Although many studies have investigated the role of cytokines in bone metastases, our knowledge of their function in spine metastasis is limited. Therefore, we performed a systematic review to map the available evidence on the involvement of cytokines in spine metastasis in solid tumors. A PubMed search identified 211 articles demonstrating a functional link between cytokines/cytokine receptors and bone metastases, including six articles confirming the role of cytokines/cytokine receptors in spine metastases. A total of 68 cytokines/cytokine receptors were identified to mediate bone metastases; 9 (mostly chemokines) played a role in spine metastases: CXC motif chemokine ligand (CXCL) 5, CXCL12, CXC motif chemokine receptor (CXCR) 4, CXCR6, interleukin (IL) 10 in prostate cancer, CX3C motif chemokine ligand (CX3CL) 1 and CX3C motif chemokine receptor (CX3CR) 1 in liver cancer, CC motif chemokine ligand (CCL) 2 in breast cancer, and transforming growth factor (TGF) β in skin cancer. Except for CXCR6, all cytokines/cytokine receptors were shown to operate in the spine, with CX3CL1, CX3CR1, IL10, CCL2, CXCL12, and CXCR4 mediating bone marrow colonization, CXCL5 and TGFβ promoting tumor cell proliferation, and TGFβ additionally driving bone remodeling. The number of cytokines/cytokine receptors confirmed to mediate spinal metastasis is low compared with the vast spectrum of cytokines/cytokine receptors participating in other parts of the skeleton. Therefore, further research is needed, including validation of the role of cytokines mediating metastases to other bones, to precisely address the unmet clinical need associated with spine metastases. Cancer metastasis is a complex process that involves access to the systemic circulation, cell migration, loss of intercellular cohesion, angiogenesis, and evasion of local immune responses. Bone metastases are common in cancer and typically predict poor prognosis. There are certain cancers with a high prevalence of bone metastases, namely prostate 85%), breast (70%), lung and kidney 40%, both) . The mos0%, both %, breastCancer cell diffusion through the venous system, mostly via Batson’s venous plexus, is the major route of spinal metastasis; more rarely, dissemination occurs via the arterial system and by contiguity . PrefereSecondary bone cancers can be divided into osteolytic and osteoblastic lesions ,8. OsteoThe preferential spread of cancer to some organs has been elegantly illustrated by the seed and soil hypothesis formulated by Stephen Paget . Paget’sFollowing endothelial transmigration and the dissemination of cancer cells into the blood system, the multi-step process of metastasis to the bone involves (i) the colonization of the bone marrow by circulating tumor cells, followed by (ii) a dormancy period when cancer cells enter a quiescent state after adapting to the bone marrow microenvironment, (iii) the reactivation of dormant cells and subsequent proliferation, and (iv) reconstruction of the bone tissue by cancer cells . A vast Therefore, a vast number of cytokines appear to mediate each step of the bone metastasis process, from colonization to bone tissue remodeling. Although a large number of studies investigated the role of cytokines in bone metastases, our knowledge of their function in spine metastasis is limited. In particular, the current literature lacks a complex overview of the involvement of cytokines across the four major steps of metastasis to the spine outlined above. Therefore, we performed a systematic review to map the available evidence on the role of cytokines in the metastasis of solid tumors to the spine and to systematize their involvement in the cancer cell invasion, dormancy, proliferation, and remodeling of spine tissue.The present review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement: an updated guideline for reporting systematic reviews . The proWe systematically searched all publications from PubMed until 30 April 2022 without any restriction to language. The terms “bone metastases” and “cytokines” were used. Abstracts identified by the search were screened, and articles found to be relevant to the topic of interest were shortlisted. All articles except reviews and case reports were considered. Full-length papers demonstrating a functional link between cytokine and bone metastases and spine metastases, in particular, were included in the final systematic review. WŁ and ŁK independently reviewed abstracts and full-text articles. Disagreements were resolved by discussion between the two reviewers.The database search yielded 2413 records, including 1903 original research articles . OverallThe extracted data included the name of the first author, publication year, type of primary tumor, name of the cytokine or cytokine receptor, study setting and findings.In total, 68 cytokines/cytokine receptors were identified to play a role in bone metastases in 12 types of cancer, most often in breast and prostate cancers  patients have an increased expression of chemokine CX3CL1 and its receptor CX3CR1 in spinal metastases . An anal−/− mice. Conversely, overexpression of CX3CR1 in human breast cancer cells increases homing to the bone by mediating both adhesion to the endothelium and extravasation. Moreover, serum samples from patients with spinal metastases from the lung, kidney, and prostate contained significantly higher levels of CX3CL1 than in healthy controls, which suggests the potential involvement of CX3CL1 in these types of cancer [CX3CR1 is also expressed on breast cancer cell surfaces . The disf cancer . StudiesIL10 was shown to inhibit the growth of primary prostate tumors and metastases in prostate cancer ,27. The The expression of the chemokine CCL2 was shown to be reduced in a highly metastatic variant of murine mouse breast cancer 4T1E cells . Overexp−/− animals. The role of the CXCL12/CXCR4 system in bone metastasis in prostate cancer has been confirmed in several in vivo studies utilizing specific inhibitors and transgenic mice [CXCR6 ligand CXCL16 facilitates mesenchymal stem cell recruitment into prostate tumors and their subsequent conversion into cancer-associated fibroblasts . In turnnic mice ,35,36,37nic mice . Interes−/− mice injected with human small-cell lung cancer cells [Moreover, the interaction between CXCL12 and CXCR4 seems to be crucial not only for the homing of prostate cancer cells to the bone but also for overcoming tumor resistance to chemotherapy. Inhibition of CXCR4 by plerixafor sensitized metastatic bone tumors to docetaxel could have a profound impact on clinical practice since all metastatic castration-resistant prostate cancer patients eventually develop resistance to taxanes . Therefoer cells .−/− mice, indicating that CXCL5 mediates the expansion of prostate cancer cells in the spine. Mechanistically, the efferocytosis of prostate cancer cells by macrophages induces expression of CXCL5, resulting in inflammation and immunosuppression, which stimulates tumor growth (see Roca et al.  demonstrowth see . FurtherTGFβ operating in the vicious cycle of bone destruction and cancer cell proliferation acts on breast cancer cells to secrete PTHrP, which subsequently induces the release of RANKL from osteoblasts. In turn, RANKL activates osteoclasts, resulting in bone resorption, which causes the activation of latent TGFβ deposited in the bone matrix. This newly activated TGFβ stimulates cancer cells in a feed-forward mechanism, resulting in the amplification of bone tissue remodeling ,47, see . InhibitTGFβ has also been implicated in bone metastases in other types of cancer, including breast, prostate, kidney, and lung. The elevated expression of TGFBR1 and the activation of TGFβ signaling has been observed at the tumor–bone interface in breast cancer . The inhSpine metastases lead to significant morbidity, reduction in quality of life and worse prognosis. Considering that the spine is one of the most common locations of metastases in several types of cancer, the involvement of the spine is a significant health problem. To improve patient functioning and quality of life, vertebral metastases are frequently managed by surgery, radiotherapy or systemic therapy. Bisphosphonates are currently the standard of care systemic therapy aiming to reduce bone loss; however, their use is associated with considerable side effects and rather limited efficacy. Therefore, new treatments are urgently needed to effectively manage metastatic disease in the spine.This systematic review is the first to summarize the available evidence on the functional role of cytokines and their receptors in the pathogenesis of spine metastases in solid tumors. Although during the review of records, we identified 68 cytokines/cytokine receptors to mediate bone metastases in 12 types of cancer, only 9 cytokines/cytokine receptors in four types of cancer appeared to play a role in metastases to the spine. This certainly does not indicate that spine metastasis is driven by only these nine cytokines/cytokine receptors. Instead, secondary cancer in the spine seems not to be specifically investigated or reported on by research studies, which is puzzling given the unmet clinical need caused by the morbidity and mortality associated with spine metastases. The fact that more cytokines/cytokine receptors have been established to play a functional role in bone metastases compared to the spine is a solid foundation for validation studies focused on the spine. An alternative explanation for the striking disproportion in the numbers of cytokines mediating bone and spine metastases could be that our search strategy was unable to identify all relevant records. For example, our broad search query did not return two clinical trials demonstrating a reduced incidence of new spine metastases in breast or prostate cancer patients treated with denosumab ,17. NeveIn conclusion, the functional role of cytokines in spine metastases remains underexplored, and most of our understanding of this process appears to be derived from studies on other parts of the skeleton. The number of cytokines confirmed to mediate spinal metastasis is low compared with a vast spectrum of cytokines demonstrated to participate in the formation of secondary tumors in other parts of the skeleton. Additionally, it is unknown whether cytokines in the primary tumor could predetermine the homing of tumor cells to the spine. Therefore, further research is needed, including validation of the role of cytokines mediating metastases to other bones, in order to precisely address the unmet clinical need associated with spine metastases.


