The neuropeptide Y1 receptor (Y1R) plays a key role in metabolic regulation, and its peripheral antagonism has shown promise in promoting weight loss and improving glucose metabolism. However, most studies are conducted at room temperature (RT, 21-22°C), where mild cold stress stimulates sympathetic nervous system (SNS) activation. The impact of Y1R blockade under thermoneutral (TN, 30°C) conditions, which eliminate cold stress, remains unclear. In this study, we investigated the effects of BIBO3304 on body weight, energy expenditure (EE), and glucose metabolism in chow- and high-fat diet (HFD)-fed mice housed at TN and compared the results with RT. We found that at RT, BIBO3304 significantly reduced body weight gain and fat mass while increasing EE and fat oxidation. These effects were abolished under TN, where SNS activation is minimized, leading to no changes in body composition or EE. Despite this, BIBO3304 improved glucose tolerance at TN, particularly in the early phase (week 2), independent of insulin sensitivity. However, these glucose-lowering effects diminished by week 6, suggesting a potential SNS-dependent mechanism for long-term benefits. TN-housed mice exhibited greater glucose excursions and reduced insulin sensitivity compared to RT-housed mice, highlighting the impact of ambient temperature on metabolic regulation. In summary, these findings suggest that BIBO3304's effects on energy balance are SNS-dependent, whereas its glucose-lowering benefits persist transiently at TN. This highlights the need to consider environmental temperature in the evaluation of pharmacological interventions for obesity and diabetes, with potential implications for climate-adjusted dosing strategies. Peripheral Y1R blockade-induced reductions in body weight and enhancements in energy expenditure at room temperature are abolished under thermoneutrality, irrespective of dietary fat content.Glucose-lowering effects of peripheral Y1R antagonism persist under thermoneutrality, independent of changes in body weight and insulin sensitivity.Chronic thermoneutrality blunts the ability of peripheral Y1R blockade to ameliorate fat-induced glucose intoleranceThese findings emphasize the temperature-dependent efficacy of metabolic drugs and the need for climate-adjusted therapeutic strategies.
Hypoglycemia is the most popular symptom of insulinoma patients. There have been no reports investigating immunohistochemical differences in the expression levels of glucose transporters, glucokinase, and glucagon-like peptide-1 receptor in insulinoma cells according to the clinical phenotypes of hypoglycemia, in particular hypoglycemia in the postprandial state alone or in both fasting and postprandial states. We immunohistochemically analyzed the expression of glucose transporters 1-3, glucokinase, and glucagon-like peptide-1 receptor in insulinoma cells of the resected pancreas from six patients. The frequency of hypoglycemia of <70 mg/dL before breakfast at the fasting state in one patient with exclusively postprandial hypoglycemia and the other five patients with both fasting and postprandial hypoglycemia was 0% and 33-100%, respectively. We found that insulinoma cells in the patient with exclusively postprandial hypoglycemia showed the higher expression of glucose transporter 2, glucokinase, and glucagon-like peptide-1 receptor than those of almost all the other five patients exhibiting both fasting and postprandial hypoglycemia. Glucose transporter 1 and 3 expression was very limited or not detected in insulinoma cells from any of the patients. In addition, we revealed that there was reduced expression of glucokinase and glucagon-like peptide-1 receptor in the patients with quite frequent fasting hypoglycemia. These findings indicate that the increased glucose transporter 2 and reduced glucokinase and glucagon-like peptide-1 receptor expression levels in insulinoma cells might be associated with the clinical phenotypes of hypoglycemic profiles in insulinoma patients.
