Inflammation and oxidative stress in vascular and renal disease: role of the inflammasome and pyroptosis” explore the redox physiology underlying these diseases, and shed light on the role of the inflammasome and pyroptosis in their progression. This editorial provides an overview of the Research Topic, highlighting its significance and summarizes the contributions made by the five included articles: four original articles and one review article.Inflammation and reactive oxygen species (ROS) production are complex processes that involve local and systemic responses to a variety of different stimuli. Dysregulation of these processes is characteristic in the pathogenesis of cardio-renal diseases. Despite the numerous publications and efforts dedicated to better understanding this issue in the last 20 years, our knowledge of the complex interplay between inflammation, oxidative stress, and redox balance in vascular and renal pathology remains scarce. In this context, recent reports highlight the critical role of the inflammasome in regulating sterile inflammation, and identify this complex as a possible key target for attenuating inflammation during cardio-renal pathologies. The articles published within this Research Topic, “Cardiovascular diseases are the leading cause of death worldwide, causing more than 17.9 million deaths in 2019, according to the World Health Organization. In particular, vascular and renal diseases, including hypertension, atherosclerosis, diabetic nephropathy, and chronic kidney disease, pose significant health challenges worldwide. Although inflammation and oxidative stress are critical and common factors in the development and progression of these conditions, we are far from having a complete understanding of the molecular mechanisms involved. This lack of understanding of how inflammation and oxidative stress contribute to vascular and renal pathology hinders the development of effective therapies for the treatment of the affected patients. This Research Topic highlights the implication of different novel pathways, from molecular mechanisms of inflammasome activation to monocyte-derived extracellular vesicles, sex-dependent pathways, and new biomarkers of oxidative stress in these diseases. Here, we briefly introduce and review the highlights of each article’s contribution in the following section.Ertuglu et al. authored a comprehensive review of the current literature regarding the role of inflammation and oxidative stress in salt-sensitive hypertension, emphasizing the role of NLRP3 inflammasome activation and discussing potential therapeutic approaches to this disease. This review paper offers valuable insights into this emerging area of research, providing updated evidence on genetic polymorphisms in NLRP3 as well as IL-1β genes associated with hypertension in humans while also reviewing evidence of activation of the inflammasome in animal models of salt-sensitive hypertension. The authors also review the NLRP3 inflammasome’s implication in the development of vascular dysfunction during hypertension, as well as recent evidence that suggests that oxidative stress triggers the activation of this inflammasome. Moreover, this review also highlights the pro-inflammatory effect of isolevuglandins (IsoLGs), lipid-derived protein modifications that have been recently associated with increased sodium reabsorption in the kidney and have an important role on T cell activation.In this Research Topic, Abdelbary et al. investigated the intriguing hypothesis that differences in apoptosis drive the decreased blood pressure and kidney inflammatory response that is common in female SHRs. After using a pan-caspase inhibitor to decrease apoptosis in both sexes, the authors observed similar decreases in renal apoptosis in male and female rats, but no alterations in the blood pressure or renal T cell profiles. Therefore, they concluded that sex differences in apoptosis do not contribute to sex differences in blood pressure or renal T cell infiltration during essential hypertension.The first original paper in this Research Topic covers the topic of sex differences in the mechanisms involved in blood pressure regulation. Using the spontaneously hypertensive rat (SHR), a well-established animal model of essential hypertension, Pitzer Mutchler et al. studied the implications of Mg2+ deficiency in the pathogenesis of hypertension. In particular, the authors investigated the interplay between Mg2+ deficiency, NLRP3 inflammasome activation in monocytes and dendritic cells, and the production of IsoLGs by these cells. As mentioned above, IsoLGs are thought to play a critical role in activating the inflammatory cascade during hypertension. By using a combination of in vivo and in vitro approaches, the authors demonstrate that depletion of dietary Mg2+ results in increased blood pressure levels, as well as exaggerated activation of the NLRP3 inflammasome and IL-1β production. These findings may have important clinical implications since commonly used medications like diuretics lead to a deficiency of Mg2+.In the second original paper, Santoyo et al. unveiled the potential role of pravastatin in reducing plasma levels of extracellular vesicles in women at risk for preeclampsia. Their findings suggest that pravastatin, commonly used for reducing high cholesterol, may prevent the endothelial dysfunction typical of this disease, highlighting this drug as a potential preventative therapy in the clinic.Preeclampsia, or new onset hypertension developed after the 20th week of gestation, is a significant complication of pregnancy, making the identification of potential therapeutic interventions of great clinical importance. Preeclampsia is characterized by excessive inflammation, endothelial dysfunction, and end-organ damage , as wellPei et al. performed an in-depth study of potential oxidative stress biomarkers associated with renal ischemia-reperfusion injury and their relationship with kidney inflammation in these conditions. By doing a comprehensive analysis of differentially expressed genes (DEGs) during oxidative stress and inflammation, they identified glutathione peroxidase 3 (GPX3) and glutathione S-transferase 1 (GSTT1) were significantly positively correlated with plasma cells and macrophage M0, while were negatively correlated with monocytes and macrophages M1 and M2. Overall, the manuscript presents valuable insights into the pathophysiological mechanisms underlying renal ischemia-reperfusion injury and suggests that GPX3 and GSTT1 might play a key role in the physiological and pathological processes involved. The authors also underline the potential utility of GPX3 and GSTT1 as potential therapeutic targets and biomarkers for diagnosing renal ischemia-reperfusion injury.Finally, In summary, this Research Topic presents a collection of diverse articles that expand our understanding of redox physiology during vascular and renal diseases. This Research Topic provides an overview of the current advances in investigation in this field, shedding light on the intricate interplay between inflammation and oxidative stress and providing valuable insights into the underlying mechanisms and potential novel therapeutic targets against cardio-renal disease.


Sarcopenia is a multifactorial disease characterized by reduced muscle mass and function, leading to disability, death, and other diseases. Recently, the prevalence of sarcopenia increased considerably, posing a serious threat to health worldwide. However, no clear international consensus has been reached regarding the etiology of sarcopenia. Several studies have shown that insulin resistance may be an important mechanism in the pathogenesis of induced muscle attenuation and that, conversely, sarcopenia can lead to insulin resistance. However, the causal relationship between the two is not clear. In this paper, the pathogenesis of sarcopenia is analyzed, the possible intrinsic causal relationship between sarcopenia and insulin resistance examined, and research progress expounded to provide a basis for the clinical diagnosis, treatment, and study of the mechanism of sarcopenia. Sarcopenia refers to the phenomenon that the quality and function of muscles decrease with age, and it is an important factor leading to disability, death, and other diseases . Its incAt present, no international consensus has been reached regarding the causes of sarcopenia. Existing studies suggest that many factors such as malnutrition, cardiopulmonary disease, endocrine diseases (such as androgen deprivation and decreased thyroid hormone levels), drugs, and congenital inheritance can cause sarcopenia. In recent years, the relationship between insulin resistance and sarcopenia has become a relatively novel hot topic. Considerable epidemiological evidence has indicated a significant association between the two . HoweverThe main target organ of insulin is the skeletal muscle, which accounts for 40–50% of lean body mass in adults. Glucose uptake and metabolism by skeletal muscle cells play a major role in glucose regulation . InsulinMuscle attenuation is associated with inadequate intake of amino acids and decreased insulin sensitivity. On the basis of several experimental reports and findings, we propose two complete signaling pathways, the insulin signal transduction pathway and amino acid signal transduction pathway; we detail the mechanism by which amino acids act in combination with insulin to promote an increase in skeletal muscle protein and emphasize the role of key factors.The decrease in muscle mass is caused by an imbalance between the rate of protein synthesis and the rate of protein breakdown in the muscle , 95. ThrInsulin receptors (INSR) are classified into IRS1 and IRS2, which play a major role in the growth and development of skeletal muscle. Long et al. used creatine kinase to block IRS1 expression in mouse skeletal muscle and found a decrease in skeletal muscle mass and skeletal muscle cell insulin sensitivity; however, blocking IRS2 did not produce the same results. However, simultaneous blockade of IRS1 and IRS2 leads to severe skeletal muscle attenuation and decreased activation of the insulin signaling pathway, suggesting that the two produce a synergistic effect in the skeletal muscle . FollowiAKT can inhibit its downstream TSC complex in the muscle, and this molecule limits Rheb activity, resulting in the inhibition of mTORC1 activity, as observed by Dibble et al. Therefore, AKT can increase MTORC1 activation levels by inhibiting the TSC complex. Although insulin stimulates AKT activation, the pathway by which insulin stimulates AKT Ser473 activation remains unknown. Dong et al. found that insulin stimulated phosphorylation of AKT Ser473 in IRS1-deficient and IRS2-deficient mice in animal experiments , but theTORC has two isoforms, and although mTORC2 is not directly associated with amino acid infusion and protein synthesis, it is similarly stimulated by growth factors such as insulin. PIP3 is