MesoAmerican endemic nephropathy is a type of chronic kidney disease highly prevalent in hot ambient climates from southwest Mexico through Latin America. There is growing evidence that this public health crisis is being spurred by greater fructose consumption in the face of dehydration and increased dehydration-dependent vasopressin secretion. Work is needed at unraveling the mechanism(s) by which fructose consumption and increased AVP levels can worsen the renal disease associated with components of the metabolic syndrome.We review the pathways by which arginine vasopressin (AVP) and hydration influence the sequelae of the metabolic syndrome induced by high fructose consumption. AVP and inadequate hydration have been shown to worsen the severity of two phenotypes associated with metabolic syndrome induced by high fructose intake–enhanced lipogenesis and insulin resistance. These findings have implications for those who frequently consume sweeteners such as high fructose corn syrup (HFCS). Patients with metabolic syndrome are at higher risk for microalbuminuria and/or chronic kidney disease; however, it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from those of hypertension, impaired glucose metabolism, and obesity. It is not surprising the prevalence of chronic renal insufficiency is growing hand in hand with obesity, insulin resistance, and metabolic syndrome in those who consume large amounts of fructose. Higher AVP levels and low hydration status worsen the renal insufficiency found in patients with metabolic syndrome. This inter-relationship has public health consequences, especially among underserved populations who perform physical labor in environments that place them at risk for dehydration.  High fructose corn syrup (HFCS) is a manufactured sweetener that contains a mixture of the monosaccharides, glucose and fructose, in varying ratios . In “sweetness,” HFCS is similar to cane sugar (sucrose), a disaccharide first hydrolyzed in the small intestines before systemic absorption; however sucrose digestion yields glucose and fructose in equal parts  are irreversible molecular adducts, damaging to cells, that are formed from the nonenzymatic reaction between reducing sugars such as fructose and glucose with proteins or lipids. Whereas, glucose contains an aldehyde, fructose has a ketone group which makes it even more reactive with amines found in proteins (the non-enzymatic “Maillard reaction”) . Second,peripheral circulation from axon terminals within the pituitary, and also, the parvocellular system with axons projecting to the median eminence of the hypothalamus where AVP is secreted into the pituitary portal circulation  is now being implicated in the development of metabolic syndrome. AVP is produced by two groups of cells—neurons of the hypothalamic paraventricular nuclei (PVN) and the supraoptic nuclei (SON). These neurons are divided into either the magnocellular system secreting AVP into the culation , 14. Thrsduction  15–17).–17.perip1b dependent manner, and repetitive stress is associated with the development of the metabolic syndrome  levels in patients with diabetes  and central (mediated by activation of Vb1 receptors and the stress response) mechanisms by which AVP contributes to hyperglycemia and the metabolic syndrome.AVP has been shown to stimulate of hepatic gluconeogenesis and glycogenolysis through the activation of hepatic Vdiabetes . It is lsyndrome . In summb1 receptor plays a critical role in regulating hypothalamic-pituitary-adrenal axis activity by contributing to pituitary ACTH secretion and corticosterone release from the adrenal gland levels under basal and stress conditions -stimulated ACTH release is not impaired. Vasopressin levels and Vb1 receptor expression were elevated in rodents with exposure to chronic stress, and the measured increase in ACTH after stress  has been found to be significantly suppressed in Vb1 receptor null mice  and metabolized in the liver while glucose, transported by GLUT1 and GLUT3, is metabolized primarily in the brain . AccordiThe potential potentiation of the metabolic syndrome from chronically increased levels of AVP, albeit at low levels, and increased fructose consumption has significant public health implications (Mesoamerican endemic nephropathy is a type of chronic kidney disease of unknown origin that is highly prevalent among manual laborers from southwest Mexico through Latin America (2 (2 (ications . This isications , 52. Ind America , 54. In erica (2 . Similarca (2 (2 . As a chca (2 (2 . The Panca (2 (2 .The increased consumption of sweetened beverages is associated with urbanization and economic growth. As such, more intensified policy efforts are needed to ensure that hydration occurs with water, not through sweetened beverages that increase the intake of sugar and, subsequently, increase the global burden of obesity and chronic diseases. There is growing evidence that hydration with beverages sweetened with high fructose corn syrup potentiates the renal insufficiency found in those who must toil in high ambient temperature climates. However, as any traveler to an underdeveloped country has observed, the advertising for sugar sweetened beverages is ubiquitous, equaled only by the fervent pitches for various cell phone carriers. In the United States, it is estimated that the average American consumes roughly 54.7 g of fructose per day and nearly 30 kg of carbohydrate each year from added sweetners , 60. In normal rodent kidneys (In a study with laboratory rodents pair fed a diet containing 60% fructose, 60% dextrose, or standard rat chow, the fructose fed rats had worse outcomes in a reduced renal mass model of chronic kidney disease. Proteinuria was increased and creatinine clearance was diminished in the rodents fed fructose when compared to glucose- and control-fed rodents. Glomerulosclerosis, tubular atrophy, tubular dilatation, and inflammation were all greater in the fructose fed rats . The tox kidneys . Endogen kidneys . In a st kidneys .Fructose can directly stimulate AVP release or induce the secretion of AVP by the hyperosmolarity generated by increasing sorbitol concentrations via the polyol pathway. Conversely, genetic ablation of fructokinase diminishes AVP secretion induced by dehydration . Given ta1 and V2 renal receptors, the polyol fructokinase pathway, and increased renal oxidative stress with reduced expression of antioxidant enzymes. Hydration with an unspecified 11% glucose/fructose sweetened beverage significantly amplified those alterations, and it is suggested that current habits of re-hydration with sweetened beverages could be a risk factor in developing kidney damage (Many of these findings have been supported by additional study. Fluid restriction followed by water hydration mildly increased urine osmolality and induced a 15% decrement in creatinine clearance while increasing two markers of tubular damage, urinary N-Acetyl-β-D-glucosaminidase and kidney injury molecule-1. These changes were accompanied by overexpression of Vy damage .The findings in rodents regarding fructose and renal injury have been recapitulated in men and women. In one study of 12 healthy adults, subjects drank 2 liters of a fructose containing soft drink or water during 4 h of exercise. Serum creatinine increased ≥0.30 mg/dl post exercise in 75% of participants in the soft drink trial compared with 8% in water trial, which is consistent with the Kidney Disease Improving Global Outcomes definition of acute kidney injury . ChangesIn summary, it is suggested that high fructose corn syrup acutely increases vascular resistance in the kidneys with simultaneous elevations in circulating uric acid and vasopressin . There aAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported, in part, by the Department of Defense and Henry M. Jackson Foundation for the Advancement of Military Medicine, HU0001-18-2-0016, HJF Award, 309833-1.00-65546.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Gamete quality and assisted reproductive technology (ART) outcomes” has collected cutting-edge original research on these key topics from an interdisciplinary perspective, representing the current research progress in this dynamic and central discipline. The Research Topic currently includes four papers.One of the most astonishing processes in nature is the creation of a new individual from two single superspecialized cells; the oocyte and the sperm. Gamete quality and fertilization process is of great interest to the general population and has wide implications for human health. Although outstanding research has been in this area, many questions remain unanswered. For example, why reproductive health seems to be declining over the last few years? . This prMicroRNA-targeting in male infertility: Sperm microRNA-19a/b-3p and its spermatogenesis related transcripts content in men with oligoasthenozoospermia,” Abu-Halima and collaborators add some spark to the role of sperm microRNAs (miRNAs) in infertility . Several papers reported on the essential role of sperm miRNAs for spermatogenesis and early embryo development  or the lower expression of target genes are associated with oligoasthenozoospermia and probably with male infertility.Firstly, in “elopment , howeverThe capacity to repair sperm DNA damage in zygotes is enhanced by inhibiting WIP1 activity,” the authors suggested a central role of wild-type p53-induced phosphatase 1 (WIP1) in paternal DNA reparation in zygotes . In their research, Leem et al., added a specific WIP1 inhibitor (GSK2830371) in oocyte culture medium after the ICSI procedure and compared it with oocytes treated with DMSO (controls). While it was known that sperm DNA damage may be repaired after fertilization in zygotes, using maternal DNA repair factors , and oxidative stress (using the MiOXSYS system). Researchers described Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes as the most abundant phyla in seminal plasma and reported that their results were consistent to previous studies (Moraxella, Brevundimonas, and Flavobacterium negatively correlate with sperm DNA fragmentation, Brevundimonas correlate with lower oxidative-reduction potential, and Actinomycetaceae, Ralstonia, and Paenibacillus correlated with a chromatin protamination status reduction and increased double-stranded DNA fragmentation. These novel findings support the hypothesis that the seminal microbiome may have an important role in male fertility, but further studies are needed to elucidate whether its effects can be overcomed.Thirdly, in the paper entitled “ studies . MoreoveXu et al. investigated the “Impact of elevated progesterone in late follicular phase on early pregnancy outcomes and live birth rate after fresh embryo transfers” retrospectively in a large cohort of patients who underwent IVF/ICSI treatment cycles. It is well accepted that progesterone treatment is a good practice in ART cycles (Finally, T cycles , but whaFrontiers in Cell and Developmental Biology shows the great effort of the scientific community in drawing a broad picture of the role of both male and female gametes in fertility and ART outcomes. In general, this Research Topic has revealed that sperm miRNAs, sperm DNA fragmentation, seminal microbiota, and time and concentration of progesterone during IVF/ICSI treatments are determinant factors for fertility. Incredible challenges and opportunities have been opened thanks to these contributions. To ensure continued progress in the field well-designed and well-funded studies are required to make significant strides.The wide range of subjects of this Research Topic in