Accumulation of visceral white adipose tissue leads to central obesity and is associated with insulin resistance and increased risk of metabolic disease. lncRNAs have been reported to regulate the growth and development of adipocytes, providing new clues for the prevention and treatment of obesity. In the present study, we identified numerous dysregulated lncRNAs by microarray analysis between human differentiated adipocytes and preadipocytes. In addition, we focused on the lncRNA ENST00000521141.1 (abbreviated as lncRNA521141) confirmed by qRT-PCR to be enriched in differentiated adipocytes. Lentivirus-mediated knockdown of lncRNA521141 significantly suppressed adipogenesis as evidenced by reduced lipid accumulation, triglyceride content, and key adipogenic markers expression, while lentivirus-mediated lncRNA521141 overexpression showed no significant effect. Given that lncRNA521141 did not alter the expression of the neighboring gene PEBP4, fluorescence in situ hybridization was employed to elucidate the cellular localization of lncRNA521141, revealing its predominant distribution in the nucleus. RNA-sequencing and western blot analysis further revealed the potential involvement of the PI3K-Akt and thyroid hormone synthesis pathways in lncRNA521141-mediated adipogenic inhibition. Among the differentially expressed genes, PDGFRA expression was significantly upregulated following lncRNA521141 silencing and was closely associated with adipocyte differentiation. Rescue experiments confirmed that knockdown of PDGFRA expression after lncRNA521141 silencing alleviated the inhibitory effects of the reduced lncRNA521141 expression on adipocyte differentiation. In summary, the present study identified lncRNA521141 as a key regulator of adipogenic differentiation in human preadipocytes and elucidated its potential regulatory mechanism, thereby providing new insights and potential intervention targets for treating obesity and its related diseases.
With a rapidly aging population and increasing use of antiresorptive agents, medication-related osteonecrosis of the jaw (MRONJ) represents a growing clinical challenge worldwide. To address the need for tailored clinical guidance, a multidisciplinary task force was convened. Five Korean academic societies-the Korean Society for Bone and Mineral Research, the Korean Association of Oral and Maxillofacial Surgeons, the Korean Society of Maxillofacial Plastic and Reconstructive Surgeons, the Korean Osteoporosis Society, and the Korean Endocrine Society-collaborated to develop this position statement. The consensus was formulated through comprehensive reviews of literature, combined with three rounds of formal surveys to consolidate expert opinion on controversial topics. This position paper provides evidence-based clinical guidelines for the prevention, diagnosis, and management of MRONJ tailored to the Korean healthcare environment. The diagnostic criteria affirm the standard definition but add a provision for diagnosis based on clinical or radiographic evidence of necrotic bone, even if the traditional 8-week timeframe has not been met. The committee advocates for retaining stage 0 in the staging system to emphasize early detection and preventive intervention. Key recommendations include prescriptive, drug-specific guidelines for prophylactic drug holidays (e.g., a 2-month pause for oral bisphosphonates; timing surgery 3 to 4 months after the last denosumab injection) to minimize MRONJ risk from dental procedures. This statement also provides a clear framework for therapeutic drug holidays in established MRONJ, carefully balancing the need for jaw healing against systemic fracture risk. For treatment, this statement advocates for early and active surgical intervention across all MRONJ stages, supported by evidence of superior long-term outcomes compared to conservative management. This position statement offers a unique, evidence-based Korean clinical practice guideline for managing MRONJ. It is intended to standardize care, reduce clinical confusion, and ultimately improve patient outcomes by providing a clear framework for decision-making.
This research intended to identify the genes related to PCOS (polycystic ovary syndrome) and verify the regulatory function of miR-486-5p as well as its target PTEN in granulosa cells (GCs). RT-qPCR was used to detect the expression of miR-486-5p in the serum, follicular fluid (FF), and GCs of PCOS patients and normal subjects. ROC curve analysis indicated strong diagnostic performance. Bioinformatic analysis via miRDB and ENCORI databases predicted PTEN as a potential target of miR-486-5p; this prediction was validated through dual-luciferase reporter gene assays. Meanwhile, a series of functional assays were performed. Cellular proliferation capacity was quantitatively assessed using the CCK8 assay, while flow cytometry was used to determine cell apoptosis ratio. The secretion of pro-inflammatory mediators was quantitatively measured employing an ELISA kit. miR-486-5p was found to be reduced in serum from patients, as well as in patient FF and GCs. The enhanced expression of miR-486-5p strengthened the proliferation of GCs and suppressed apoptotic activity, while concurrently attenuating pro-inflammatory cytokine secretion. Conversely, miR-486-5p inhibitor yielded opposing effects. Further investigation revealed that PTEN functioned as a negative regulatory factor of miR-486-5p. The increase of miR-486-5p caused a significant down-regulation of PTEN mRNA expression. Forced expression of PTEN reversed the cellular effects induced by miR-486-5p, including the enhanced proliferation rate, suppressed apoptosis, and attenuated inflammatory response. miR-486-5p can inhibit cell apoptosis and secretion of inflammatory factors by negatively regulating the expression of target gene PTEN, suggesting that miR-486-5p may be a potential target for PCOS.