produced after PI3K activation by insulin, and PIP3 activates Akt while also activating mTORC2. Pearce et al. demonstrated that although PIP3 can directly activate Akt, Akt requires additional phosphorylation of its carboxyl terminal site S473 by mTORC2 to achieve the highest level of activation; phosphorylation at this site can increase Akt activity by more than several folds. In addition, mTORC2 plays a role in stabilizing Akt conformation . Thus, sWhen activated, Rheb can stimulate the activity of the downstream mTORC1 kinase , 92. PRAThrough negative feedback, S6K1 can regulate protein synthesis pathways by degrading IRS1; however, this effect is maintained at very low levels in normal physiological states. Barbour et al. found that long-term increases in S6K1 lead to degradation of the insulin receptor IRS1 in patients with impaired glucose tolerance postpartum ,this effKim et al. found that another important factor in the insulin action pathway is AMP-activated protein kinase (AMPK), which can activate TSC2; transgenic induction of the gene expression of TSC2 led to decreased activation of mTORC1 in Drosophila. TSC2 antagonizes the physiological effects of insulin, reducing protein synthesis and increasing autophagy levels .Many studies have shown that insulin and amino acids together promote increased protein synthesis and thereby muscle mass, while amino acid and insulin action ultimately play a synergistic role in activating mTORC1. Arguably, mTORC1 unites two separate pathways of action. To confirm that mTORC1 is a key node in activating protein synthesis, Dickinson et al. designed an experiment in which subjects in the experimental group ingested 10 g of essential amino acids; muscle biopsy results confirmed a 60% increase in muscle protein synthesis levels. In control group subjects, who ingested amino acids after the use of mTORC1 inhibitors, muscle biopsy showed little change in muscle protein synthesis levels. This study strongly confirmed the key role of mTORC1 in the insulin–amino acid costimulatory pathway . In addiHowever, insulin does not stimulate an increase in the synthesis of all proteins, and the sensitivity of different proteins to its stimulatory effects is different: for example, myosin heavy chain synthesis is not directly associated with insulin levels. An important effect of insulin on cells is maintaining the function of mitochondria, and insulin stimulation of mitochondrial protein synthesis is important for maintaining the normal metabolism of skeletal muscle cells.Insulin can regulate mitochondrial function through the mTORC and FoxO transcription factor pathways because mTORC and FoxO1 can regulate PPAPγ activity factor 1α . PGC1A cA large body of experimental evidence indicates that sufficient amounts of available amino acids are initiators, which recruit large amounts of mTORC1 , while iIn this section, we focus on the FoxO-family-regulated protein breakdown pathway. A large increase in protein breakdown is an important cause of muscle attenuation, and several studies have confirmed that insulin mainly maintains the number of skeletal muscle cells and skeletal muscle mass by inhibiting protein catabolism.The most important function of the FoxO family is to regulate protein catabolism levels. In eukaryotic cells, most proteins are degraded through the ubiquitin–proteasome  and autoDifferent isoforms of FoxO play a role in sarcopenia through different pathways. FoxO1 can inhibit mTORC levels, which leads to elevated levels of myostatin and, consequently, abnormalities in myogenic differentiation . TherefoNumerous clinical experiments have demonstrated that 125 genes involved in the ubiquitin–proteasome pathway have significantly elevated gene expression levels in patients with diabetes, and this change disappears after FoxO is specifically knocked down. Among these genes, scientists have paid special attention to the levels of ubiquitin-activating enzyme (Ube4a), E2-ubiquitin-conjugating enzyme (Ubeq2q), and E3-ubiquitin ligase (Itch). O'Neill et al. used streptozotocin (STZ) to induce diabetes in mice for detection of gene expression, and the experimental results showed that Ube4a, Ube2q2, and Itch tended to gradually increase with the progression of diabetes; however, the levels of the above three genes did not change significantly in mice with FoxO gene-specific knockout . The autAdditionally, experimental evidence indicates that the FoxO family can directly induce the development of sarcopenia. When cells develop insulin resistance, the activity of FoxO target genes is significantly increased, in particular, the Gadd45a gene. Ebert et al. specifically induced its overexpression in the skeletal muscle and found that Gadd45a can directly mediate atrophy of skeletal muscle  and causOveractivation of the autophagy pathway leading to muscle attenuation has been a hot research topic; however, considerable evidence also indicates that high expression of the autophagy pathway and reduced levels of the autophagy pathway can have different effects on insulin resistance and muscle attenuation. Therefore, its specific role needs to be further explored.Autophagy refers to the process in which eukaryotes use lysosomes  to degrade their own cytosolic proteins and damaged organelles under the regulation of autophagy-related genes or molecules and finally perform recycling. The muscle is one of the most active organs of the autophagy pathway . Two cauWe have discussed in the previous section that insulin can inhibit the FoxO family, resulting in decreased levels of the autophagy–lysosomal pathway. The FoxO family, especially FoxO3, is involved in the induction of the autophagic ligase FBXO32. Seri et al. induced muscle attenuation in mice by knocking out arginine methyltransferase 1 (PRMT1) and found that transcripts of FoxO3 were expressed by more than two-fold in mice with muscle attenuation. Additionally, immunostaining showed that more FoxO3-positive myonuclei were found in the mouse muscle than in healthy mice from controls and that even the central nucleus of muscle fibers with low distribution increased by different levels in different physiological states, which was positively correlated with the increase in autophagy levels . UpregulMore worthy of our in-depth consideration are the experiments of Kim et al. ATG7 is a key protein in autophagosome formation, and the team found that mice with specific deletions in the ATG7 gene developed severe muscle atrophy; however, these mice showed higher resistance to diet-induced insulin resistance. Attenuation of autophagy may preserve insulin sensitivity, possibly because upregulation of FGF21 actin levels promotes insulin sensitivity . HoweverIn recent years, many experiments have shown that decrease in autophagy pathway activity can lead to the aggravation of insulin resistance. Frendo-Cumbo et al. found that the knockdown of Atg16l1 in L6 myocytes leads to a decrease in autophagy levels, while the level of IRS1 is significantly reduced . RecentlOur review of the literature indicates that, according to experimental evidence, both the rise and fall in autophagy levels have demonstrated an inverse association with insulin sensitivity, which may require further investigation.Insulin resistance can lead to the occurrence of sarcopenia through many pathways, and the above mechanisms of action are popular topics for in-depth research. The PI3K–AKT–mTORC pathway as the most important mechanism underlying this effect builds a bridge between the skeletal muscle and insulin, and a series of pathways such as FOXO and autophagy can be regulated through this pathway. By continuously exploring the downstream targets of each protein, we can continuously discover new sites to identify new treatment strategies for insulin resistance and sarcopenia. In recent years, an increasing number of downstream factors have been discovered, which will be a hot field of future research.Numerous studies have confirmed that sarcopenia can induce insulin resistance through: (1) abnormal lipid infiltration distribution and lipotoxicity in the skeletal muscle, (2) increased amino acid catabolites in skeletal muscle branch chains, and (3) decreased proportion of skeletal muscle type I fibers.Abnormal fat production and intracellular lipid deposition in the skeletal muscle are among the most important factors causing insulin resistance. In this section, we review a large number of studies that show that lipid infiltration can cause the development of insulin resistance through several different mechanisms.Studies have shown that with the progression of age, human body fat will undergo proliferation, hypertrophy, and redistribution, and considerable fat infiltration will occur in the skeletal muscles, leading to myosteatosis. Myosteatosis is different from obesity, and the occurrence of both obesity and sarcopenia is called obesity-associated sarcopenia (SO). Adipocytes exist in three forms in the muscle, namely, intermuscular adipose tissue, intramuscular adipose tissue, and intramyocellular adipose tissue. Studies have shown that a large part of lipid infiltration occurs in the cytoplasm. Myocyte lipids play an important role in inducing insulin resistance, and many lipid intermediates affect insulin signaling, resulting in lipotoxicity. Intramuscular lipids (IMCLs) exist as lipid droplets (LDs) surrounded by members of the periphospholipid protein (PLIN) family, among which the bone expresses mainly PLIN2, 3, and 5. PLIN2 maintains the stabilization of lipid droplets and prevents degradation, which is a main factor limiting IMCL deposition. de Wilde et al. demonstrated through animal experiments that upregulation of lipotropic proteins such as PLIN2 is associated with improved insulin sensitivity . In thisDiacylglycerol (DAG) exists as three isomers in the muscle, of which 1,2-DAG forms the vast majority, and it is the only one that has been demonstrated to negatively correlate with insulin sensitivity in humans. Accumulation of DAG in cells leads to activation of isoforms of protein kinase C (PKC), the most important of which is PKCθ. PKCθ in the muscle leads to inhibition of ISR1, leading to the development of insulin resistance . HoweverCeramide (CER) can be transported intracellularly by transport proteins (CERT), which are significantly increased in patients with obesity. Accumulation of CER leads to decreased insulin sensitivity and decreased activity of Akt, probably because activation of protein phosphatase 2A leads to inhibition of dephosphorylation of Akt , 19. In Acylcarnitine (ACC) accumulates when lipids are incompletely oxidized, which leads to the development of insulin resistance , 57. BotIn addition to adipocytes themselves affecting insulin sensitivity through multiple pathways, lipid infiltration of myocytes leads to massive activation of proinflammatory factors, such as tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP-1), and interleukins. MCP-1 recruits monocytes to sites of inflammation , 50, andThe mitochondria and endoplasmic reticulum are important organelles for maintaining normal metabolism in myocytes. In this section, we focus on the effects of lipotoxicity on these organelles.2O2 in high-fat diet (HFD)-fed mice [The infiltration of lipids into myocytes results in the production of large quantities of reactive oxygen species (ROS), which opens the mitochondrial membrane permeability pores (PT pores) and induces the release of calcium ions, cytochrome C, and the apoptosis-inducing factor (AIF). These events subsequently activate caspase 9, which leads to the uncoupling of the mitochondrial electron transport chains. This leads to an increase in the expression of the pro-apoptotic protein Bax and induces the rupture of the mitochondrial outer membrane, resulting in apoptosis. A large number of damaged mitochondria are removed by autophagy in the body , causingfed mice . When lifed mice .