.1, and Bsx are highly expressed in the ventral hypothalamus during embryonic development. Loss-of-function studies indicated that while Nkx2.1 and Otp are essential for the normal morphological development of the hypothalamus, including the ARH, Bsx is not required53 , plays a particularly important role in ARH specification. The ablation of Nkx2.1 impairs the formation of the ventral hypothalamic primordium, resulting in the absence of ARH formation54. However, the ventromedial nucleus (VMH), dorsomedial nucleus (DMH), and lateral hypothalamic area (LHA) are present. The expression of Nkx2.1 in postmitotic cells suggests that it further plays a role in the differentiation and maintenance of ARH neurons in the ventral portion of the hypothalamus56. Deficiency in Nkx2.1 prior to the onset of Pomc expression markedly reduces Pomc cell numbers57. However, the number of NPY neurons was not affected in Nkx2.1 knockout mice, and the POMC neuronal cell number was not affected if Nkx2.1 deletion occurred in postmitotic Pomc neurons57. The LIM-homeodomain transcription factor Islet 1 (Isl1) is upregulated in hypothalamic Nkx2.1 progenitor cells at E10, i.e., just before the onset of neuropeptide expression59. Consistent with the role of Isl1 in the phenotypic determination of ARH neurons, loss-of-function studies revealed that Isl1 promotes the terminal differentiation of Pomc, Agrp, and Npy expression59. In contrast, the deletion of the transcription factor Dlx1/2 in Nkx2.1-expressing progenitors increases Agrp expression without affecting Pomc expression60. More in-depth molecular studies revealed that Dlx1/2 controls Agrp expression by binding to and repressing the expression of the homeodomain transcription factor Otp, which is also known to influence ARH morphogenesis60. Thus, the loss of Otp in Agrp neurons results in a dramatic reduction in the number of Agrp mRNA-expressing cells61. Notably, Otp expression is absent in the hypothalamus of Isl1 knockout embryos58, suggesting that, in addition to Dlx1/2, Isl1 is also required for the expression of Otp in the future ARH. Sonic hedgehog (Shh), SIX homeobox 3 (Six3), and retinal anterior neural fold homeobox (Rax) were also identified as critical regulators of ventral hypothalamus development and POMC development. Shh signaling increases Nkx2.1 expression62, and the deletion of Shh in Nkx2.1 progenitors affects the development of POMC neurons63. Six3 is a regulator of forebrain development, including the hypothalamus64, and is required for Shh expression65. Finally, Rax is also important for the formation of the ventral neural tube. Mice lacking Rax in Six3-expressing cells do not show ventral hypothalamic Nkx2.1 expression and never express POMC66.Homeobox genes belong to a class of transcription factors that play important roles in regionalization, patterning, and cell differentiation during embryogenesis and organ development. The homeobox genes orthopedia (Olig1 and Olig2) are basic helix–loop–helix (bHLH) transcription factors highly expressed in the periventricular regions of the brain, such as the hypothalamus68. Lineage tracing experiments indicate that a number of POMC and NPY cells are derived from Olig1 progenitors69. The majority of Olig1 progenitors also express bone morphogenetic protein receptor 1A (Bmpr1A)69, and when Bmpr1A is deleted in Olig1-expressing cells, it decreases and increases the number of POMC and AgRP neurons, respectively69. Neurogenin 3 (Ngn3) is another bHLH transcription factor expressed in hypothalamic progenitors, and it plays an opposite role in the specification of Pomc and Npy neurons: while neurogenin 3 promotes the embryonic development of Pomc neurons, it inhibits Npy neuronal development71. However, not all POMC neurons are derived from Ngn3 progenitors. Using a mouse model of Mash1 deficiency, McNay et al.72 further reported that this bHLH transcription factor has a pro-neural function and acts upstream of Ngn3 to regulate neurogenesis in the ventral hypothalamus. A loss of Mash1 results in the disappearance of Ngn3 expression in ARH progenitors and is associated with a dramatic reduction in the number of POMC and NPY neurons72. The Notch signaling pathway also appears to mediate its developmental effects on POMC and NPY neuronal development through Mash1. Mice lacking Notch signaling in Nkx2.1-expressing cells display an increased number of POMC and NPY neurons associated with an induction in Mash1 expression73. In addition, mice with a constitutively active Notch1 intracellular domain show a complete loss of POMC and NPY neurons73, mirroring the effects of Mash1-deficient mice72.The oligodendrocyte transcription factor family 75. Because the majority of miRNAs exert their effects on gene expression by targeting transcription factors, it would be interesting to study whether there is a link between miRNAs and Tbx3 and Pomc/Npy gene expression.As described above, ion Fig. . A loss 76. The diffusible axon guidance cues semaphorins are highly expressed in the PVH during development, and POMC neurons express the semaphorin receptors neuropilin 1 and 2 (ref. 77). Supporting a role for neuropilins/semaphorins in POMC axon guidance, a loss of neuropilin 2 receptors in POMC neurons specifically disrupts the development of POMC axonal projections to the PVH77. These structural alterations are accompanied by metabolic dysregulation, including increased body weight and glucose