Mitochondria are unique intracellular organelles that have their own DNA and are inherited intact in the oocyte. They have multiple functions, the most important of which is producing energy in the form of ATP by oxidative phosphorylation (OXPHOS) using a range of metabolic substrates. As energy requirements increase with intrauterine growth and the onset of new postnatal functions at birth, mitochondria develop structurally and functionally in utero to meet these energy demands. In part, the developmental and prepartum maturational changes in mitochondrial OXPHOS capacity depend on the endocrine environment and the natural rise in the fetal concentrations of hormones, such as cortisol and tri-iodothyronine (T3), towards term. This review discusses the development of mitochondrial respiratory function during late gestation with an emphasis on tissue OXPHOS capacity. It considers the role of cortisol and thyroid hormones, in particular, in the intrauterine development and prepartum maturation of mitochondrial OXPHOS capacity in preparation for extrauterine life. Finally, it briefly examines the potential longer-term consequences of abnormal hormonal exposure before birth on mitochondrial OXPHOS function later in postnatal life. Endocrine regulation of mitochondrial OXPHOS in the fetus is shown to be multifactorial, dynamic and tissue specific with a central role in determining functional development. It optimises energetics for survival both in utero and at birth and has implications for adult metabolic fitness and the inheritance of mitochondrial phenotype.
C-X-C motif chemokine ligand 13 (CXCL13) is a crucial regulator of lymphoid tissue development and immune function. It orchestrates homeostasis in secondary lymphoid organs, inflammatory responses in tertiary lymphoid structures (TLSs), and immunometabolic balance within fat-associated lymphoid clusters (FALCs) by mediating the homing of CXCR5+ cells and activating stromal cells. In the context of obesity-related metabolic inflammation, CXCL13 acts as a central hub of immunometabolic dysregulation, driving pathological processes across multiple organs with significant organ- and stage-specific heterogeneity, which reflects spatiotemporal heterogeneity. It mediates the pathological transformation of FALCs in adipose tissue, inducing insulin resistance; promotes TLS formation within pancreatic islets, accelerating β-cell destruction; dynamically regulates atherosclerotic plaque stability in the blood vessels; and undergoes a functional shift from compensatory suppression to profibrotic and procarcinogenic roles during the progression of liver disease. The effects of CXCL13 are highly dependent on the local microenvironment, exhibiting both pro-inflammatory and repair-suppressive effects in diabetic complications. Although targeted therapies show experimental promise, the context-dependent functions of CXCL13 - encompassing both physiological protection and pathological disruption - along with its organ and stage specificity, necessitate spatiotemporally precise interventions. This review systematically elucidates the pivotal role of CXCL13 in obesity-related metabolic inflammation, providing a theoretical foundation for the development of precision intervention strategies tailored to disease subtypes, stages, and specific organ targeting.
Disruptions in iron homeostasis are common during obese states and are related to chronic inflammation and insulin resistance. Exercise exerts well-recognized anti-adiposity and anti-inflammatory effects, besides modulating iron control. The vagus nerve (VN) influences immune and metabolic responses, in a spleen-dependent manner with an unknown impact on iron. Here, we evaluated the effects of the absence of the VN and of the spleen on adiposity, metabolism, and iron homeostasis in non-obese and hypothalamic-obese rats submitted to swimming training. Hypothalamic obesity was induced by the administration of monosodium glutamate (MSG; 4 g/Kg) during the initial postnatal days (PNDs). Non-obese control (CTL) rats received equimolar saline. At PND 60, MSG and CTL were submitted to surgery consisting of bilateral subdiaphragmatic vagotomy (Sv), splenectomy (Spl), Sv + Spl, or sham surgery. At PND 80, the rats were subdivided into exercised (Ex) or sedentary (Sd). Exercised rats swam for 30 min/day for 40 days. At PND 120, the growth, adiposity, metabolism, and iron homeostasis of rats were evaluated. Major results indicate that the absence of the VN and spleen favors the anti-adiposity effects of exercise, particularly in MSG-obese rats. In CTL rats, exercise increased plasma iron, in association with changes in iron transport capacity and a reduction in circulating hepcidin levels, a response that is influenced by the VN and spleen. In contrast, in the MSG-obese animals, vagal and splenic absence resulted in increased hepcidin, including following exercise, via a response that is independent of systemic iron fluctuations, suggesting disturbed hepcidin-iron homeostasis during hypothalamic obesity.