+) do not face the action of ATP synthase but return to the matrix directly through the inner mitochondrial membrane. Normally, state 3 respiration and state 4 respiration of the mitochondria are performed alternately; therefore, electron leakage from the mitochondria is the main source of ROS. When respiratory chain activity is blocked, ROS levels rise, which has been confirmed in clinical studies of patients with T2DM.Mitochondrial proton leak refers to ATP synthesis by mitochondria in the absence of phosphorylated ADP. Protons , and obesity downregulates Mfn2 gene expression . The keyEndoplasmic reticulum (ER) stress is one factor leading to insulin resistance. ER stress occurs in association with massive accumulation of lipids and lipotoxicity. To improve ER stress, the ER activates a series of signaling pathways, such as enhancing the folding ability of proteins and accelerating protein degradation, known as the unfolded protein response (UPR). ER stress is primarily caused by three transmembrane proteins, namely, inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and the protein kinase-like endoplasmic reticulum kinase. Among them, IRE1 can lead to JNK phosphorylation. JNK is a pro-inflammatory transcription factor whose increased levels result in decreased AKT and GSK3β levels and can directly contribute to the development of insulin resistance . Scienti2+ in the mitochondria, which causes an increase in ROS production and leads to mitochondrial damage. Additionally, overactivation of mTORC1 may be linked to ER stress. Ozcan et al. found experimentally that TCS2-specific-knockout mice exhibit profound ER stress that further aggravates insulin resistance through multiple pathways.Interaction between the ER and mitochondria is another focus of research. Scientists have found that ER stress can cause an increase in the concentration of CaUbiquitination of IRS1 showed generally elevated levels in HFD-fed mice. E3 ubiquitin–proteasome ligases have been found to be critical in determining substrates for degradation by ubiquitination, and they can degrade IRS directly through the ubiquitin–proteasome pathway (UPS); for example, IRS1 can bind to E3 ligases such as MDM2, Cbl-b, and MDM27 and undergo degradation, thereby reducing cellular sensitivity to insulin. PDCD5, an apoptosis-accelerating protein, is widely present in the skeletal muscle, and Zhou et al. found in animal experiments that it specifically promotes ubiquitination of MDM2 itself to protect IRS1 from damage . The ubiScientists have recently explored new ways to link lipotoxicity to insulin resistance. Skeletal muscle PANX1 is a channel involved in the release of ATP into the extracellular space, and extracellular ATP (eATP) can activate many inflammatory responses  and partMitogen-activated protein kinase phosphatase-1 (MKP-1), an enzyme expressed in the muscle, is abnormally elevated in the skeletal muscle of patients with obesity, and MKP-1 prevents phosphorylation of Akt Ser473 and signaling of molecules such as p38 AMPK, resulting in insulin resistance. Lawan et al. demonstrated this result in mice in which the MKP gene was specifically knocked out .The complex relationship between lipid infiltration of myocytes and insulin resistance is a topic of interest, and, in this section, we focus on the effects of lipids on different sites of the insulin action pathway and on organelles and summarize the results of research conducted in recent years Fig. .Fig. 3PoIncreased levels of branched-chain amino acids (BCAA) promote muscle protein synthesis, and evidence suggests that leucine may partially suppress muscle wasting by reducing proteolysis . HoweverBCAA are abundant in the muscle, accounting for approximately 30% of muscle protein content. The skeletal muscle is a major site of BCAA catabolism, and branched-chain amino acid transferase 2 (BCAT2) is mainly expressed in the skeletal muscle. Mice with systemic BCAT2 knockout exhibited increased phosphorylation of S6K1 and increased plasma levels of BCAA . DecreasIn recent years, several studies have focused on the relationship between BCAA and insulin resistance. In this regard, overall, two hypotheses have been proposed: (1) increase in BCAA overactivates MTORC1, leading to hyperactivation of S6K1, which causes dephosphorylation of IRS1 and, consequently, the development of insulin resistance, and (2) accumulation of BCAA leads to mitochondrial dysfunction, which has been elaborated in other reviews , 109. HoCrossland et al. found that intermediates of BCAA breakdown accumulated significantly after the culture of myotubes in a culture medium with high concentrations of BCAA, and these metabolites inhibited the activity of Akt and ISR1, leading to the development of insulin resistance. BCAA levels were found to decline after promotion of BCAA breakdown with lead however, the levels of BCKA did not change, which may indicate damage to a link in the catabolic pathway of BCAA .Valine is catabolized to produce an intermediate, 3-HIB, a paracrine regulator of transendothelial fatty acid transport. Jang et al. found that endothelial cell trafficking was activated in the presence of 3-HIB, stimulating muscle fatty acid uptake and lipid deposition in the muscle . They teHowever, BCAA supplementation alone does not induce the development of insulin resistance in regular food-fed rats. However, manifestations of insulin resistance appear in HFD-fed rats. Therefore, controversy exists regarding whether increased BCAA levels can directly lead to the development of insulin resistance or lead to its further development in patients who are already insulin resistant. In a mouse model of insulin resistance induced by fructose feeding, David et al. found that an increase in BCAA levels occurs early, preceding the development of insulin resistance . Other sAsghari et al. followed 1205 Iranian men and women for 2.3 years and showed that dietary intake of high BCAA increased the risk of insulin resistance; however, a limitation of this study was that serum BCAA concentrations were not determined .Hernández-Alvarez et al. showed through clinical studies that T2DM leads to decreased mRNA expression of BCKDHβ and BCAT2 in the skeletal muscle, causing increased levels of BCAA. Defining whether increased levels of BCAA are a secondary consequence of insulin resistance or a predisposing factor is therefore a critical issue. Additionally, future research needs to explore whether primary diseases such as sarcopenia can lead to catabolic disorders of BCAA and, thus, the development of insulin resistance.Type I muscle fibers have a higher aerobic metabolic capacity than type II muscle fibers. It has been found that the decrease in the proportion of type I muscle fibers in patients with insulin resistance and diabetes is positively correlated with the severity of insulin resistance, which is an important cause of the development of insulin resistance.A positive correlation between the concentration of free fatty acids (NEFA) and the degree of insulin resistance has been discussed earlier; it can be shown by objective data from the HOMA homeostasis model, which is positively correlated with results from HOMA-IR and negatively correlated with the proportion of type I muscle fibers. Zhou et al. measured the type of myofibers in HFD-fed mice and found a decreased proportion of type I myofibers, likely due to decreased phosphorylation levels of AMPK because of increased activation of FNIP1 and FLCN. Following the treatment with dihydromyricetin (DHM), TG levels were found to decrease  and typeType I fibers play an important role in insulin sensitivity because they contain more mitochondria and can undergo more lipid oxidation compared to type II fibers. Another possible mechanism is that the number and density of tiny capillaries surrounding type I fibers is higher than that in type II fibers, possibly because muscle fibers with greater oxidative capacity and selective sensitivity to insulin have a greater number of capillaries, which may alleviate the symptoms of insulin resistance . HoweverThe correlation between insulin resistance and sarcopenia has become a hotspot of research. The two can be mutually etiological, resulting in a vicious cycle. The relationship between the two is very complex, involving several molecules and genes. The role of mitochondria in the skeletal muscle in the above two diseases is likely to be an attractive avenue of future research; an increasing number of mechanisms are considered to be related to abnormal mitochondrial function, and good efficacy has been achieved after intervention therapy against mitochondria.In this paper, we focus on some of the most important mechanisms linking insulin resistance to sarcopenia. In recent years, with the progress of science and technology, experts can perform more in-depth studies to identify pathogenesis mechanisms, such as mutations and deletions at the genetic level, which enrich the connection between the two diseases. However, the impact of a single mechanism is insufficient to explain the pathogenesis of both diseases. Most mechanisms interact with each other and induce further deterioration of the disease. In addition, these two diseases are closely related to various external factors such as age, gender, and amount of exercise, which greatly affect the course of the disease. With the aging of the population, an increasing number of patients will be afflicted with these two diseases; thus, we urgently need to develop practical interventions against the occurrence and progression of insulin resistance and sarcopenia.The specific mechanisms of insulin resistance and sarcopenia are extensive; thus, the focus of this paper was to elaborate the main mechanisms of their correlation and establish a framework for their connection. In addition, the articles cited herein were sourced from PubMed and may have been incomplete in the elaboration of some mechanisms. Furthermore, the review may have been subjective in the process of literature screening, collation, and analysis.