The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common cortical malformations and their manifestation in the human brain. Understanding the origins of higher cortical functions and their malfunction in developmental diseases requires delineating how brain areas are formed during development. It has been long appreciated that the human brain is composed of defined areal and laminar structures that differ in composition ,2,3,4. TThe first indication of the developing human central nervous system (CNS) appears in the third week of human embryonic development in a process termed neurulation. A plate of thickened ectoderm appears in the mid-dorsal region of the tri-laminar embryo, the neural plate. The formation of the anterior neural plate, which will give rise to the forebrain, is induced by signals from the prechordal plate (PrCP), a cell population that originates from the mesendoderm and migrates rostrally from the primitive node along the midline between the ectoderm and the endoderm layers. In a series of extensive morphogenetic movements, the neural plate bends inwards to generate a tubular structure with open neural folds, then brought together at the dorsal midline to generate the neural tube  and dorsal–ventral (DV) axes of both the spinal cord and the anterior structures of the CNS is governed by the production of instructive molecules—morphogens—that are expressed by small cell populations, often referred to as patterning centers or organizers. A fundamental question is how positional information is conveyed and interpreted by the cells to express subsets of transcription factors that will execute the developmental fate. A model for the interpretation of morphogens areal information into distinct cell fates was proposed by Wolpert (the French flag model) . AccordiThe anterior neural ridge (ANR) is an example of an organizing center that governs forebrain patterning via positional information. The ANR is a temporary structure located at the most-rostral edge of the neural plate a. The ANSimilarly, ablation of the ANR or loss of Fgf8 in the anterior neural plate cells of zebrafish embryos resulted in a distorted telencephalon with abnormal morphology, altered gene expression, and axonal misprojection . FurtherFollowing the formation of the left and right telencephalic vesicles, the mediolateral axis of their dorsal cortical primordium develops into two signaling centers: the hem and the anti-hem. Both centers flank the cortical neuroepithelium and express different types of signaling molecules. The cortical hem expresses Wingless (Wnt) genes  and bone morphogenetic protein (BMP) genes  and serves as the organizer of the hippocampus. Indeed, the induction of ectopic hem structures adjacent to Lhx2 null cells can produce multiple hippocampal fields ,28. The In addition to FGF, BMP, and Wnt signals governing the AP and mediolateral patterning of the dorsal telencephalon, additional signaling factors participate in the patterning of the ventral and the lateral telencephalon. Sonic Hedgehog (Shh), a morphogen known for its graded function in the ventral spinal cord, has been shown to work in two phases during forebrain development. In the early stage, Shh is expressed in the PrCP and mediates the initiation of forebrain development from the anterior neural plate as well as the subdivision of the anterior prosencephalon into left and right vesicles. Next, the early Shh signal triggers a secondary induction activity in the forebrain, where it will sequentially specify the progenitors of the medial ganglionic eminence (MGE) and, later, of the lateral ganglionic eminence (LGE) c 29]..29].Retinoic acid (RA), a metabolite of retinol (vitamin A), functions as a ligand for nuclear retinoic acid receptors (RARs), which regulate the expression of numerous downstream target genes during both early embryogenesis and adulthood. Early in development, RA appears in a morphogenic gradient  established by an interplay between diffusion gradients and localized RA metabolism, thereby allowing RA to control the patterning of various structures . RA is lAn essential principle in forebrain induction and patterning is that signaling molecules, such as those mentioned, do not work independently but rather display an intricate regulatory network. Different secreted morphogenetic molecules in and around the patterning centers govern direct or indirect interactions between multiple signaling pathways and their downstream transcription factors. For instance, Fgfs, expressed at the ANR, are regulators of mid-line patterning and antagonize Wnt and BMP of the cortical hem . At lateFinally, while the local AP planar induction sets up a transverse regionalization of the major forebrain parts, DV patterning along the neural tube is also fundamental for defining longitudinal zones. The best-studied DV patterning of cellular and molecular events in the CNS is that that shapes the hindbrain and the spinal cord DV axis, in which distinct neuronal subtypes emerge from pre-patterned progenitor domains at a defined location along the DV axis ,38,39,40The cerebral cortex has an intrinsic functional architecture critical for its proper performance. It is derived from the dorsal and ventral telencephalon. The dorsal telencephalic domain gives rise to the significant neuronal population that will occupy the brain, the excitatory neurons, while the ventral telencephalon includes the ganglionic eminences (GE) from which the minor population of GABAergic interneurons originates. The emergence of different functional areas results from orchestrated events discussed elsewhere ,44.Cortical development involves several modes of migration during which cells move away from their place of birth. Migratory events are generally categorized based on their general movement pattern  or by the characteristic morphological or dynamic behavior of the migrating cells . An important example of how cell migration shapes the brain is that of the early-born neurons, the Cajal–Retzius cells (CRs). CRs are one of several transient cell populations in the developing brain  and spreThe primordial progenitors of the cortex are the neuroepithelial cells (NECs). NECs are elongated cells that span the entire thickness of the neuroepithelium from the ventricular  surface to the laminal  side ,49 Figu. During This cyclic motion, termed interkinetic nuclear migration or motion, was first discovered by Schaper in 1897 and re-discovered by Sauer in 1935 ,53,54. LNotch is a central signaling pathway that acts at several key time points during corticogenesis, ensuring progenitor pool expansion and maintenance, differentiation and neurogenesis, as well as folding of the cortex. The Notch pathway was first identified in the fruit fly and is highly conserved . DecadesEarly studies showed that forced activation of Notch signaling (NICD expression) in the mouse forebrain promoted radial glia identity , pointinNotch activity suppresses neurogenesis and promotes the maintenance of neural precursors by activating canonical Notch target genes, Hairy/Enhancer of Split (HES), and Hairy/Enhancer of Split related to the YRPW motif (HEY) . This weFinally, Notch activity was linked to the evolutionary expansion and folding of the human cortex. Disturption of neurogenic symmetry, regardless of bRG expansion, is suggested to allow cortical folding. This is achieved by local disruption of Notch activity while maintaining niches of sustain Notch activity . Three pAs radial migration proceeds, early-born neurons will generally contribute to the deep layers, whereas late neurons will migrate through the earlier neurons to form the more superficial layers . This orOne group of human genetic diseases that exhibits aberrant signaling related to brain patterning is holoprosencephaly (HPE) ,91,92,93The genetic etiology of HPE is highly heterogenous and may exhibit a highly variable phenotype. Different cytogenic abnormalities are a leading cause of HPE among live-born patients, and the most prominent ones are trisomy 13 and trisomy 18 . MutatioThe four major mutated genes in HPE are SHH, ZIC2, SIX3, and FGFR1 . SHH wasMutations in the transcription factor ZIC2 are common in HPE. Mice with hypomorphic alleles exhibit middle interhemispheric variant HPE ,121.ZIC2 has been suggested to act downstream of NODAL, a secreted member of the transforming growth factor ß (TGF-ß) family, as it is essential for stabilizing the epiblast state and the specification of mesoderm and endoderm, including the PrCP mesoderm, whose instructive functions were discussed. Nodal signals as a heterodimer with TGF-ß family members GDF1/3 and the activated receptor complex phosphorylates the signal transducers Smad2/3 at their C-terminal. ZIC2 possibly acts by direct interaction with SMAD2 and SMAD3 . In addiMutations in SIX3 are another leading cause of HPE . SIX3 isMicrodeletions and missense mutations in 5′-TG-3′-interacting factor (TGIF) also result in HPE. TGIF interacts with several pathways that are important in the developing brain. TGIF regulates the TGFb/Nodal signaling pathway and SHH signaling independently . In addiBMP signaling has a clear role in brain patterning. Nevertheless, so far, there are no specific mutations in HPE patients related to this pathway. However, several mouse mutants are exhibiting HPE-like phenotypes with mutations in genes associated with this signaling pathway. These mutations include BMP receptors , chordinMutations in additional genes causing HPE include proteins with several known functions that are likely to regulate the signaling pathways, as mentioned earlier. However, direct connections are yet to be identified. Mutations in CNOT1 that encode for a subunit of the CCR4–NOT Transcription Complex Subunit 1 result in HPE ,144. MutConsistent with the known functions of RA, loss of RA signaling in the developing fetus has detrimental effects on early arealization and later neurodevelopmental processes. Mutations in genes involved in RA signaling have been implicated in a wide range of diseases, including cancer, metabolic disorders, eye development, retinal function, and neurodegenerative diseases ,152. MutInterestingly, abnormal RA signaling is not exclusively the result of a genetic mutation. Exposure of developing fetuses to alcohol is known to cause congenital disabilities and intellectual and neurodevelopmental disabilities. Fetal alcohol syndrome (FASD) was first described in the early 1970s as a specific cluster of congenital disabilities resulting from chronic prenatal alcohol exposure. In the case of the severe form of FASD, the patients have craniofacial malformations , a high prevalence of microcephaly, prenatal and postnatal growth restriction, and central nervous system neurodevelopmental abnormalities . FASD isThe connection between ethanol metabolism and retinol arises from the biochemical similarity between ethanol clearance from the body and RA biosynthesis ,159. EthIn the mature brain, the areal organization can be manifested in differences in the cytoarchitecture, cell number, cell density, and lamination in different brain areas. Histological differences define anatomical subdivisions rooted in the developmental phases of forebrain development. They may result in differential sensitivity to pathological mutations or variations in gene dosage that dictate the disease phenotype.The lissencephaly–pachygyria spectrum of diseases defines a variety of brain malformations that cause relative smoothness of the brain surface and includes lissencephaly (smooth brain surface), agyria (no gyri), and pachygyria (broad gyri) . These bSeveral of the lissencephalies exhibit area-specific severity of the phenotype ,162. In LIS1, Lissencephaly 1 [DCX, Doublecortin [LIS1 mutations result in a more severe phenotype in the parietal and occipital cortex, whereas in the case of mutations in DCX, the malformation is more pronounced in the frontal cortex [ARX [KIF2A [MACF1 [DYNC1H1 [TUBA1A [TUBG1 [TUBB2B, TUBB3 [TUBB5 [TUBA8 [Regional severity has been noted in lissencephaly caused by mutations in ephaly 1 , or DCX,lecortin ,166. LISl cortex ,168. A stex [ARX ,170, KIFX [KIF2A , MACF1 [A [MACF1 , DYNC1H1[DYNC1H1 ,174,175. [TUBA1A ,177,178,A [TUBG1 , TUBB2B,B, TUBB3 , TUBB5 [3 [TUBB5 , TUBA8 [5 [TUBA8 . Mutatio5 [TUBA8 . A diffe5 [TUBA8 .ACTG1 [ACTB [CRADD [RTTN [Anterior-to-posterior increased severity also involves genes of the actin superfamily of proteins: ACTG1 , ACTB [1G1 [ACTB ,186, CRAB [CRADD , and RTTDD [RTTN .Understanding and identifying developmental principles and signaling pathways that shape the anterior CNS have progressed considerably. The areal organization of the human brain is tightly linked to brain function. Thus, the proper progression of the developmental plan is critical for brain functions. A deeper understanding of the etiology of neurodevelopmental conditions is rooted in uncovering the essential steps during brain patterning. This may be true not only when gross brain abnormalities are seen but also when abnormalities are manifested in subtle arealization defects that are not always appreciated but can profoundly influence an individual’s cognitive and social skills.