This review summarizes current knowledge on the mineralocorticoid receptor (MR), a nuclear receptor encoded by the NR3C2 gene, and its ligand aldosterone. In epithelial tissues, such as the kidney, colon, salivary glands, and skin, particularly within the sweat glands, the MR plays a key role in regulating sodium reabsorption. In non-epithelial tissues, such as the brain, adipose tissue, and heart, glucocorticoids are the main physiological MR ligands due to the absence of the 11β-hydroxysteroid dehydrogenase type 2. MR expression begins during development with tissue-specific patterns. In the kidney, MR levels peak mid-gestation, decrease at birth, and then increase postnatally. Loss of MR function, as observed in pseudohypoaldosteronism type 1 causes salt-wasting syndrome. Similar patterns are seen in the heart and brain, especially the hippocampus, where it influences stress regulation. On the contrary, MR expression is maintained at birth in the lung for neonatal fluid clearance via epithelial sodium channels. It is also present in tissues such as skin, retina, and gastrointestinal tract, indicating broad physiological roles. MR expression during fetal development correlates with adaptations to extra-uterine life, such as changes in amniotic fluid osmolality and aldosterone levels. MR gene expression and activity are tightly regulated through multiple mechanisms. These include transcriptional control via two promoters, post-transcriptional regulation involving RNA-binding proteins and microRNAs, and post-translational modifications, such as phosphorylation, sumoylation, and ubiquitination. These regulatory levels ensure appropriate MR function across different tissues and developmental stages and may have implications for conditions such as hypertension and heart failure.
Next-generation sequencing (NGS) is increasingly used for diagnosing monogenic forms of diabetes, including maturity-onset diabetes of the young (MODY). We aimed to evaluate the utility of NGS in patients with clinical suspicion of MODY, analyzing genotype-phenotype correlations. A total of 150 unrelated patients from the Region of Murcia (Spain) with suspected MODY were included. Whole-exome sequencing was performed and validated with Sanger and multiplex ligation-dependent probe amplification (MLPA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Relevant clinical data were collected per the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) criteria and analyzed using SPSS v.27.0.2.0. The diagnostic yield was 16.67% (25/150). Pathogenic or likely pathogenic variants were mainly identified in GCK (38.89%) and HNF1A (33.33%). Significant differences were found between patients with and without genetic diagnosis in family history, age of onset, and body mass index (P < 0.05). Variants of uncertain significance (VUS) were identified in 22 families (14.66%). One VUS was reclassified as likely pathogenic, and three were prioritized for further evaluation. NGS is a valuable tool for the genetic diagnosis of MODY. Integration of clinical data and systematic re-evaluation and prioritization of VUS can enhance diagnostic accuracy and inform clinical decision-making.
Polycystic ovary syndrome (PCOS) is a common disorder among women of reproductive age, characterized mainly by metabolic and endocrine disturbances caused by interactions of genetic, environmental, and other factors. Bile acid metabolism, as a key link between gut microbiota and the host, has been increasingly associated with the onset and development of PCOS. However, no systematic summary of this relationship is available so far. This review first discusses potential factors leading to bile acid pool changes in PCOS patients, including sex hormones, diet, and certain bacterial genera, which may promote PCOS by regulating bile acid metabolism. Bile acid signaling critically regulates host glucose and lipid homeostasis, follicular development, and sex hormone synthesis in a tissue-specific manner, indicating the limitations of focusing only on a single organ or cell type. Clinical studies show that bile acid metabolic profiles can distinguish PCOS patients from healthy controls, although the profiles are not fully consistent. Their heterogeneity is related to metabolic phenotypes, suggesting that bile acid profiling may help subtype PCOS. Given its role in insulin resistance, ovarian function, and steroid hormone synthesis, bile acid metabolism may act as a core hub in PCOS pathogenesis. Further mechanistic research is needed to better understand these processes and support the development of precise diagnostics and targeted therapies for PCOS.