Oryza sativa) several ERFVII genes have been identified and characterized, including SUBMERGENCE 1A (SUB1A), which enables rice to tolerate submergence. The SUB1A gene was used in the development of SUB1 rice varieties, which are now widely grown in flood-prone areas and have been shown to improve yields and farmer livelihoods. The oxygen sensor in plants was discovered using the model plant Arabidopsis. The mechanism is based on the destabilization of ERFVII protein via the N-degron pathway under aerobic conditions. During hypoxia, the stabilized ERFVIIs translocate to the nucleus where they activate the transcription of hypoxia-responsive genes (HRGs). In summary, the identification and characterization of ERFVII transcription factors and their mechanism of action could lead to the development of new crop varieties with improved tolerance to low oxygen stress, which could have important implications for global food security.In this review, we focus on ethylene transcription factors (ERFs), which are a crucial family of transcription factors that regulate plant development and stress responses. ERFVII transcription factors have been identified and studied in several crop species, including rice, wheat, maize, barley, and soybean. These transcription factors are known to be involved in regulating the plant’s response to low oxygen stress—hypoxia and could thus improve crop yields under suboptimal growing conditions. In rice ( Arabidopsis thaliana belong to TFs (Transcription factors (TFs) are proteins that can specifically bind to cis-acting elements in the promoter region of eukaryotic genes in order to regulate gene expression . They arg to TFs . TFs areArabidopsis thaliana) and rice (Oryza sativa L. subsp. japonica), respectively  SUBMERGENCE1 (SUB1), which contains two or three ERF genes belonging to group VII of this large family of transcription factors  genes, which cause the stem to elongate rapidly. This results in an ‘escape’ from submergence, enabling the plant to keep its leaves above the water surface, thus allowing oxygen to be transported from the air to the submerged parts of the plant. SNORKEL1 and SNORKEL2 belong to the ERFVII transcription factor’s subgroup, which triggers a gibberellin-dependent internode elongation   boosted The oxygen sensing mechanism has been clarified in both animals and plants, and in both cases unrelated TFs have been identified as being responsible for the perception of oxygen. In mammals the Hypoxia Inducible Factor (HIF-1) is responsible for low-oxygen sensing, while in plants the transcription factor RAP2.12 belonging to ERFVIIs is the oxygen sensor , togetheThe oxygen sensor in plants was discovered thanks to the model plant Arabidopsis . In Arab2-replete conditions, ERFVIIs are indeed easily degraded. ERFVIIs experience a series of N-terminal modifications, including N-terminal methionine excision, oxidation of the cysteine residue, and N-terminal arginylation, which boosts their degradation by the N-recognin E3 ligase PROTEOLYSIS6 (PRT6)  . Under h residue , althoug residue . Nitric  residue .Oxygen sensing is also controlled by the energy sensor target of rapamycin (TOR). If hypoxia occurs in a plant with limited sugar reserves, the activity of ERFVIIs is severely dampened because the TOR controls the phosphorylation of ERFVII, which is required for optimal activity of these proteins as transcription factors . PhosphoAs previously mentioned, SUB1A plays a crucial role in submergence tolerance in rice but, despite belonging to the ERFVII class of transcription factors and showing a Cys-residue at the N-terminus, it is not a substrate for the PCO-dependent N-degron pathway . The SUBERF66 and ERF67) which controls the activation of several HRGs. Although plant species other than rice do not appear to have developed such a sophisticated mechanism for submergence tolerance, their response to submergence is still likely to be more complex than the response to hypoxia per se.This raises the question as to how during submergence rice senses low oxygen conditions. Interestingly, SUB1A transcriptionally activates ERF66 and ERF67, which are ERFVII proteins that are substrates of the N-degron pathway and promote submergence survival . The oveHRGs when hypoxia follows ethylene perception, which thus converges with oxygen sensing in order to ensure that the response is localized in the tissues that are actually experiencing hypoxia due to submergence and not developmental hypoxia  is very sensitive to waterlogging, resulting in a 20%–30% yield loss (PROTEOLYSIS6 (PRT6) gene. They found that PRT6 plays a crucial role in regulating the plant’s response to waterlogging stress. The barley ERFVII BERF1, most closely related in sequence to Arabidopsis RAP2.12, is a substrate of the N-degron pathway in vitro. By reducing the expression of PRT6 in barley plants, the authors were able to enhance the plant’s waterlogging tolerance, presumably because the lower level of PRT6 expression leads to a higher stability of ERFVII proteins and thus increased expression of hypoxia-associated genes. The study suggests that manipulating the expression of PRT6 in crops could be a promising strategy for improving waterlogging tolerance.Barley  were significantly upregulated in the ZmEREB180 transgenic plants compared with WT under submerged conditions   . Interescysteine .Hypoxic niches can affect plant development and can exist in otherwise aerobic plants . The shoBotrytis infection, local hypoxia was established allowing the stabilization of ERFVII proteins (The contribution of ERFVII proteins in hypoxic niches is under investigation. In Arabidopsis during proteins . The resRegarding the hypoxic niches that are generated during development, ZPR2  and VRN2The outstanding work carried out in rice, in which the discovery of SUB1A as the gene responsible for this trait was rapidly translated from the lab to the field, demonstrating that a clever combination of genetics with physiology can produce breakthroughs in agriculture. Since the discovery of SUB1A  and otheThe existence of hypoxic niches also during plant-microbe interactions is another promising research area, which will help in highlighting the importance of oxygen-labile transcription factors that influence plant life .After the identification of the SUB1A gene, despite the success of the new rice varieties that were highly tolerant to flooding, there have been few positive results in translating the discovery of oxygen sensing into new crop varieties. One likely explanation for this is that, unlike SUB1A, the regulation of oxygen sensing following a flooding event is shared by hypoxic niches that control developmental processes. One outstanding challenge is to uncouple the responses to flooding conditions from those linking hypoxia to plant growth and development in order to make biotechnological approaches toward flooding-tolerant plants feasible.


Glaucoma is a neurodegenerative condition in which increased intraocular pressure (IOP) causes progressive degeneration of retinal ganglion cells (RGCs), the neurons projecting from the retina to secondary visual areas of the brain. Raised IOP results in apoptosis of RGCs because of damage to RGC axons at the optic nerve head. Axonal damage triggers disruption of RGC mitochondria, metabolism, and active transport. It also disturbs the anatomic distribution of excitatory connections in RGC targets, including the superior colliculus and the thalamic dorsal lateral geniculate nucleus (dLGN). However, the timeline of the processes linking initial damage to RGC death is not well characterized. It is especially unclear at which point functional changes begin in excitatory synapses between RGCs and target structures like the thalamocortical (TC) neurons in the dLGN. To solve this conundrum, After establishing the age of onset of IOP elevation at approximately seven months in D2 mice, the authors first measured anterograde axonal transport along RGCs to the dLGN using injection of fluorescently tagged cholera toxin (CTb-594) into the eye. D2 mice showed a progressive decline of anterograde transport, which was significant in the nine-month age group. Similarly, D2 mice showed progressive loss of glutamatergic RGC presynaptic terminals in the dLGN, as indicated by a decreased density of immunolabelled vGLUT2 puncta. This effect was significant by nine months of age, was severe by 12 months, and occurred to a greater extent in areas of the dLGN with impaired axonal transport as determined by the CTb-594 assay.r), and the AMPA/NMDA ratio, which indicates the relative activations of postsynaptic AMPA receptors (AMPARs) and NMDA receptors (NMDARs). They discovered a progressive increase in the PPR, indicating a falling Pr, and coincident decreases in both the AMPAR and NMDAR components of EPSCs, but no changes in the overall AMPA/NMDA ratio. These findings point toward a presynaptic locus of effect for the reduction in synaptic transmission, indicating that the release probability in RGCs terminals progressively decreases with age, but finding no evidence that postsynaptic sites on TCs change in receptor composition. Using a reduced stimulus to evoke single-axon synaptic vesicle release from RGCs (single fiber EPSC), the authors found that the EPSC amplitude recorded in TCs was unchanged. However, the ratio of the single fiber EPSC to the maximal EPSC was increased in the 12-month-old group, suggesting that TC neurons in D2 mice receive overall less inputs than the controls. In summary, the effects observed in both spontaneous and evoked synaptic transmission converge onto a pathologic change in transmitter release at the RGC to TC synapse.Smith and colleagues then sought to investigate changes in functional synaptic transmission at the RGC-TC synapse using whole-cell electrophysiology in acute slices. Spontaneous EPSCs (sEPSCs) in TCs did not display changes in amplitude but had a decreased frequency at nine months of age. This effect suggests that a proportion of synapses had been lost as opposed to individual synapses being individually weakened. Next, the authors assessed the paired pulse ratio (PPR), which relates inversely to presynaptic vesicle release probability (PTCs are known to be affected in the context of elevated IOP, with defects in intrinsic excitability and soma atrophy . To inveFinally, even if the axonal defects are well advanced in 11- and 12-months D2 mice, the density of RGC somas in the central and peripheral retina was unchanged, showing that at this stage pathology has not yet caused cell loss. RGC degeneration is rather a late event in the D2 mouse model, starting after 15 months of age .In conclusion, this study uses an elegant combination of anatomic and physiological approaches to describe the progressive dysfunction of the retinogeniculate synapse in the D2 mouse model of glaucoma . Some ofAs emphasized in the paper’s Discussion, some points remain to be answered considering these results. For example, it is still unclear if decreased vGLUT2 staining is caused by degenerating RGC-to-TC synapses or by defects in axonal transport. In addition, knowing if dendritic remodeling in TCs is followed, or alternatively preceded, by a loss of postsynaptic markers will be key to understanding the pathologic processes operating at retinogeniculate synapses. To conclude, the authors highlight an interesting paradox: while this study shows decreased synaptic transmission between RGCs and TCs, they reported increased TC excitability in D2 mice in previous work . Smith aThis study adds unprecedented value to glaucoma research. Further work describing cellular and molecular mechanisms behind retinogeniculate synapse dysfunction will be essential to fully understand the pathologic underpinnings of this disease.