Nature,1 Iram et al. are the first to identify fibroblast growth factor 17 (Fgf17) from the young mice cerebrospinal fluid (YM-CSF) as a key molecule to improve cognitive functions in aged mice by driving the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), indicating that effective remyelination induced by young CSF factors may provide a novel and promising therapeutic strategy to rejuvenate the ageing brain, which again confirms that factors present in the young tissue can serve as therapies in ameliorating ageing-related symptoms.In a recent article published in 2 However, the recently developed concept of brain active milieu suggests that the brain functions are determined by orchestrated interactions among neurons, glia, non-neuronal cells, and non-cellular elements.3 Thus, senescence of all elements of the active milieu can play a role in brain ageing. For example, we recently showed that astrocytic dystrophy parallels the impairment of synaptic plasticity in old brains.4 In addition, oligodendrocytes and they produced myelin sheaths have also been shown to play crucial roles in learning and memory,2 because a long-range signaling in the brain that relies on myelin functions and mature oligodendrocytes are important for the maintenance of axonal health and for regulation of neuronal function. Therefore, myelin degeneration and diminished myelin renewal contribute to ageing-related deficits in memory.5 An interesting finding showed that myelination is very intense in young mice and is greatly inhibited in aged mice, coinciding with spatial memory deficits.5 Unfortunately, the detailed reasons of the marked differences in myelin regeneration between young and old remains unclear. As we know, myelin remodeling in brain is primarily orchestrated by mature oligodendrocytes, which are derived from OPCs’ differentiation. Therefore, maintaining the dynamic balance between OPCs and oligodendrocytes during aging to promote effective myelin remodeling could be beneficial for improving ageing-related symptoms.People have been searching for the secret of longevity since ancient times, but no breakthrough has been made to date. However, leaving aside the question of whether longevity is feasible, there is an urgent need to resolve the issue of ageing-related health deterioration. For example, cognitive decline remains an unsolved issue for the elderly. The senescence of neurons has long been considered as a major cellular mechanism of such decline.In this study, Iram et al. first tested whether administration of young CSF to aged mice via intracerebroventricular (ICV) would effectively rejuvenate the brain. When age-related cognitive decline  was reversed by YM-CSF, they investigated the cellular and molecular changes in hippocampus with bulk RNA sequencing (RNA-seq). They found that highly upregulation of transcription factors driven by YM-CSF were involved in promoting oligodendrocyte differentiation and major myelin protein components. Given that the OPCs are the initiating myelination process, their growth was assessed in the aged hippocampus and in primary OPC cultures. The results showed that YM-CSF enhances OPC proliferation and differentiation both in in vivo and in vitro. These results suggest that young CSF contains rejuvenating factors that promote cell growth for the oligodendrocyte lineage or neutralize inhibitory factors.Next, to gain a deeper mechanistic insight into the cell growth for OPCs induced by YM-CSF, nascent mRNAs from cultured OPCs 1 or 6 h after exposure to young human CSF (YH-CSF) were metabolically labeled with 4-thiouridine (s4U) and then detected by thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAMseq). The results of this experiment showed that many of the differentially expressed genes peaking at 6 h after YH-CSF exposure are known as serum response factor  target genes. The most strongly upregulated genes were enriched for “target genes of SRF”. The following experiments demonstrated that the suppression of the OPC proliferation and differentiation in the aged brains was caused by the depressed SRF signaling pathway in OPCs, which was reactivated in vivo by young CSF treatment. Therefore, these experiments indicate that SRF signaling in OPCs is inhibited with ageing and may serve as a therapeutic target against the ageing-related deficits.Because the source and quantity of CSF may be the most critical factors restricting its widespread application in clinical practice, revealing the active components of CSF can address this issue. Then, based on the observation of SRF signaling pathway, two published CSF proteomic datasets were cross-referenced with the predicted SRF targets, which generating a list of 35 potential SRF inducers. Among them, Fgf17 gained the favor of researchers because it is a brain-enriched protein, and its levels decrease with age in human plasma, CSF and mouse neurons. It also induced the strongest dose-dependent activation of SRF. In addition, Iram et al. found that Fgf17 activates SRF signaling through actin modulation by enhancing or inhibiting actin polymerization using jasplakinolide and latrunculin A, respectively. In vitro experiment showed that Fgf17 induces OPC proliferation and differentiation when primary rat OPCs exposure to Fgf17. To further confirm these effects observed in in vitro, the aged mice received 1 week of infusion with Fgf17 showed markedly increased OPC proliferation in the aged hippocampus and improved long-term memory performance. In contrast, blocking Fgf17 in young mice showed impaired performance and impaired neuronal plasticity, suggesting that Fgf17 is necessary for normal memory function. These results strongly demonstrate that Fgf17 is sufficient to activate OPCs in the hippocampus and consolidate memory in aged mice, which was comparable to the effects of young CSF.Iram et al. have provided solid evidence that young CSF is capable of restoring memory in aged mice via Fgf17 at the OPCs (Fig.