Triac (3,3',5-triiodothyroacetic acid) is a thyroid hormone metabolite with thyromimetic properties. We investigated the effect of Triac on skeletal formation in larval zebrafish. Compared to other iodothyronines (T4, T3, and 3,5-T2), Triac at nanomolar concentrations stimulated larval zebrafish osteoblast activity in vivo, measured in an sp7:luciferase transgenic line and by the expression of osteoblast-specific genes. The mineralisation of bone elements and whole-body calcium content were enhanced, and the expression of osteoblast and bone matrix marker genes was stimulated. Triac increased the density of integumental ionocytes in the skin epithelium, and the expression of genes involved in calcium uptake increased significantly. No direct effect of Triac on osteoblasts of isolated zebrafish scales was found. The expression of stc1l, encoding the hypocalcaemic hormone stanniocalcin, was suppressed. We propose that Triac affects bone mineralisation by regulating both the uptake of calcium from the ambient water and the exchange of calcium between its major body compartments: bone, blood, and soft tissue. We discuss possible direct and indirect pathways via which Triac affects bone mineralisation. Triac is present in effluents from sewage treatment plants and has biological effects in sub-nanomolar concentrations. We postulate that Triac is an environmental endocrine disruptor.
The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.
Glial fibrillary acidic protein antibody-associated astrocytopathy (GFAP-A) is an autoimmune central nervous system inflammatory disorder diagnosed via cerebrospinal fluid (CSF) glial fibrillary acidic protein-immunoglobulin G detection. Clinically, it typically presents with meningoencephalitis or myelitis, accompanied by periventricular perivascular enhancement on brain magnetic resonance imaging (MRI) (findings that guide most routine diagnoses). Yet isolated spinal cord abnormalities (with negative brain MRI) in GFAP-A remain rarely reported, especially when occurring in patients with comorbidities like diabetes mellitus and active infection; these overlapping conditions often mask GFAP-A's typical features, consequently increasing the risk of clinical misdiagnosis. By reporting this atypical case, the study aims to supplement the existing imaging spectrum of GFAP-A and provide practical diagnostic references for complex clinical scenarios where underlying diseases obscure classic GFAP-A manifestations. It further carries significance in emphasizing the critical role of CSF GFAP-immunoglobulin G detection: this biomarker enables accurate identification of such atypical cases, directly addressing the misdiagnosis risk highlighted earlier. A 47-year-old Chinese male patient with a 13-year history of type 2 diabetes mellitus was admitted to the hospital due to fever and headache. Initially, the patient was diagnosed with upper respiratory tract infection based on positive Mycoplasma pneumoniae and parainfluenza virus antibodies; however, his symptoms persisted and worsened after treatment with moxifloxacin combined with oseltamivir. Emergency CSF examination showed increased pressure, elevated protein level, and monocytosis. Subsequent examination results revealed positive glial fibrillary acidic protein antibodies in the CSF; combined with lumbar MRI showing linear enhancement on the surface of the cauda equina nerves (and negative brain MRI findings), the patient was diagnosed with GFAP-A. The patient received anti-infection treatment, intracranial pressure reduction, and blood glucose control. After receiving the treatment, the patient's symptoms improved and he was discharged. At the 2-month follow-up after discharge, the patient still had postural tremor in both upper limbs, but no pathological reflexes were elicited. This case confirms that GFAP-A can be detected with positive spinal cord MRI findings alone, while negative brain MRI findings. Its key clinical significance lies in emphasizing the diagnostic value of CSF glial fibrillary acidic protein antibody detection for atypical cases, providing a new reference for the imaging spectrum of GFAP-A.