On November 26, 2022, the Tazewell (Illinois) County Health Department (TCHD) contacted the Illinois Department of Public Health (IDPH) concerning a large acute gastroenteritis outbreak linked to restaurant A in Illinois. TCHD conducted an outbreak investigation with the assistance of IDPH, including a case-control study that identified 317 norovirus infections among respondents (excluding the primary patient) who dined at restaurant A during November 19–26, 2022.A probable case was defined as the occurrence of diarrhea (three or more loose stools within 24 hours) or vomiting in a person who dined at restaurant A during November 19–26; probable cases with norovirus RNA detected in a stool specimen submitted to the IDPH laboratory were considered confirmed. Notification of the outbreak and requests for information from persons who had dined at restaurant A during November 19–26 were disseminated to the public by TCHD and restaurant A. The press also shared information about the outbreak on November 28, 2022, encouraging all persons who dined at restaurant A to report this to TCHD; after the release of news stories by the press, the number of reported ill persons doubled.Overall, 317 case-patients (three with confirmed and 314 with probable norovirus infection) and 40 control patients (persons who dined at restaurant A during November 19–26 and did not become ill) were interviewed initially through an online form to identify epidemiologic links and common food exposures. When secondary phone interviews were conducted to confirm the illness onset date, pizza toppings, salad dressings, and condiments consumed, only 268 ill persons and 40 controls participated; the additional 49 ill persons were lost to follow-up. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.*Although the outbreak originated in Tazewell County, ill persons resided in 10 additional Illinois counties and 12 other states; some secondary cases were reported within the households of restaurant patrons and were not included in the total of 317 case-patients. Restaurant patrons shared illness information and menu items consumed, via an online questionnaire and follow-up interview; among the 317 ill persons sharing information through the online questionnaire and phone calls, 268 (85%) participated in the secondary interview; 49 (15%) ill persons were lost to follow-up. Among the 268 interviewed persons with information on illness onset date, symptoms commenced during November 20–28, with 114 (43%) cases occurring on November 24 . The meaBased on data obtained from the questionnaire, the suspected food vehicle was salad ; 227 of 268 ill persons and 15 of 40 controls consumed salad. Twenty-seven ill persons did not eat salad but did consume additional sauces and dressings. Environmental and epidemiologic investigations indicated that contamination occurred throughout the food preparation process includes the division of the salad, toppings, and dressings into individual portions that are refrigerated for consumption on the following day. Preparation with ungloved hands by a food handler who had vomiting on November 22, and worked during November 21–23, likely served as a main contributor to the outbreak. The restaurant voluntarily closed on November 26 for disinfection and reopened on November 29, after a health inspection. TCHD provided education to food handlers on hand hygiene, staying home from work when ill with diarrhea or vomiting, and cleaning procedures.Noroviruses are a leading cause of reported foodborne disease outbreaks associated with contamination of food in restaurants during preparation by infected food workers (–The Food and Drug Administration’s 2022 Food Code cites noroviruses as the leading cause of foodborne illness in the United States, and proper hand hygiene and exclusion of symptomatic employees are essential for preventing outbreaks


Pancreatic Ductal Adenocarcinoma (PDAC) is a very lethal disease that typically presents at an advanced stage and is non-compliant with most treatments. Recent technologies have helped delineate associated molecular subtypes and genetic variations yielding important insights into the pathophysiology of this disease and having implications for the identification of new therapeutic targets. Drug repurposing has been evaluated as a new paradigm in oncology to accelerate the application of approved or failed target-specific molecules for the treatment of cancer patients. This review focuses on the impact of molecular subtypes on key genomic alterations in PDAC, and the progress made thus far. Importantly, these alterations are discussed in light of the potential role of drug repurposing in PDAC. KRAS, SMAD4, P53, and CDKN2A observed in pancreatic cancer  is the most common form of pancreatic cancer accounting for more than 90% of all pancreatic malignancies . This agc cancer . In thisc cancer . These ec cancer . HoweverHence this mini-review delves into the current knowledge regarding the molecular subtypes and genetic landscape of pancreatic cancer and their clinical impact. Then, we discuss some drugs that have been demonstrated to have potential clinical impact when repurposed for PDAC treatment highlighting recently completed and some ongoing clinical trials. Ultimately, we highlight the challenges of repurposing drugs for PDAC treatment and the opportunities for overcoming them.Several studies have stratified patients into distinct subtypes using cutting-edge techniques such as single-cell analyses  Table 1Table 1. GATA6), KRAS, and SMAD4 in addition to KRAS G12V high mutational level  promoting metastasis  to probe KRAS-mutant human PDAC cell lines and it showed classical subtypes are more dependent on KRAS than quasi-mesenchymal . This suADEX subgroup identification is vital in the later stages of pancreatic development and differentiation via the upregulation of genes that regulate networks, such as NR5A2 involved in KRAS activation . The proKRAS pathway has been one of the most characterised pathways in PDAC. Genetic approaches have demonstrated that KRAS mutations occur in over 95% of PDAC tumours  and cyclin-dependent kinase 4 (CDK4) which triggers the activation blocks G1 to S phase (CDKN2A induce cyclin-dependent kinase 4 and 6 (CDK4/6) activity and lead to cell proliferation  have been demonstrated to be crucial in PDAC therapy . SMAD4 mutations occur in over 50% of PDAC cases promoting invasion, metastasis and poor prognosis via the inhibition of TGF-β signalling pathways by affecting cell arrest, apoptosis, invasion and metastasis  medication have been shown to have anti-neoplastic effects because of their ability to inhibit the prostaglandins precursors, COX-1 and COX-2 enzymes that regulate inflammatory processes . AcetylaThis is an oral biguanide used to treat diabetes but is associated with decreased overall cancer incidence . The ant2 and D3 are the most important compounds in this group. Studies have demonstrated that Vitamin D reduces the risk of pancreatic cancer by regulating cell cycle and differentiation. Although the effect of Vitamin D on the molecular mechanism underlying pancreatic cancer development is not well understood, Vitamin D receptors (VDR) are involved in several metabolic pathways, immune responses, and malignancies  inhibitors used as maintenance treatment for advanced ovarian, fallopian tube, or peritoneal cancer responding to platinum-based chemotherapy . They inDrug repurposing capitalises on matching the established mechanisms of existing drugs with the disease profile. Although, the past years have shown a leap in our understanding of the inception and progression of PDAC, the molecular underpinnings are still being unravelled. Hence matching the right drug with the right molecular subtype becomes a big challenge when the intricacies of the disease are only partially understood. Pancreatic cancer is characterised by its high degree of complexity and intra-tumoural heterogeneity . DiffereWith the preponderance of enigmatic drug resistance in cancer treatment, there is an unmet need to delve into a new trajectory of therapeutic strategies. Stratification of PDAC into clinically and genetically associated groups could open a gateway for discovering novel biomarkers. New technologies such as single-cell-RNA-sequencing and single-cell-omics could be explored to provide a more comprehensive classification of PDAC patients in the different subtypes based on their biology, prognosis, therapeutic targets, and pharmacologic response to drugs. Strikingly, drug repurposing has been implemented for cancer research to facilitate the drug design process and cost. Repurposing drugs to target genomic alterations in PDAC subtypes is the future perspective that should be leveraged for personalized medicine. Hence more future clinical studies targeting repurposed drugs in PDAC could be beneficial in identifying effective treatments.