In this paper, we propose that lithium may exert its therapeutic effect in bipolar disorder by acting on insulin signaling pathways. Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium , and sodium myo-inositol transporters) are putative mediators of insulin signaling. This novel mode of action of lithium is consistent with an emerging consensus that energy dysregulation represents a core deficit in bipolar disorder. It may also provide context for the significant co-morbidity between bipolar disorder, type 2 diabetes, and other forms of metabolic illness characterized by impaired glucose metabolism. It is suggested that developments in assessing neuronal insulin signaling using extracellular vesicles would allow for this hypothesis to be tested in bipolar disorder patients. Lithium is currently the most effective treatment for bipolar disorder (BD), but even after 60 years of research, its mechanism of action is not fully understood. Previously, we hypothesized that impaired glucose metabolism and mitochondrial dysfunction in BD, characterized by disrupted oxidative phosphorylation and increased glycolysis, are best explained as a result of disruption of a primary insulin signaling mechanism in the brain: the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) pathway . HistoriEnergy dysregulation has been recognized as a core deficit in BD along several lines of evidence. At the macroscopic level, significant shifts in circadian rhythm, rest, and activity strongly indicate a dysregulation of energy generation and expenditure , 4. At tInsulin signaling also plays an important role in regulating glucose metabolism in glial cells. Astrocytes express insulin receptors in the (IR)-B isoform . InsulinReviews of the mechanism of action of lithium note a wide range of effects , and bcl-2, and downregulation of sodium myo-inositol transporter, protein kinase C, and myristoylated alanine-rich C-kinase (MARCKS)) but the inhibitory effects of lithium on GSK3 and the phosphatidylinositol cycle (PI-cycle) have emerged as the leading hypotheses for therapeutic effects in BD . These pGSK3 plays a central role in this insulin signaling pathway and is directly influenced by Akt, thereby mediating many of the downstream mitochondrial and metabolic effects of insulin . GSK3 isActivation of the PI3K/Akt pathway Fig.  occurs wStates of insulin resistance can occur through chronic overactivation and consequent blunting of this pathway. Such conditions can occur under prolonged hyperinsulinemia leaving the constitutively active GSK3 in a state of chronic overactivity as shown in Fig. This state of metabolic dysfunction has been observed to occur in the CNS as well as in peripheral tissues . OveractLithium is not generally considered to exert therapeutic action through metabolic pathways. However, it has been demonstrated to have metabolic effects. Notably, it has been demonstrated to restore insulin sensitivity in animal models of insulin resistance, as summarized by Lee and Kim , 31. InsGSK3 is an important node at the intersection of multiple signaling pathways involved in metabolism, inflammation and cellular signaling. These include the Wnt pathway which regulates cell fate determination and migration  and tollInhibition of the PI-cycle is a well-studied hypothesis for the mechanism of action of lithium in BD. The PI-Cycle is a series of cyclical biochemical reactions that generate a variety of phosphoinositides from inositol maintained at a stable level. These phosphoinositides act as signaling molecules via interactions with a diverse range of external biological systems playing roles in cell survival, metabolism, autophagy, division and migration as well as vesicular trafficking and ion channel regulation –42.Levels of inositol in the brain are significantly higher than in the blood and other tissues, suggesting an important role in neuronal function . PI-cyclThe PI-cycle plays a signficant role in PI3K/Akt insulin signaling generating the second messenger phosphoinositide PIP3 and diacylglycerol (DAG) which activate or inhibit insulin signaling respectively as Fig. Inhibition of the PI-cycle by lithium slows the turnover of PIP2 and reduces the pool available for generation of PIP3 and activation of the insulin signaling pathway. Disruption of these phosphoinositide second messengers have been observed in the occipital, temporal, and frontal cortex of bipolar subjects . MembranPIP2 has two fates in the PI-cycle; it can go on to form PIP3 and activate insulin signaling or it can be cleaved to form DAG and inhibit the pathway  has been associated with BD pathophysiology in many studies . Howeverreatment . Increasreatment . Since tImpaired DGK leaves the PI-cycle activity free of its normal self-regulatory capacity and it may therefore alternate between states of overactivity through increased flux of phosphoinositides and under-activity due to depletion or decreased flux of phosphoinositides. Lithium acts primarily to stabilize overactivity of the PI-cycle which may explain its strong anti-manic effect , 58.The effects of lithium on the PI-Cycle and PKC are well established, however, the mechanisms that may lead to mood stabilization are still unclear. Lithium-induced reduction of myo-inositol level is not always associated with mood stabilization and so the interactions of the second messenger phosphoinositides on downstream signaling mechanisms may have better explanatory scope . ResearcSodium myo-inositol transporters (SMIT) are a proposed, indirect target of lithium. SMIT determines the level of available inositol in the cell to act as a substrate for insulin signaling and therefore plays an important role in metabolic function. A study on SMIT mRNA in BD reported a significantly higher expression of SMIT mRNA in untreated bipolar type 1 patients and that this was downregulated by treatment with lithium . UpregulGlucose and inositol are transported into the cell by SMIT and hyperglycemia has been shown to inhibit SMIT uptake of inositol . AdditioAcute experimental diabetes reduces the concentration of free myo-inositol in peripheral nerves in both animals and humans , 70. HypMarkers of insulin signaling can be measured in peripheral blood mononuclear cells as performed by Tye et al. and such approaches may have the potential to lead to a treatment response biomarker . ExtraceThe primary measurement obtained in intranasal insulin experiments is the phosphorylation of insulin receptor substrates . The ratThe need for MRI and delivery of insulin makes this test difficult to perform, however, new alternatives are emerging. Kellar’s 2020 review highlights measuring the same phosphorylation in IRS derived from neuronal-enriched extracellular vesicles in plasma as a promising and non-invasive approach for future research . ExtraceCalkin et. al noted a strong association between IR and BD as well as a strong antidepressant effect of insulin-sensitizing medication Metformin in BD , 80. HowDisruption of the PI3K/Akt insulin signaling pathway has wide explanatory scope for several features of BD. It unites several important mechanisms of lithium action within a coherent context; the PI-cycle and GSK3β are linked via this pathway, as well as effects on SMIT and PKC. Insulin resistance is defined as a blunting of the PI3K insulin signaling pathway and chronic overactivation of GSK3β is an expected outcome of this state. Chronic GSK3β overactivation of this kind has been shown to disrupt brain energy regulation via impairment of glucose metabolism and mitochondrial function. While regulation of brain glucose metabolism has historically been regarded as largely insulin-independent, increasing evidence indicates that PI3K/Akt insulin signaling plays an important role in the hippocampus and cerebellum, and these brain regions have been identified as particularly vulnerable sites of gray matter loss in BD .The significant acceleration in the increase in burden of disease from BD in recent decades may require an explanation which extends beyond genetic causes and takes into account increasing allostatic load from environmental stressors . SignifiThe insulin-sensitizing effects of lithium via its action on several nodes of the insulin signaling pathway  have been demonstrated but are not generally considered relevant to mood stabilization in BD. However, when BD is conceptualized as a disorder of energy regulation, these mechanisms become highly plausible because of their effects on mitochondrial function, circadian rhythm, and glucose metabolism.We hypothesize that in a proportion of BD patients insulin resistance acts as a chronic stressor leading to impairment of PI3K/Akt insulin signaling in the brain. The resultant chronic overactivation of GSK3 and dysregulation of glucose metabolism in neurons leads to mitochondrial dysfunction and energy dysregulation, manifesting as manic or depressive symptoms. Lithium acts on several stages of the PI3K/Akt insulin signaling pathway to restore sensitivity to insulin, resulting in improvements in downstream glucose metabolism and mitochondrial function. The targets of lithium action discussed in this paper lie at the intersection of many signaling pathways and mechanisms which regulate metabolism, inflammation and immune response. There may therefore be a wide variety of immuno-metabolic stressors which play a role in BD onset in those who are genetically susceptible. Increased IR appears to be the most significant environmental shift which could explain increasing burden of disease of BD worldwide . This hyIt is now possible to assess neuronal insulin signaling using extracellular vesicles and a study in bipolar patients has established preliminary evidence for impaired PI3K/Akt insulin signaling . We sugg


The noted changes in fatty acid profile were primarily prescribed to the migration of fats. C1 and C2 influenced a comparable reduction in EVOO total identified phenolic content , despite having a different content of total proteins and moisture, whereas C3 influenced a slightly lower reduction (−85.0%). Besides the protein profile, other cheese compounds  have been shown to have a considerable role in the development of the EVOO phenolic profile. Finally, compositional changes in EVOO used as a medium for cheese preservation are under significant influence of the cheese’s chemical composition.The influence of semi-hard (C1), hard (C2), and soft whey cheese (C3) immersed in extra virgin olive oil (EVOO) on its oxidative and hydrolytic parameters, fatty acids, and phenolic composition during two months of simultaneous storage was investigated. Accelerated hydrolytic and oxidative degradation was noted in EVOO stored with the immersed cheese compared to control oil. Oxidation indicator (K The Mediterranean diet is an excellent model of healthy eating, mainly attributed to preventing cardiovascular and chronic diseases along with extended longevity ,2. Its bβ-lactoglobulin as the main representative, while high nutritional value and beneficial health attributes contribute to its classification as a functional food , me, metransIn The presence of any type of cheese influenced significant losses in the EVOO TIPC compared to the control EVOO stored without the addition of cheese . As expeDespite the known lower interaction between whey proteins and phenolic compounds compared to casein , expecteThe described differences between the two reduction rates for each cheese type were larger when comparing the results of the Folin–Ciocalteu method (TPC) with the ones obtained with HPLC-UV/Vis (TIPC). The determined levels of phenolic compounds in EVOO + C3 samples were particularly higher with the Folin–Ciocalteu method (120 mg GAE/kg) compared to HPLC-UV/Vis 54.0 mg/kg) after two months, whereas in EVOO + C1 and C2 the TPC values  were comparable to the ones detected with HPLC-UV/Vis . Corresp.0 mg/kg p-DHPEA-EDA), decreased strongly after storage with the immersed cheeses; therefore, being primary contributors to the overall TIPC decrease , and oleocanthal , and trans-oleic fatty acid (C18:1t) exceeded highly above the prescribed maximum for EVOOs [In the present study, the influence of different cheese types immersed in EVOO on its oxidative and hydrolytic parameters, fatty acid, and phenolic composition during two-month storage was investigated. Accelerated hydrolytic and oxidative degradation was noted in EVOOs stored with the immersed cheese compared to EVOOs stored without cheese addition. The negligible role of hydrophilic phenolic compounds in the oxidative stability under the circumstances elaborated in this study was indicated by the quality parameters and fatty acids analysis, where the notable compositional changes were primarily prescribed to the migration of compounds between the two food matrixes. Kor EVOOs , which iTaken together, our findings indicate that the presumed severe compositional changes in the EVOO used as a medium for cheese preservation were confirmed and under significant influence of the specific chemical composition of cheese. This study contributes to the understanding of EVOO and cheese compounds’ interaction in the course of real storage conditions during simultaneous storage. In further investigations, it would be of significant importance to consider other authenticity parameters, such as the content of sterols, due to the vegetable and animal components that consist in this food product. Furthermore, investigations including other food matrixes during prolonged contact with virgin olive oils would provide new knowledge on the mechanism behind the interaction of food components, unrevealing the phenol–protein interaction.