Clinical use of glucocorticoids in large quantities over a long period of time causes glucocorticoid-induced osteoporosis (GIOP). lncRNA OIP5-AS1 has elevated levels in delayed fracture healing, so the present study explored the role of OIP5-AS1 in a model of GIOP. The GIOP model was induced in mice by different doses of dexamethasone. The levels of OIP5-AS1, miR-335-5p, LC3-II, P62 mRNA, and four markers of osteogenic differentiation were assessed by RT-qPCR in the serum of GIOP mice and MC3T3-E1 cells. Cell proliferation was assessed by the CCK-8 kit. Lactic acid (LA) was assayed by a LA kit. The binding sites of OIP5-AS1 and miR-335-5p were predicted by the ENCORI database. DLR assay verified the binding relationship between OIP5-AS1 and miR-335-5p. GIOP mice had elevated levels of OIP5-AS1 expression, elevated lactate levels, increased oxidative stress, active autophagy, and reduced levels of osteogenic differentiation. After knocking down OIP5-AS1 in cellular models, miR-335-5p levels were elevated, lactate levels were decreased, oxidative stress levels were decreased, autophagy was inhibited, and osteogenic differentiation was increased. However, after transfection of miR-335-5p inhibitor, the cells had elevated lactate levels, decreased proliferative capacity, increased oxidative levels, active autophagic behavior, and decreased osteogenic differentiation. OIP5-AS1 levels were elevated in the GIOP model. Knockdown of OIP5-AS1 resulted in elevated miR-335-5p levels, enhanced proliferation and differentiation of osteoblasts, and suppression of autophagy and oxidative stress. Therefore, OIP5-AS1 may alleviate the development of GIOP through miR-335-5p.
Diabetic osteoporosis is a metabolic disease that seriously endangers human health and Previous studies have found that denosumab and metformin have certain effects on bone metabolism and glucose metabolism, respectively. However, there is still a lack of relevant research on the effect of the combined use of two drugs. In this study, we sought to analyze the therapeutic effect of these two drugs combined on the glycemic and bone metabolic parameters in the treatment of type 2 diabetes with postmenopausal osteoporosis. A prospective cohort study was designed to include 537 cases of patients with type 2 diabetes with postmenopausal osteoporosis. Patients were treated with placebo alone (placebo, n=135), metformin alone (MET, n=132), denosumab alone (DEN, n=136), and the combination group (n=134) for 30 months. Baseline data at 10 months, 20 months, and 30 months, Dual Energy X-ray Absorptiometry (DEXA), and pQCT were used to identify spine and tibia bone microstructures, respectively. The combination therapy group demonstrated significantly greater improvements in bone mineral density (tibia, radius, spine, and whole body) and bone microstructure (tibia and radius) compared to MET or DEN monotherapy (P<0.05). Bone absorption markers such as CTX and ALP were decreased, the level of bone formation markers was further increased, and the progression of glucose metabolism was improved significantly (P<0.05) compared to DEN alone or using MET alone. Denosumab monotherapy (DEN) ameliorated bone loss while exerting modest effects on glucose metabolism progression. In contrast, metformin monotherapy (MET) significantly improved glycemic control but demonstrated limited efficacy against bone loss. Crucially, the metformin-denosumab combination synergistically mitigated bone loss in diabetic postmenopausal osteoporosis patients.
The immunopathogenesis of autoimmune neurological syndromes (AINS) with antibodies against the 65 kDa isoform of glutamic acid decarboxylase (anti-GAD65 AINS) remains poorly understood. To elucidate underlying disease mechanisms and identify relevant cell populations, we performed single-cell RNA and immune repertoire sequencing of cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) of eight anti-GAD65 AINS individuals compared to eight noninflammatory controls. In addition, PBMCs from 19 anti-GAD65 AINS individuals and 20 healthy controls were analyzed by multidimensional flow cytometry, and brain tissue specimens from four anti-GAD65 AINS individuals were examined histologically. We detected higher frequencies of stem cell-like memory T cells (TSCM) within the PBMCs and a marked enrichment and clonal expansion of activated CD4+ TSCM in the CSF of anti-GAD65 AINS individuals. Expanded T cells exhibited increased expression of proinflammatory genes. Histological analyses confirmed intraparenchymal CD8+ TSCM in three of four anti-GAD65 AINS individuals and rare meningeal/intraparenchymal CD4+ TSCM in one person. Although CSF B cell receptors (BCRs) displayed little to no clonal expansion, recombinant expression of 40 CSF BCRs revealed that 25% were GAD65-reactive with increased somatic hypermutations compared to non-GAD65-reactive BCRs. These findings further support the concept of an antigen-specific intrathecal immune response. In summary, we characterize the immune landscape of anti-GAD65 AINS at single-cell resolution and identify clonally expanded TSCM with cytotoxic properties as a hallmark of this disease.