Hypoplastic left heart syndrome is a rare critical congenital heart defect constituting a prevalence of 1/3,500 to 1/12,500 live births in which there is obstructions to the blood flow within the left heart. Here we present a case of a full-term 38 weeks male baby with a birth weight of 3.5 kg, and no obvious physical deformity referred to our centre at 22 hours of life for respiratory distress and cyanosis. At 23 hours of life, he was diagnosed with hypoplastic left heart syndrome and kept on Prostaglandin E1 infusion till the 12th day of life. The baby had a large ventricular septal defect and atrial septal defect with a severely hypoplastic left ventricle, hypoplastic aortic root, ascending aorta and post-ductal coarctation of the aorta. The diagnosis was reconfirmed by computed tomography cardiac angiography on the 10th day of life with the same cardiac findings suggestive of hypoplastic left heart syndrome. The baby developed respiratory distress with cyanosis at 20 hours of life and was referred to our centre for neonatal intensive care. A lethargic, cyanosed, hypotensive baby was received at 22 hours of life at emergency with pre-ductal saturation of partial pressure of oxygen (SPO2) was 65%. The baby was intubated with initial resuscitation and kept under a mechanical ventilator after shifting to the neonatal intensive care unit (NICU) of KMCTH. Despite under mechanical ventilation, the baby's saturation did not improve and bedside echocardiography was done at 23 hours of life which revealed a hugely dilated right ventricle (RV), dilated right atrium (RA), severely hypoplastic left ventricle (LV), 10 mm membranous ventricular septal defect (VSD) , 5 mm atrial septal defect (ASD) , hypoplastic ascending aorta, small patent ductus arteriosus (PDA) 1.2 mm with post-ductal coarctation , cardiac computerized tomography (CT) angiography was done only on the 10e aorta. .th day of life but, unfortunately, the baby could not survive.The baby was referred to the cardiac surgery centre for the operative procedure on the 126The left-sided heart structures are underdeveloped as a result of the complex aetiology of HLHS. The causes of this defect can be divided into two categories: obstruction of flow into the left ventricle , or obstruction of flow out of the left ventricle (obstruction of the left ventricular outflow tract). Aortic stenosis-related obstruction to left ventricular (LV) outflow during fetal development raises LV afterload and results in LV hypertrophy, which eventually causes LV dilatation and reduced LV contractility. Furthermore, decreased blood flow through the LV hinders the ventricle's growth, resulting in hypoplasia. The neonates with HLHS are reliant on a patent ductus arteriosus (PDA) for blood supply to the coronary arteries and systemic circulation. To keep the ductal patency after birth, prostaglandin E1 (PGE1) must be continuously infused. In contrast to the normal heart's series circulation, these patients are thought to have systemic and pulmonary circulations operating simultaneously.7As this is one of the rare critical congenital heart diseases with severe forms of cardiac malformation, very less case notes have been reported so far. An autopsy case published in Sao Paulo, Brazil highlighted that HLHS is a lethal congenital heart disease and despite the availability of improved management and surgical treatment in developed countries, it is still associated with high mortality, especially in the early neonatal period and before the second stage of reconstruction surgery.8 Similar to this, in our case also, the baby had a hypoplastic left ventricle, hypoplastic aortic arch and ascending aorta along with large VSD and ASD.The HLHS, which is characterized anatomically by an insufficiently sized left ventricle to support the systemic circulation and varying degrees of valvular obstructions, involves a spectrum of blood flow obstructions inside the left heart. The main problems mentioned include hypoplasia of the aortic arch and ascending aorta, as well as atresia or stenosis of the mitral and aortic valves. Additionally, an ascending aorta diameter of less than 3 mm is substantially related to aortic coarctation.As HLHS is one of the critical mixed-flow congenital heart diseases with various cardiac malformations, it is very much difficult to save these types of babies, particularly in low-middle-income countries like Nepal where neonatal cardiac surgical infrastructure is suboptimal.


Endometrial cancer is the most common gynecologic cancer in the developed world and in the recurrent setting has a dismal prognosis. As the endometrium is a hormonally active tissue, hormonal therapy has long been an integral treatment modality. There are many options for hormonal therapy including progesterones, agents that target the estrogen pathway, and combinations with targeted therapies, which are described in detail in this review. High disease control rate, long duration of response, and easy tolerability make hormonal therapy an excellent option for patients with low-grade hormone receptor-positive disease who would like to avoid or cannot tolerate cytotoxic chemotherapy or other targeted therapies.Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents. Endometrial cancer is the most common gynecological cancer in the developed world, and it is one of the few cancer types that is not only increasing in incidence, but also mortality . RecurreThe endometrium is a hormonally active tissue. Unopposed exposure to estrogen leads to increased mitotic activity in endometrial cells, resulting in more frequent replication errors and subsequent accumulation of somatic mutations ,6. TheseMolecular analysis of endometrial cancer has led to further classification of the disease beyond just type I and type II. The Cancer Genome Atlas (TCGA) project identified four prognostically distinct molecular subtypes of endometrial cancer which include: ultramutated, microsatellite instable, copy-number high, and copy-number low . In ordeProgestational agents have long been the prototypical hormonal therapy . HoweverA second, further downstream target that has been studied extensively in breast cancer and is now being evaluated in endometrial cancer are the cyclin-dependent kinases 4 and 6 (CDK4/6). In addition to direct activation by ER, both the PI3K/Akt/mTOR pathway and a second pathway that is commonly altered in endometrial cancer , the recGiven the rapidly changing landscape of the classification and management of endometrial cancers, it is important to review the current and future literature on hormonally relevant biomarkers and treatment regimens for advanced or recurrent disease. In preparing for this review, PubMed was searched using the following terms: endometrial cancer, hormonal therapy, endocrine therapy, progesterone, estrogen receptor modulator, and aromatase inhibitor. Results were then filtered to include the last 30 years (1993–2023). Phase II and III clinical trials in patients with advanced or recurrent endometrial cancer were included for review. Clinical trials were supplemented with the relevant literature on pathophysiology. ClinicalTrials.gov was then searched for the same terms to find ongoing or future studies. In this review, we aim to summarize the most relevant literature for hormonal therapy in endometrial cancer, including single-agent and combinations of progesterones, selective estrogen receptor modulators and degraders, aromatase inhibitors, as well as hormonal combinations with other targeted therapies. Additionally, we will discuss the current literature regarding hormonal receptor status and molecular testing as it relates to hormonal therapy. Lastly, we aim to preview the ongoing hormonally based clinical trials to give insight into some of the promising therapies of the future.When used alone, progestational agents such as medroxyprogesterone acetate (MPA) and megestrol acetate (MA) have shown modest activity in advanced or recurrent endometrial cancer. The most contemporary studies assessing single-agent progesterone include two studies by the Gynecologic Oncology Group (GOG). The first evaluated high-dose megestrol acetate (800 mg/d) in 63 patients with advanced or recurrent endometrial cancer that had either failed to respond or was considered incurable with local therapy and had not received prior cytotoxic or hormonal therapy; MA was found to have an overall response rate (ORR) of 24% with a clinical benefit rate (CBR) of 46%. The median progression-free survival (PFS) and overall survival (OS) were 2.5 and 7.6 months, respectively. Although the response rate of patients with low-grade tumors  was significantly higher than that of patients with high-grade tumors , there was no difference in response rates between cell types, including serous tumors. Grade 3 and 4 toxicities were rare (weight gain and hyperglycemia). Three deaths secondary to cardiovascular events were possibly related to therapy; diabetes was also a contributing factor in all three cases . In a seIn order to improve the modest responses to single-agent hormonal therapy and overcome hormonal resistance thought to be secondary to the down-regulation of progesterone receptors, combination hormonal therapy has been utilized. Selective estrogen receptor modulators (SERMs) lead to increased progesterone receptor expression, making them attractive for combination therapy . Pandya The GOG conducted two studies utilizing alternating treatment strategies to take full advantage of progesterone receptor upregulation by tamoxifen. The first study evaluated MPA (200 mg/d) and tamoxifen (40 m/d) given every other week in 61 patients with recurrent or metastatic disease not amendable to local therapy. The overall response rate was 33% (10% complete response rate), with median PFS of 3 months and median OS of approximately 13 months . In thisSingle-agent tamoxifen has been studied as one of the earliest non-progesterone, hormonally active agents in recurrent endometrial cancer, primarily in patients who had progressed on prior progesterone therapy. In an Australian study, single-agent tamoxifen was evaluated in 49 patients and found to have an ORR of 20%. The median overall survival of responders was 34 months, and the toxicity was minimal . The rolAromatase is an important hormonal enzyme that catalyzes the peripheral conversion of androgens to estrogens . AromataGiven the modest activity of aromatase inhibitors alone, they have been evaluated in combination with other therapeutic agents to improve efficacy. Specifically, AIs have been found to be complementary with targeted therapies that take advantage of downstream molecular pathways. In order to leverage the well-established crosstalk between the