Chronic kidney disease (CKD) is a highly prevalent and potential progressive condition with life-threatening consequences. Glomerular diseases (glomerulopathies) are causes of CKD that are potentially amenable by specific therapies. Significant resources have been invested in the identification of novel biomarkers of CKD progression and new targets for treatment. By using experimental models of kidney diseases, periostin has been identified amongst the most represented matricellular proteins that are commonly involved in the inflammation and fibrosis that characterize progressive kidney diseases. Periostin is highly expressed during organogenesis, with scarce expression in mature healthy tissues, but it is upregulated in multiple disease settings characterized by tissue injury and remodeling. Periostin was the most highly expressed matriceal protein in both animal models and in patients with glomerulopathies. Given that periostin is readily secreted from injury sites, and the variations in its humoral levels compared to the normal state were easily detectable, its potential role as a biomarker is suggested. Moreover, periostin expression was correlated with the degree of histological damage and with kidney function decline in patients with CKD secondary to both inflammatory (IgA nephropathy) and non-inflammatory (membranous nephropathy) glomerulopathies, while also displaying variability secondary to treatment response. The scope of this review is to summarize the existing evidence that supports the role of periostin as a novel biomarker in glomerulopathies. Periostin is a 90 kDa non-structural matricellular protein originally described in osteoblastic cells lineages, hence the reason it was initially referred to as OSF-2—osteoblast stimulating factor 2 ,2,3. It -A C-terminal domain which is a site of proteolytic cleavage that renders the different isoforms of periostin;-An N-terminal EMI domain which renders the capacity to interact with collagen I and fibronectin;-Vβ3 and αVβ5 integrins, through which it manifests its aforementioned capacity to mediate cell adhesion and migration. A middle region consisting of four fasciclin-I domains that contain binding sites for bone morphogenetic protein 1 (BMP-1) and αThe periostin molecule comprises three distinct regions with different purposes ,5,6:-A This palette of sites for interaction with extracellular matrix (ECM) components and cell-surface receptors provides periostin with unique capabilities, to modulate both the architectural properties of the surrounding connective tissue and the cell–matrix interactions .Thus, periostin plays an important role in tissue regeneration, remodeling, and fibrosis . In addiThe multiple fibrotic and inflammatory mechanisms through which periostin expression is stimulated and thereafter exerts its actions have been described and are subject to further update.There is proof that angiotensin-II (AT-II) stimulates periostin expression in myocardial fibroblasts and smooth muscle cells through the phosphatidil-inositol-3 kinase (PI-3 kinase), Ras/p38 MAPK/CREB, and ERK1/2/TGF-β1 pathways ,20, as iAnother well-described relationship is that with TGF-β1, which also seems to act in both directions: on one hand, TGF-β1 induces periostin expression and facilitates the transition to a mesenchymal phenotype for the tubular renal cells by de novo expression of mesenchymal cell phenotypes markers , loss of epithelial cell markers (E-cadherin), and disruption of intercellular junctions  ,24; on tThere is also compelling evidence from Prakoura et al. that periostin induced by the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) promotes renal injury in a glomerular disease model . PlateleThe mechanisms involved in the downstream effects of periostin are multiple and constantly updated, as it does not only trigger specific paths, but often, as previously described, provides positive autocrine-like feedback loops that enhance the expression of its inducers. It binds to cell-surface integrin receptors integrin αVβ3 and αVβ5 and throughout the activation of the PI-3 kinase mediates migration, differentiation, and adhesion of tumoral, vascular smooth muscle, and mesenchymal stem cells . PeriostA more illustrative take on the potential mechanisms of periostin action in kidney disease can be seen in Chronic kidney disease (CKD), an increasing public health problem with a prevalence of 10–13% worldwide , can be In the renal biopsies of healthy kidney donors, periostin was constantly expressed in the vascular pole of the glomerulus and around Bowman’s capsule, and lacking in the tubular compartment , while tDuring the last two decades, increasing evidence has unraveled the involvement of periostin in CKD. Various experimental models revealed an increased expression of periostin, including in the 5/6 nephrectomy, unilateral ureteral obstruction, and streptozocin-induced diabetic nephropathy ,24,33. ISimilarly, a significant increase in the expression of periostin in renal tissue during progressive kidney injury was also observed in adult humans, with specific topography depending on the underlying injury: in areas of glomerular sclerosis, Bowman capsule, ischemic lesions and tubular cytoplasm in diabetic subjects ; in areaOn the other hand, mice lacking periostin gene expression presented with a more attenuated interstitial fibrosis and were protected against CKD progression . In vivoGlomerular diseases are conditions that comprise a distinct subset of CKD causes that are potentially amenable by specific therapy. Bearing in mind their individual specific pathways for development and progression, they are all characterized by local inflammation and activation of pro-fibrotic mechanisms. In order to assess the efficacy of treatment and prognosis in glomerular diseases, novel biomarkers are needed, since currently kidney injury is monitored in clinical practice only through markers that measure kidney functional loss—i.e., serum creatinine, urine protein, albumin, and urine cystatin-C—but not kidney cellular injury. These newly proposed markers of kidney function loss may have the advantage of recognizing kidney injury before the onset of proteinuria or before the decline in eGFR, therefore providing an opportunity for early nephroprotection. Some other urinary proteins are also markers of tubulointerstitial injury but are not routinely measured or used in clinical practice .A 2021 paper by Chimenz et al. highlights the potential of other ECM molecules to serve as biomarkers of glomerular disease, as high mobility group box 1 (HMGB1) and TGFβ-1 were able to predict subclinical fibro-inflammatory changes in the kidney by their early detection in the serum and urine of Alport disease subjects as compared to healthy subjects before the onset of proteinuria. HMGB1 appears to play several roles in cellular signaling and pro-inflammatory pathways, and several studies have reported elevated serum and urine levels in lupus nephritis and in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with renal involvement. TGFβ-1 seems to be directly upregulated by HMGB1-triggered routes, and there is supporting evidence of elevated urinary levels of TGFβ-1 in children with idiopathic nephrotic syndrome and in focal and segmental glomerulosclerosis (FSGS) . In ordePeriostin has already proven its usefulness as a biomarker in fibrotic diseases and in cancer states ,45, owinPeriostin checks several criteria of biomarkers: its expression is minimal in healthy subjects, while it is highly induced in several kidney disease models  and its local magnitude of expression correlates with kidney function decline and histological involvement ,23,27,42Similar to the blood fraction, the urinary fraction of periostin shares a magnitude of less than 1 ng/mg creatinine, but this fraction can significantly increase and there is evidence that points towards a positive correlation with disease severity in multiple CKD causes ,40,41.The urinary fraction of periostin seems to originate from the tubulointerstitium since serum periostin levels have not shown a reliable prognostic value in kidney disease and urinary periostin levels have not been significantly different between proteinuric and non-proteinuric conditions ,48.As previously mentioned, glomerular diseases are causes of CKD that are potentially amenable to specific ethiopathogenic treatments that are proven to impact long term prognosis. Glomerulopathies can be divided in inflammatory and non-inflammatory diseases, depending on the main pathogenic mechanism that drives the initial injury: conditions like IgA nephropathy are characterized by the mesangial cellular proliferation with local inflammation and ECM expansion secondary to local immunoglobulin complex deposition, whereas diseases like membranous nephropathy or focal segmental glomerulosclerosis are mainly characterized by direct podocyte injury that initially lack overt histological inflammatory features.Of all these glomerulopathies, IgA nephropathy (IgAN) is the most incident and prevalent and is a leading cause of CKD, being the most common glomerular disease in adults, with an overall incidence of 2.5 in 100,000 individuals as predicted by biopsy registry data; this in fact might underestimate the true disease burden due to selection bias imposed by kidney biopsy indications . In addiLupus nephritis (LN) is the second most common causes of nephritic syndrome in the general population  and a geMembranous nephropathy (MN) is the leading cause of nephrotic syndrome in the adult non-diabetic population and the identification of PLA2R antigen involvement in primary MN has led to a paradigm shift in terms of potential non-invasive diagnosis and an efficient prognostic monitoring of disease response through the anti-PLA2R antibodies . The traSimilar findings are also reported in the analysis of Sen et al.  for the Regarding kidney allograft dysfunction, antibody-mediated rejection (ABMR) is currently the leading cause of kidney allograft failure , with hiEarly detection is also mandatory in the early stages of diabetic nephropathy (DN), before the onset of albuminuria. Satirapoj et al.  evaluateAs previously mentioned, other molecules belonging to the ECM domain have been described not only as elevated in multiple kidney disease states with glomerular involvement , but as potentially upregulated before the onset of proteinuria and overt kidney functional decline as evaluated by eGFR . Future One of the mainstays of periostin’s prognostic value, as described in the case of kidney allograft dysfunction, could be that of differentiation between chronic active and chronic histological lesions in the kidneys of glomerulopathic patients, with subsequent impact on immunosuppression prescription.These individual biomarkers can be combined in assays that can thereafter be tested and validated in multiple diseases, including glomerulopathies, as similar combined detections of urinary markers are already reported in settings like acute kidney injury (AKI) , with prFavorable prospects are also available in regard to the potential blockade of the periostin axis through specific delivery of antisense oligonucleotides, as Mael-Ainin et al. proved in their 2014 murine models . SimilarAlthough these data are encouraging regarding the potential role of periostin in kidney and glomerular diseases, one must bear in mind that the molecular pathways presented are intertwined and “escape routes” of fibro-inflammatory mechanisms are not uncommon, as proven in the past by the fact that basic science data cannot be fully translated and replicated in vivo and in real-life settings.In conclusion, periostin seems to bear multiple features that could support its role in the future for the prognostic evaluation of patients with glomerular disease, as reports in murine disease models and in human biopsies have highlighted the minimal expression in healthy individual and the enhancement of expression in disease models, although further prospective evaluation is necessary to support its prognostic utility. Furthermore, the forever expanding field of novel molecular biomarkers could potentially lead to standardized and potentially combined (with other biomarkers) assays for urine and blood samples in order to construct and validate large-scale prognostic models.Besides the aim of suggesting that periostin has prognostic potential in glomerulopathies, the review also intends to bridge the gap between basic science and clinical medicine, by covering available data in both fields in a translational manner, thus providing rationale for further clinical research on the roles of periostin.