intolerance77. Notably, exome sequencing experiments identified variants in the semaphorin and neuropilin families associated with severe obesity in humans77, demonstrating the translational importance of these findings. The formation of POMC neural neuronal connectivity also involves cell–cell adhesion proteins. Supporting this idea, POMC neurons are enriched in the cell-to-cell contact molecules Efnb1 (EphrinB1) and Efnb2 (EphrinB2) during postnatal development, and a loss of Efnb1 or Efnb2 in Pomc-expressing progenitors decreases the amount of excitatory glutamatergic inputs78. In addition, mice that are deficient in contactin, a cell adhesion molecule involved in the formation of axonal projections, have a reduced density of POMC fibers in the PVH during postnatal development79.Axons grow by sending out a highly plastic and sensitive structure called a “growth cone,” which travels toward the target with the elongating neurite trailing behind. As described above, metabolic hormones, including leptin, are critical factors influencing initial POMC and AgRP/NPY axon outgrowth. Growing POMC axons must then choose a path to follow and decide the direction to go on this path to innervate the proper nucleus . The pathways are defined by cell–cell interactions and diffusible chemorepulsive and chemoattractive cues80. This cellular process is also critical in the supply of nutrients for survival during starvation81. Constitutive autophagy is detected in the hypothalamus, including in arcuate POMC neurons, during critical periods of axon growth and development82. A loss of the autophagy-related protein (Atg) gene Atg7 disrupts the maturation of POMC axonal projections and causes lifelong metabolic perturbations82 . A disruption of cilia formation in developing POMC neurons, but not in adult POMC neurons, increases body weight, fat mass, and food intake; reduces energy expenditure; and alters glucose homeostasis during adult life86. Neuroanatomically, a reduction in the number of POMC neurons was observed in juvenile mice lacking primary cilia on POMC neurons, but POMC cell numbers were normal in adult mutant mice. This reduction in POMC cell numbers during the preweaning period is attributed to a decrease in neurogenesis during embryonic development (in opposition to an effect on apoptosis), and the adult normalization in POMC cell number is attributed to a compensatory increase in neurogenesis after weaning86. A loss of primary cilia also alters axonal and dendritic growth, resulting in a reduced density of POMC fibers innervating the PVH, DMH, and LHA86 , it is not surprising that mice lacking primary cilia from embryonic POMC neurons also display a reduction in NPY cell numbers and NPY fibers innervating the PVH86. The interaction between primary cilia and the melanocortin system appears bidirectional. Consistent with this idea, Siljee et al.87 reported that MC4-R colocalizes with adenylate cyclase 3 in the primary cilia of a subset of PVH neurons and that the inhibition of primary cilia adenylyl cyclase signaling increases body weight.Another cellular signaling system that plays an important role in brain development and function is the primary cilium, which is a microscopic sensory antennae that cells in many vertebrate tissues use to gather information about their environment. It is an organelle found on the cell surface of most mammalian cells, including hypothalamic neurons89. These metabolic alterations are associated with a disrupted development of POMC and AgRP/NPY projections to the PVH in both mice and rats93  developed by Levin et al.94 also provides a valuable tool for studying obesity, in part because Levin’s DIO rats share several features with humans with obesity, including polygenic inheritance. Therefore, this animal model is particularly well suited for studying the relative contribution of genetic versus environmental factors in metabolic programming. Animals born to genetically obese-prone DIO dams display a reduction in the number of POMC and AgRP axons innervating the PVH95. In addition, significant remodeling of synapses onto POMC neurons has been observed in DIO rats, particularly in response to nutritional challenges96. DIO rats fed a chow diet display increased inhibitory inputs to POMC neurons compared to obesity-resistant rats. In addition, DIO rats fed an HFD display a loss of synapses onto POMC neurons, whereas high-fat feeding in control obesity-resistant rats causes an increase in POMC synaptic coverage96.Obesity has reached alarming rates worldwide and is associated with several life-threatening conditions, such as hypertension and type-2 diabetes. The prevalence of obesity among pregnant women is also at an all-time high, and it represents a significant risk factor for the development of metabolic diseases in offspring. Obesity is determined by genetics and obesogenic environments, such as diets rich in fat and/or sugar. Maternal high-fat diet (HFD) feeding during pregnancy and/or lactation in rodents is a useful experimental approach for studying the consequences of maternal obesity on the development of offspring’s future health outcomes. Similar to what is observed in humans, offspring born to obese females fed an HFD  during gestation and/or lactation become progressively overweight, hyperphagic, and glucose intolerant, and they display an increase in adiposity95. Moreover, animals born to obese dams are hyperleptinemic, which