Gut dysbiosis and an increased risk of respiratory infection in type 2 diabetes have been well recognised. However, the relationship between the gut and respiratory pathobiont carriage rates in the type 2 diabetic Malaysian population is understudied. To address the knowledge gap, we profiled the gut and upper respiratory tract (URT) microbial composition, and the urine metabolome of 31 type 2 diabetic adults and 14 non-diabetic adults. We showed a higher prevalence of opportunistic URT pathogens in diabetes patients. A higher abundance of pro-inflammatory bacteria Escherichia coli was detected in the gut of the diabetic subjects. This coincided with the higher levels of sorbitol and taurine in the urine. The former is produced by aldose reductase, an enzyme strongly associated with airway inflammation, while the latter is a substrate for bacterial antioxidants (i.e. H2S). Despite a small sample size, our study revealed the potential relationship between the carriage rates of URT pathobionts with the gut microbial and urine metabolomic profiles of diabetes patients.
The expression of vaspin and GRP78 has been shown in the testis and ovary. The postnatal testis undergoes several changes in the expression of different proteins. The expression of vaspin and GRP78 has not been shown in the postnatal testis. It has also been shown that modulation of adipokine function could affect testicular germ cell proliferation and apoptosis. Whether vaspin regulates testicular proliferation and apoptosis in the early pubertal stage is still unknown. The aim of this study was to determine the expression of vaspin/GRP78 in postnatal testes of mice. Next, we investigated the effects of vaspin on cell proliferation and cell death (apoptosis, ferroptosis, and autophagy) in the pubertal testis. Immunohistochemistry and western blot analyses revealed that vaspin and GRP78 exhibit dynamic expression levels through developmental stages. In the testis, both proteins showed mild to moderate immunostaining in Leydig cells at early stages (PND7 and 14), with increasing intensity at PND21 and 42 in Leydig cells and spermatocytes, and round and elongated spermatids. The expression of vaspin and GRP78 was significantly down-regulated at postnatal day 21 (PND21). Moreover, exogenous vaspin treatment (PND21 to PND35) suppressed germ cell proliferation (BrdU labelling, PCNA, and GCNA) and apoptosis (decreased expression of active caspase-3 and TNFα) in the testis. The marker of autophagy, LAMP2, was elevated by vaspin treatment. Furthermore, vaspin treatment showed both stimulatory and inhibitory effects on markers of ferroptosis. In conclusion, vaspin/GRP78 could be a new regulator of cell proliferation and cell death in pubertal mouse testes.
Osteosarcopenia (OS) is a syndrome defined by the concurrent presence of sarcopenia and osteoporosis in the elderly population, which markedly elevates the risk of falls, fractures, and mortality. Recent studies demonstrate that disruption of muscle-bone biochemical crosstalk emerges as a key driver of OS pathogenesis, and that targeting pivotal mediators and pathways can concurrently restore musculoskeletal homeostasis. However, the precise molecular mechanisms and targeted therapeutic strategies remain inadequately explored. This review systematically summarizes the epidemiological risk factors and pathophysiological mechanisms underpinning OS, with emphasis on the interplay within musculoskeletal metabolism among myokines (e.g., fibroblast growth factors 21, FGF21, and irisin), osteokines (e.g., osteocalcin, OCN, receptor activator of nuclear factor-κB ligand, RANKL, and sclerostin, SOST), adipokines, and shared signaling pathways such as mitochondria-associated axes, Wnt/β-catenin, and nuclear factor-κB (NF-κB), as well as discusses the potential efficacy of direct and indirect interventions targeting these factors and biochemical signals, which provides innovative strategies and prospective research directions for developing precision-targeted therapies against OS and other degenerative musculoskeletal disorders. In addition, we propose that precise modulation of muscle-bone signaling constitutes a promising approach to treat OS. Future efforts should prioritize standardizing diagnostic criteria and advancing the development of therapies targeting critical muscle-bone biochemical interaction nodes to optimize the management of musculoskeletal comorbidities in the aging population.