Obesity is a state of low-grade chronic inflammation that causes multiple metabolic diseases. During obesity, signalling via cytokines of the TNF family mediate cell death and inflammation within the adipose tissue, eventually resulting in lipid spill-over, glucotoxicity and insulin resistance. These events ultimately lead to ectopic lipid deposition, glucose intolerance and other metabolic complications with life-threatening consequences. Here we review the literature on how inflammatory responses affect metabolic processes such as energy homeostasis and insulin signalling. This review mainly focuses on the role of cell death in the adipose tissue as a key player in metabolic inflammation. Obesity induces cell death and inflammation in the adipose tissue.Cell death within the adipose tissue induces inflammation-associated metabolic syndromes.Cell death machinery and NF-κB-mediated inflammation regulate energy homeostasis and insulin sensitivity.The crosstalk between adipocytes and adipose-tissue macrophages initiates systemic metabolic inflammation during obesity.Is cell death required to induce metabolic inflammation?Is there a “healthy” and an “unhealthy” way to die during excessive lipid uptake? And does it depend on the metabolic organ in which these events happen?Does activation of cell death machinery directly modulate metabolic processes, such as energy expenditure, during obesity?Obesity is now considered a global disease as it affects over 1.9 billion people worldwide . In receThe white adipose tissue (WAT) is an endocrine and lipid storage organ that plays a pivotal role in obesity-associated disorders. Efficient lipid storage prevents ectopic lipid deposition and toxic lipid accumulation (lipotoxicity) in non-specialised organs, such as muscle, liver and heart, and it correlates with preserved metabolic function . The WATAdipocytes do not only play a role in lipid storage, but also on metabolism and inflammation through the secretion of cytokines and adipokines, such as leptin and adiponectin . Leptin In obesity, there is a dynamic remodelling of the WAT in which adipocytes can either increase in size (hypertrophy) or in number, following differentiation from AP, or adipogenesis, (hyperplasia). WAT can be classified in two main compartments, subcutaneous (SAT) and visceral (VAT). Each of them bearing specific metabolic functions and characteristics. They present different patterns of gene expression, including genes involved in adipocyte function and development . NotablyInflammation, cell death and metabolic processes are highly interlinked processes during obesity and a tight balance between these processes is crucial to prevent metabolic diseases. Here we review the literature of the signalling events governed by the pleiotropic immune mediator, TNF, and a pathogen sensing system, the inflammasome, during obesity with a focus on the current knowledge regarding cell death regulation in the WAT and its impact on metabolic inflammation.The key importance of TNF signalling in obesity-induced inflammation and metabolic complications was vastly demonstrated in animal models and also in humans. Indeed, although still a matter of debate, TNF neutralisation improves glucose homeostasis and reduces diabetes risk in human patients . LikewisThe signalling cascade that is unleashed following binding of TNF to its cognate receptor, TNFR1, results in activation of the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) via the formation of a receptor signalling complex, also known as complex I  Figs. 1. This coTNF, in certain circumstances, can also induce cell death by recruitment of Caspase-8 and RIPK1 or TRADD to FADD to form the so called, complex II or cell death complex  Fig. 2)2). This Another type of cell death, that was best described to occur in immune cells, can be triggered as a result of Caspase-8 and -3 activation. Emerging evidence shows that proteins called Gasdermins are substrates of these caspases –43. GasdObesity is associated with inflammatory changes in WAT that lead to IR, which is the inability to sense insulin and uptake blood glucose and other nutrients. This is the primary cause of several metabolic syndromes such as Type 2 Diabetes . During Ikkβ+/−), is accompanied by decreased FFA and improved insulin sensitivity in genetically obese db/db mice and Zuckerfa/fa rats [ob/ob mice [ob/ob mice [beclin1 in the liver  model demonstrated the impact of Caspase-8-mediated apoptosis in the WAT. Induced expression and activation by dimerisation of Caspase-8 in this model resulted in local inflammation and adipocyte death which was accompanied by marked glucose intolerance [ob/ob mice. This indicates that the adipocytes from these mice have an impaired ability to uptake lipids independently of leptin signalling or food intake, and that this failure causes lipotoxicity in peripheral organs. FAT-ATTAC mice presented increased ATM infiltration and, curiously, the majority of these ATMs were alternatively activated anti-inflammatory M2-like macrophage upon Caspase-8 activation [The Fat Apoptosis Through Targeted Activation of Caspase-8 olerance . This dativation . Hence, tivation   in human pathologies. Yet, obese individuals with or without Type 2 Diabetes showed massive expression of RIPK3 which correlated with activation of necroptosis as shown by increased phosphorylated MLKL . In addiThe last piece of evidence suggesting that necroptosis is implicated in the inflammatory consequences of obesity comes from studies using mice deficient for MLKL. Two independent reports showed that loss of MLKL prevents inflammation, metabolic dysfunction and hepatic steatosis upon HFD , 80. HowApoptosis and necroptosis are highly interlinked cell death pathways. Therefore, in order to understand what is happening at the physiological level requires the study of both cell death modalities in parallel. Importantly, because of the crosstalk between inflammation and energy homeostasis, it is quite crucial to dissect the cell death versus the non-cell death functions of these components in order to clearly understand the processes that regulate obesity-induced inflammation.IL-1β is, together with TNF, amongst the most important proinflammatory cytokines known to interfere with insulin signalling, which in the case of IL-1β, it is mediated by targeting IRS-1 . RandomiThe role of Caspase-1 during obesity is controversial since some studies reported that its loss results in an increased body weight gain but without metabolic abnormalities , 86. FurA recent study reports that both Caspase-1 and NLRP3 are implicated in adipogenesis and insulin sensitivity and, contrary to previous reports, Caspase-1-deficient mice are protected against body weight gain as well as from becoming IR upon HFD . SimilarContrary to NLRP3 and ASC, which are upregulated in WAT in obese individuals. Other NLR family members including NLRP1, NLRC4, and AIM2 showed similar levels of expression in WAT between lean and obese individuals . In miceIn the last years, inflammasome research has slightly shifted towards understanding the role of Gasdermins, the final executor of pyroptosis, in different pathological conditions , 97. A vIn sum, although the implication of inflammasome activation in adipocytes has not been entirely demonstrated, there is no question that macrophage-inflammasome activation triggers systemic inflammation during obesity and it is one of the main culprits of metabolic syndromes. Despite a huge amount of work on the role of inflammasome activation in metabolic disorders, we are still lacking an understanding of pyroptotic cell death in WAT upon obesity and its metabolic implications. Also, the importance of pyroptosis in different cellular compartments can have distinct contributions to inflammation and energy homeostasis and this topic warrants future investigation.Obesity is a disease that has a multifactorial origin and is associated with multiple metabolic syndromes. Understanding the aetiology of obesity-induced inflammation has, therefore, caught the attention of many scientists and clinicians alike. After a huge amount of work during decades of research, we now understand how the inflammatory signalling cascades that are a hallmark of obesity are highly interlinked with energy homeostasis and insulin signalling. The role of cell death in metabolic syndromes has also received some attention in the last decade given the importance of cell death in regulating inflammation and metabolism. Yet, there is still a long way to go to address important questions, regarding the interplay between inflammation and obesity as well as the crosstalk between different metabolic tissues. At present, what type of cell death prevails during obesity is ill-defined. We also lack a clear picture of whether and how different cell death types that can be triggered by different factors  affect metabolic inflammation.In the modern world, the environmental pressure is no longer determined by the lack of nutrients, but rather by their excessive availability. Human beings have not yet adapted to these modern circumstances and hence obesity is a factual clinical issue. Therefore, understanding and defining molecular processes taking into consideration the function of each individual organ is required in order to tackle, either by pharmacological or behavioural means, metabolic syndromes.Glossary