is associated with hypothalamic leptin resistance, and improving leptin sensitivity with the endoplasmic reticulum stress-relieving drug tauroursodeoxycholic acid normalizes metabolic and neurodevelopmental deficits in these animals91. At the cellular level, a reduction in cilia length and frequency has been reported in the ARH of pups born to obese dams, suggesting that the alteration of this cellular system is critical for hypothalamic development and that leptin signaling could contribute to obesity-induced perturbations of hypothalamic development86. Changes in insulin signaling could also mediate the neurodevelopmental effects of maternal obesity. Mothers fed an HFD and their offspring are hyperinsulinemic, and deleting the insulin receptor in POMC neurons prevents the diet-induced disruption of POMC projections90. More recently, Dearden et al.97 reported that the offspring of obese dams display a reduction in POMC cell numbers that likely results from a diminished neurogenic action of insulin during embryonic development. Similarly, amylin, which is coreleased with insulin by pancreatic β-cells, appears to be involved in the nutritional programming of melanocortin circuits. The offspring of obese dams are hyperamylinemic from embryonic age throughout adulthood. Amylin fails to activate hypothalamic amylin receptor signaling if animals are born to obese mothers, which is associated with an inability of amylin to promote POMC neurogenesis48. Similarly, knocking down CTR in the ventromedial part of the hypothalamus of obesity-resistant rats (a region that encompasses the ARH + VMH) alters the development of POMC circuits98. In contrast, neonatal amylin treatment in DIO rats enhances STAT3 signaling in the ARH, accompanied by a restoration of AgRP and POMC fibers98.The precise mechanisms that underlie the maternal obesity-induced alterations in melanocortin system development have only begun to be elucidated. Several studies have indicated that abnormal leptin and insulin signaling during postnatal development may represent a likely cause of HFD- and DIO-induced alterations in hypothalamic development. For example, DIO rats and animals born to obese dams display an abnormal organization of projection pathways derived from the ARH that appear to be the result of the diminished responsiveness of ARH neurons to the trophic actions of leptin during critical periods of postnatal development99, Widdowson and McCance100, who reported more than 60 years ago that pups raised in small litters (SL) display an almost fourfold difference in preweaning growth compared to pups raised in large litters. This weight difference persisted throughout life and even increased as the rats were weaned onto a regular chow diet. Similar to animals born to obese dams, pups raised in SL display early life hyperleptinemia associated with hypothalamic leptin resistance102. Postnatal overnutrition also results in reduced responsiveness of hypothalamic neurons to ghrelin during neonatal life, which appears to be the consequence of altered transport of the hormone across the blood–brain barrier103. These endocrine changes during critical periods of postnatal development are associated with a dysregulation of the melanocortin system  that are critical for leptin and insulin’s effects on Pomc gene expression105. Similarly, human studies have shown that childhood obesity is associated with Pomc hypermethylation106. In addition to altering Pomc gene expression in the ARH, postnatal overfeeding also disrupts the neurophysiological responses of PVH neurons to αMSH and AgRP107.In part because of the importance of postnatal brain development in rodents, including that of POMC and AgRP neurons, animal models of postnatal metabolic programming have also been extensively studied. The reduction in litter size in rodents has proven to be a very useful model to manipulate the postnatal diet specifically. This model was first characterized by the pioneering works of KennedyIt is now clear from a variety of epidemiological and experimental studies that many chronic diseases, including obesity and type-2 diabetes, may have their roots during neonatal development. A perturbed environment in early life is thought to elicit a range of cellular adaptive responses in key systems, the melanocortin system being one of them. In rodents, the development of the melanocortin system is initiated during mid-gestation and continues during the postnatal period. These developmental windows represent important periods of vulnerability during which perturbations in the perinatal environment may lead to abnormal POMC and AgRP neuron development, causing lifelong metabolic diseases. Therefore, it will be critical to have a comprehensive knowledge of factors that are detrimental or beneficial for the development of the melanocortin system if we want to design intervention studies or treatments. The marked species difference in terms of hypothalamic developmental trajectories is important to consider, as rodents and humans may exhibit different periods of vulnerability to developmental insults or different responses to therapeutic interventions based on the temporal and regional maturation patterns of the hypothalamus. Nevertheless, the mature hypothalamus, whether in rodents or primates, can still exhibit neuroplastic responses, although the degree and nature of hypothalamic remodeling may differ between adults and neonates.