PI3K/AKT/mTOR pathway and hormonal signaling , the comIn addition to mTOR inhibitors, aromatase inhibitors are now being evaluated in combination with another class of targeted therapies, CDK4/6 inhibitors. CDK4/6 inhibitors have been studied extensively in breast cancer and have already gained regulatory approval. The first study published in endometrial cancer with the combination of letrozole and ribociclib, a third generation CDK4/6 inhibitor, showed that out of 20 ER+ endometrial cancer patients, 55% of patients were still on treatment at 12 weeks and 35% at 24 weeks. A total of 60% of patients had at least one grade 3 adverse event, the most common being bone marrow suppression and fatigue . RecentlGrade has long been the main predictive factor for response to hormonal therapy, with grade 1 tumors being most responsive and grade 3 being least responsive . More reAt this time, in addition to molecular classification, guidelines recommend estrogen receptor testing in the setting of advanced-stage or recurrent disease ,50. GiveHormonal therapy has long been an integral treatment modality and alternative to cytotoxic chemotherapy for endometrial cancer. Despite the long history, advances continue to improve the hormonal treatment options available to patients by increasing response rates, extending the duration of response, and overcoming resistance mechanisms. Though traditional hormonal therapy (progesterones and tamoxifen) will continue to be an option for many patients , the introduction of molecular classification has begun to transform the management of endometrial cancer. With this transformation, hormonal therapy will not only continue to be an important therapeutic option, but will be a vital component of future targeted therapy combinations as we have already started to see with mTOR inhibitors and CDK4/6 inhibitors. There are ongoing clinical trials to maximize the activity of combination therapies. The future of systemic treatment for recurrent endometrial cancer, like many cancers, is based on individualized targeted treatments based on molecular markers of each patient and each tumor. Based on what has been discovered regarding the molecular and genetic makeup of endometrial cancers, targeted therapies beyond mTOR and CDK4/6 have the possibility to increase activity when combined with hormonal therapy . High d


In the published article, as a result of an error in some of the calculations of physical activity variables, there were mistakes in [Abstract], [Results], [Paragraph 1]. This sentence previously stated:Furthermore, because of an error in some of the calculations of physical activity variables, there were some mistakes in the body text in article as published. A correction has been made to “Physical activity levels  Met-min/week: standardized B-coefficient −0.42 ) and grip strength  kg: standardized B-coefficient ) were lower in the Kuwaiti cohort, and the odds of having short sleep , being classed as inactive , and having muscle weakness  were higher.”The corrected sentence appears below:“Physical activity levels  and grip strength  kg: standardized B-coefficient  were lower in the Kuwaiti cohort and the odds of having short sleep , being classed as inactive  and having muscle weakness were higher .”[Abstract], [Conclusions], [Paragraph 1]. This sentence previously stated:In addition, a further correction has been made to “The aim of the current study was to determine the prevalence of low muscle strength and to evaluate physical activity and sleep characteristics in people with type 2 diabetes in Kuwait. Additionally, equivalent data from the UK Biobank cohort were compared”The corrected sentence appears below:“This study demonstrates that insufficient sleep, physical inactivity, and muscle weakness are prevalent in people with type 2 diabetes, especially in Kuwait. Importantly, these observations warrant urgent and effective interventions to improve sleep, muscle strength, and physical activity, especially in Kuwait.”The authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated.


Recent evidence suggests that stem cell therapy has beneficial effects on nerve damage. These beneficial effects were subsequently found to be exerted in part in a paracrine manner by the release of extracellular vesicles. Stem cell-secreted extracellular vesicles have shown great potential to reduce inflammation and apoptosis, optimize the function of Schwann cells, regulate genes related to regeneration, and improve behavioral performance after nerve damage. This review summarizes the current knowledge on the effect of stem cell-derived extracellular vesicles on neuroprotection and regeneration along with their molecular mechanisms after nerve damage. So far, stem cells with different origins and types have been used for in vitro Schwann-like cell generation and cell-replacement therapy, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSC), and neural stem cells (NSCs).,,,in vitro) or injection site (in vivo).,Functional impairment and long-term disability caused by nerve injury are among the major clinical and public health problems.This study is focused on the neuroprotective and regenerative effects of stem cell-derived EVs along with the molecular mechanisms responsible for these properties following nerve injury.2in vivo”, and “in vitro".The literature search was performed using PubMed and Scopus, supplemented with Google Scholar and reference lists of relevant articles based on articles published from 1951 to 2023. The key terms used (MeSH database) were “stem cell”, “extracellular vesicle”, “neural injury”, “clinical trial”, “2.1in vivo experimental investigations on the protective and regenerative benefits of stem cell-derived EVs against neuronal injury along with their molecular mechanisms have begun to accumulate, which are listed in in vitro) and synergistically improved nerve regeneration as well as sensory and motor function of the damaged sciatic nerve (in vivo).,NT−3) was loaded in nerve guidance conduit (ExoNT−3-NGC) to create a bridge in the damaged part of rat sciatic nerve. The results of this study indicated that ExoNT-3-NGC significantly accelerates the regeneration of the damaged nerve and improves gastrocnemius muscle function compared to the control. Li et al documented that intrathecally administration of the bone marrow mesenchymal stem cell-derived exosomes loaded with miR-150–5p alleviate mechanical allodynia through targeting neurogenic locus notch homolog protein 2 (NOTCH2) in microglial cells following L5 spinal nerve ligation model in rat.A growing number of 2.2in vitro studies have begun to accumulate on the neuroprotective effects of extracellular vesicles derived from stem cells and their underlying molecular mechanisms, which are listed in in vitro proliferation, migration, and neurotrophic factor secretion of Schwann cells.A few 2.3Despite the existence of several studies demonstrating the benefits of extracellular vesicles derived from stem cells as a cell-free treatment in experimental models of nerve injury, the application of this technology in clinical trial studies continue to be elusive and no reliable report has been presented in this field.3in vivo and in vitro preclinical studies. In this regard, it is mentioned that these beneficial effects are mainly caused by anti-inflammatory and anti-apoptotic effects, autophagy reduction, optimization of Schwann cell function, and regulation of regeneration-related genes. The results of these researches indicated that, in general, there is no significant difference between the use of the cells or their extracellular vesicles regarding the amount of nerve regeneration, although in some cases extracellular vesicles had better therapeutic effects. At the same time, delivery by non-invasive methods, crossing the blood–brain barrier and lack of tumorigenicity are among the advantages of extracellular vesicles derived from stem cells compared to stem cells themselves. However, additional preclinical studies are necessary to directly compare the efficacy of different sources and therapeutic doses of EVs, as well as different miRNAs-loaded EVs in another nerve injury models to reach a final accepted protocol with maximum benefits. On the other hand, due to the lack of data demonstrating the neuroprotective effects of stem cell-derived extracellular vesicles in human nerve injury, the design of clinical trial studies on the neuroprotective effects of extracellular vesicles and its possible mechanisms as well as the course of treatment and dose determination is needed. Because generalizing experimental studies to humans requires precision in the differences between animal and human models, such as disease characteristics, drug administration time, and drug efficacy. Another important point is the use of autologous or allogeneic sources of these vesicles, which requires more accuracy and investigation. Therefore, it may be because of these unclear and unresolved issues that clinical use of extracellular vesicles has not yet been reported.Currently, stem cell-derived extracellular vesicles have attracted the attention of researchers as a cell-free therapy due to their promising biological properties. The neuroprotective properties of extracellular vesicles derived from stem cells as a therapeutic option have been confirmed due to the results of several Nil.