Hepatic fibrosis is the typical result of an exuberant wound healing reaction occurring after repeated or prolonged tissue injury Mlkl alleviates hepatic insulin resistance and glucose intolerance via non-necroptotic functions In recent years, it has become clear that programmed cell death was not restricted to apoptosis, but comprised other forms of regulated cell death Theranostics4- and bile duct ligation (BDL)-induced liver injury and fibrosis . They showed that MLKL content positively correlated with a number of fibrotic markers in liver samples from both patients with and animal models of liver fibrosis. Mlkl deficiency in mice significantly reduced CCl4- and BDL-induced liver injury and fibrosis. Considering that hepatocyte injury is the main trigger of liver fibrosis, an adeno-associated virus (AAV) type 8 carrying Mlkl shRNA was used to specifically knock down Mlkl in hepatocytes. The authors demonstrated that AAV8-mediated specific knock down of Mlkl in hepatocytes remarkably alleviated CCl4-induced liver injury. The authors also showed that fibrosis reduction was not only due to the reduction in hepatocyte necroptosis but also to a reduction of HSCs activation, suggesting that targeting MLKL may be an effective way to treat liver fibrosis by acting both on the initiation  and progression  stages of fibrogenesis.In the study from the group of Xin Xie published in the previous issues of Mlkl deficiency protects mice from CCl4- and BDL-induced liver injury and fibrosis. However, Mlkl deficiency also reduced the activation of HSCs in vitro, possibly via the regulation of TGFβ/Smad 2/3 signaling pathway. It has been demonstrated that fully activated HSCs are resistant to apoptosis and can survive to prolonged serum deprivation, exposure to Fas ligand, NGF, TNF‐α, doxorubicin, etoposide, and oxidative stress mediators such as hydrogen peroxide, superoxide anion, and 4‐hydroxynonenal Bcl-2, which was overexpressed in HSCs in areas localized near fibrotic septa Given the assumption that hepatocyte death is the key trigger of liver disease progression towards fibrosis, and the privileged role of MLKL in regulating necroptosis, it is not surprising that MLKL deficiency compromises the invasion of the nasopharyngeal carcinoma cells by reverting epithelial-mesenchymal transition (EMT) Cytoplasmic MLKL is translocated into the plasma membrane for necroptosis induction. However, preceding necroptosis induction, MLKL is also located to the nucleus et al. indicate that Mlkl deficiency does not influence bone marrow-derived macrophages (BMDM) polarization and cytokines production. Previous reports exploring the role of necroptosis in cerebral ischemia have shown that defective necroptosis induced polarization of macrophages/microglia toward M2 phenotype, but had not impact on polarization of naïve blood macrophages While activation of MLKL has been reported to induce macrophage necroptosis, and targeting macrophage necroptosis may have therapeutic and diagnostic value in atherosclerosis Next to its role as an effector of necroptosis, MLKL also participates in the assembly of the NLRP3  inflammasome et al. contributes to a better understanding of the role of MLKL in the development of liver fibrosis. It clearly confirmed that MLKL does not only serve as an effector of necroptosis but exhibits non-necroptotic functions that should be considered in future drug therapy. Nevertheless, further studies are needed to evaluate the differential contribution of MLKL in non-parenchymal cells vs. hepatocytes and whether pharmacological inhibition can hold promise as a therapy for liver fibrosis.The evidence presented by Ren Guo


For patients with moderate/severe ARDS , prone positioning was recommended for at least 16 hours per day. By contrast, high-frequency oscillation was not recommended. The use of inhaled vasodilators was recommended in patients with persistent hypoxemia despite invasive ventilation and prone position until extracorporeal membrane oxygenation (ECMO). The use of a conservative fluid management strategy was suggested for all patients. Mechanical ventilation with high positive end-expiratory pressure (PEEP) was suggested for patients with ARDS with a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios. ECMO was suggested as an adjunct to protective mechanical ventilation for patients with severe ARDS. In the absence of adequate evidence, research recommendations were made for corticosteroids and extracorporeal carbon dioxide removal. While decades of research have been conducted, treatment options for underlying pathologies remain limited, and mechanical ventilation, which removes carbon dioxide from the body, remains essential to achieving better clinical outcomes. This review aims to identify the best ARDS treatments that are currently available.Acute respiratory distress syndrome (ARDS) is an inflammatory process in the lungs that induces non-hydrostatic protein-rich pulmonary edema. ARDS occurs in roughly half of coronavirus disease 2019 (COVID-19) pneumonia patients, with most of them requiring intensive care. Oxygen saturation, partial pressure of the oxygen, and the fraction of the inspired oxygen are health indicators that may indicate a severe illness necessitating further investigation. As treatments have evolved, a typical pattern of ARDS has likewise evolved. In cases where mechanical ventilation is required, the use of low tidal volumes  and airway pressures (plateau pressure <30 cmH The Berlin definition uses the PF ratio to distinguish mild ARDS (200 <PF ≤300 mmHg), moderate ARDS (100 <PF ≤200 mmHg), and severe ARDS (PF ≤100 mmHg)  is an inflammatory process in the lungs that induces non-hydrostatic protein-rich pulmonary edema. The immediate consequences of the condition are profound hypoxemia, decreased lung compliance, and increased intrapulmonary shunt and dead space. The clinicopathological aspects include severe inflammatory injury to the alveolar-capillary barrier, surfactant depletion, and loss of aerated lung tissue. The European Society of Intensive Care Medicine defines ARDS as the presence of respiratory symptoms within seven days of a known clinical insult or new or worsening respiratory symptoms involving a combination of acute hypoxemia with a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios (≤300 mmHg) in a ventilated patient with positive end-expiratory pressure (PEEP) of at least 5cmH2O]  -8. High-Pathophysiology and risk factorsPathological StagesARDS occurs as a consequence of an alveolar injury due to various causes producing diffuse alveolar damage. This leads to the release of pro-inflammatory cytokines , which recruit neutrophils to the lungs, where they get activated and release toxic mediators (reactive oxygen species and proteases) that damage the capillary endothelium and alveolar epithelium leading to alveolar edema . This, eThe initial exudative stage is characterized by diffuse alveolar damage. The second stage of proliferation develops after approximately 10-14 days, characterized by the resolution of pulmonary edema, the proliferation of type II alveolar cells, squamous metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen. Some patients progress to the third stage of fibrosis, characterized by the obliteration of normal lung architecture, diffuse fibrosis, and cyst formation .Management of ARDSCurrently, no specific drugs or therapies are available to treat/prevent ARDS directly. Mechanical ventilation to minimize ventilator-induced lung injury (VILI) and management of refractory hypoxemia are the keystones in the supportive management of ARDS . We engaThe treatment of ARDS typically aims to increase blood oxygen levels, provide breathing support, and treat the underlying cause of the disease. Most ARDS patients are placed on a mechanical ventilator, usually in the ICU. The Faculty of Intensive Care Medicine and Intensive Care Society (FICMICS) Guideline Development Group has used the GRADE methodology to make the following recommendations for managing adult patients with ARDS. In this review article, we aim to discuss the following treatment interventions based on recent guidelines Figure .Mechanical ventilation at a low tidal volume2O is strong despite the moderate quality of evidence for hospital mortality and barotrauma, but the low quality of evidence for 60-day mortality. The evidence was downgraded for serious indirectness for hospital mortality and inconsistency and imprecision for 60-day mortality. For example, the beneficial effects of low tidal volume ventilation were only seen in one large trial, and the means of managing respiratory acidosis in the ARDS Network ARMA trial is not generally applied. However, a lack of adverse effects associated with the intervention, a strong mechanistic rationale for its use, and supportive data from ARDS prevention studies have resulted in its universal acceptance as a gold standard of care  or inherent patient characteristics, such as alcoholism or the expression of particular single nucleotide polymorphisms known to be associated with a predisposition to ARDS. The ultimate aim is to identify subgroups, so-called endotypes of ARDS, that predict a positive response to a certain class of therapy .CurrentARDS is a clinically and biologically heterogeneous disorder associated with various disease processes that lead to acute lung injury, increased non-hydrostatic extravascular lung water, reduced compliance, and severe hypoxemia. Despite significant advances in the field, mortality associated with this syndrome remains high. Mechanical ventilation remains the most important aspect of managing patients with ARDS. In-depth knowledge of lung protective ventilation, optimal PEEP strategies, modes of ventilation, and recruitment maneuvers is essential for the ventilatory management of ARDS. Although the management of ARDS is constantly evolving as new studies are published, guidelines are being updated, and further data is warranted from RCTs for the early and late phases of ARDS, including severe ARDS.