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Ras-related associated with diabetes (RRAD), a member of the Ras-related GTPase superfamily, is primarily a cytosolic protein that actives in the plasma membrane. RRAD is highly expressed in type 2 diabetes patients and as a biomarker of congestive heart failure. Mounting evidence showed that RRAD is important for the progression and metastasis of tumor cells, which play opposite roles as an oncogene or tumor suppressor gene depending on cancer and cell type. These findings are of great significance, especially given that relevant molecular mechanisms are being discovered. Being regulated in various pathways, RRAD plays wide spectrum cellular activity including tumor cell division, motility, apoptosis, and energy metabolism by modulating tumor-related gene expression and interacting with multiple downstream effectors. Additionally, RRAD in senescence may contribute to its role in cancer. Despite the twofold characters of RRAD, targeted therapies are becoming a potential therapeutic strategy to combat cancers. This review will discuss the dual identity of RRAD in specific cancer type, provides an overview of the regulation and downstream effectors of RRAD to offer valuable insights for readers, explore the intracellular role of RRAD in cancer, and give a reference for future mechanistic studies. Ras-related associated with diabetes  is a member of small GTP binding family of proteins within the Ras superfamily, sometimes referred to as the RGK family, which was first identified in type II diabetes patients because of its abnormally high expression ,2. As a Generally, the current studies on intracellular function of RRAD have been limited to specific cancer type. Tissue type plays a larger role in cancer genetics than previously realized, for example, drugs that target the drivers of proliferation will have variable efficacy depending on where the cancer is located. RRAD is found to play opposite roles as a tumor suppressor gene or oncogene in human cancers, depending on cancer and cell type. There has been no systematic summary based on the dual role of RRAD in cancer genesis, which would allow them to roundly review the position, function, and mechanism of RRAD.We reviewed 130 published papers related to this topic and provide a glimpse into the mechanism of tissue specificity in tumorigenesis of RRAD . This reDNA methylation within the promoter of genes, as one of the main epigenetic mechanisms, leads to decreased gene expression . Accumulating evidence suggests that the RRAD promoter is hypermethylated in human cancers, such as nasopharyngeal carcinoma ,18, breaRRAD is epigenetic silenced in cancer by histone demethylation. Pseudogene DUXAP10 is significantly upregulated in 93 human NSCLC tissues and cell lines, which are associated with patients’ poorer prognoses and short survival time. As a key downstream mediator of DUXAP10, RRAD is epigenetic silenced through the interaction of DUXAP10 and LSD1 in NSCLC cells . LSD1 alRRAD epigenetic silencing in cancer depends on more than changes in DNA methylation. BRG1/SMARCA4 is the only one of the two mutually exclusive ATPases in SWI/SNF chromatin-remodeling complex, which uses the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin ,50,51. LRRAD silence results from transcription factor inactivation. RRAD is a direct transcriptional target of p53 and NF-κB, and the activation of p53/NF-κB leads to upregulation of RRAD ,60. MultPrevious work identified RRAD as an early growth response protein 1/2 (EGR1/2) target gene, and EGR expression levels are positively related to RRAD expression levels in prostate cancer . CorepreNAB2 and CHD4 colocalize to an EGR2 binding site 90 bp upstream of the start site within the RRAD promoter. To repress activation of EGR2 target RRAD transcription, CHD4-interacting domain (CID) of NAB2 recruit the nucleosome remodeling and deacetylase (NuRD) complex and associate with its chromodomain helicase DNA-binding protein 4 (CHD4 subunit). The repression through the CID is dependent on histone deacetylases (HDAC), subunits of the NuRD complex, which impede dissociation of DNA from histone octamer .The role of RRAD is not necessarily independent; the regulation and downstream targets of RRAD as tumor suppressor gene may interact with each other .RRAD can negatively regulate TNFα-stimulated NF-κB pathway which promotes GLUT1 translocation. In lung cancer, RRAD directly bounds to the subunit p65 in the NF-κB complex and negatively regulates the activation of NF-κB by inhibiting p65 translocate to the nucleus ,42. The Inhibiting the phosphorylation of p65 subunit in the NF-κB complex can also negatively regulate the activation of NF-κB . In a reRRAD lowers cell proliferation, arrests the cell cycle, and increases apoptosis by binding and downregulating ACTG1 which acts as a functional downstream effector of RRAD in HCC cells. Expression of RRAD is low when ACTG1 is overexpressed in HCC tumor specimens and is linked to poor prognosis . ACTG1 pRRAD disturbs cancer cell migration through Rho signaling pathway by binding to 14-3-3 and ROCK (Rho-associated protein kinase), thus interfering in the abundance of pSer3-cofilin that is a regulator of actin dynamics in NSCLC cells . ROCK isRRAD decreases energy utilization efficiency of cancer by inhibiting the Warburg effect. Altered metabolism includes increased glucose uptake, and fermentation of glucose to lactate is observed even in the presence of completely functioning mitochondria, which is known as the Warburg Effect . It has As oncogene, RRAD participates in various molecular pathways and promotes cancer progression by facilitating cell proliferation and migration .RRAD promotes malignant glioma progression via endosome-mediated epidermal growth factor receptor (EGFR)/STAT3 signaling . AlthougRRAD modulates cancer cells’ proliferation and motility by directly interacting with CaM, CaMKII , and β-tFurthermore, in Tseng, Vicent et al. ’s study, the function of RRAD, is blocked by the co-expression of nm23, and in addition, similar effects are also seen when these cells are injected into nude mice . RRAD exRRAD binds and inhibits Grap2 and cyclin D interacting protein (GCIP), a cell cycle-inhibitory molecule, to promote carcinogenesis. Lee, Yeom et al. have demonstrated that RRAD binds directly to GCIP in vitro and coimmunoprecipitates with GCIP from cell lysates. RRAD translocates GCIP to the cytoplasm and inhibit the tumor suppressor activity of GCIP, which ultimately increases Rb phosphorylation and upregulates cyclin D1 .Although RRAD is mainly found as a negative regulator of Warburg effect, Kim, H.K. first found the level of lactate was decreased without increasing uptake of glucose when transfected with siRRAD in GC or CRC, which suggests that RRAD may be a positive regulator of the aerobic glycolysis . This opCellular senescence is a state of irreversible growth arrest in cells with a variety of stresses that could lead to transformation, and senescent cells are observed as the first barrier against tumorigenesis in precancerous lesion . HoweverRRAD is the first reported p53 target gene that functions to impede cellular senescence. It is possible that in the context of oncogenesis, RRAD downregulation may promote cellular senescence and consequently reduces apoptosis by increasing the level of reactive oxygen species (ROS) . DiffereRRAD may also restrain senescence by inhibiting the function of NF-κB that usually upregulates in senescent cells and promotes senescence. As senescent cells also favor glycolysis for the high-efficient output of biosynthetic precursors similar with tumor cells . RRAD liIn addition, cell senescence is associated with cell cycle inhibitors . Rb phosRRAD hypermethylation is mediated by RasV12 oncogenic transformation . WhetherIn view of its pro-tumorigenic role in cancer, RRAD may serve as a promising target for therapeutic intervention. Based on screening analyses, five classes of drugs were determined as potent inhibitors of RRAD-expressing glioblastoma, including antitussive agents(oxeladin), anthelmintics (AH), microtubule inhibitors (MI), and topoisomerase inhibitors (TI). However, owing to the nonspecific cytotoxicity (MI/TI) and efficacy (AH) against cancers, Lee, Yeom demonstrated that RRAD inhibition results from the hydrogen bonding between oxeladin and the Gln250 of RRAD, and the pi-pi stacking interactions of oxeladin with the Lys228 or Arg249 of RRAD . ComponeRRAD functions as an oncogene or tumor suppressor gene depends on different cancer. The expression level of RRAD can be modulated epigenetically and by multiple transcription factors, which is associated with cancer progression. In addition, RRAD interacts with diverse downstream effectors to play the dual roles in cancer genesis. It can regulate cell cycle transition, cytoskeletal stability, cell motility, and the tumor micro-environment composition, thus influencing tumor progression and metastasis.In conclusion, by reviewing the intracellular role of RRAD in cancer genesis, we summarized the detailed function of RRAD in specific cancer and cell type, providing an overview of regulation mode and downstream targets of RRAD in both tumor suppressing and oncogenic aspect. We hope that these descriptions can help readers further understand the role of RRAD in cancer cell progression, explore the genetic changes that underlie human cancer, and provide practical ideas for targeted therapy for the disease.


In 2020 Global Poverty Monitoring saw the largest one-year increase since its beginning, with an increase of 11% of people living below extreme poverty (from 648 million to 719 million). The economic impact brought by COVID-19, apace with ongoing wars and conflicts, has created a bigger setback toward progress. Low income countries (LIC) and lower middle income countries (LMIC) suffered the highest increases in extreme poverty due to restrictions, as many households, already impoverished before the pandemic, lost their income  allele against heavy burdens of diarrhea in weaning-age children living in adverse environments and poverty in developing countries  is polymorphic and harbors three common alleles: APOE2, APOE3, and APOE4, coding distinct isoforms with changes in amino acids at position 112 and 158, which influences the protein's function and stability  mice infected with Cryptosporidium parvum, a protozoon commonly associated with diarrhea in children living in endemic areas of malnutrition, showed a more regulated inflammatory response and more efficient pathogen elimination with higher levels of Toll-Like receptor 9 (TLR9) transcripts which are mediators of the innate immune system against Cryptosporidiosis  in the ileum, and this may promote a better intestinal barrier function, mucosal blood flow and repair  and glucose levels and decreased cognitive performance   rs429358 and rs7412 are linked with ischemic cerebral infarction contributing to cerebrovascular diseases in the pathophysiology of many cases of dementia , this deposit being more severe in the presence of the E4 isoform, as demonstrated in studies with transgenic mice for the gene, in addition to the absence of apoE reducing the β-amyloid deposit   would impact brain development in children and adults living in adverse environments and poverty. Caution should be taken as neurodegenerative diseases are complex and multifactorial borne conditions, however, under certain aggravating circumstances, APOE4 and COVID-19 may be strong drivers toward neurodegeneration.There is still a gap of knowledge in addressing whether APOE4 carriers chronically exposed to adverse environments and limited access to healthcare. Embedding genomics into routine public health practice in LIC and LMIC groups will provide accurate information regarding the stratification of molecular markers and assist in early intervention.In summary, we call for awareness of the potential public health issue of long COVID-19 as a cumulative risk factor for neurodegenerative diseases in All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.