Pancreatic islets respond to obesity-related insulin resistance by increasing β cell mass and insulin secretion. However, the molecular mechanisms behind this vital compensation are not fully understood. This study shows that adaptive islet-derived small extracellular vesicles (aid-sEVs) play a key role in β cell adaptation in obesity. Aid-sEV production rises under hyperlipidemic conditions, and uptake by adjacent cells occurs via F11R-mediated recognition. Mesenchymal stem cells (MSCs) act as downstream effectors after they internalize aid-sEVs, promoting β cell-adaptive responses. These vesicles deliver miR-151 to MSCs, triggering miR-151-dependent cellular reprogramming toward a Wnt-secreting phenotype. Restoration of miR-151 in microRNA-deficient aid-sEVs restores their proadaptive effects on β cells. Klf9, a direct target of miR-151, is involved in regulating MSC proliferation and WNT secretion by controlling Wnt3a and Ccnd1 transcription. These findings reveal a critical pathway controlling β cell compensation in diet-induced obesity and indicate that targeted enhancement of aid-sEV secretion could be a therapeutic strategy to counteract β cell dysfunction in diabetic patients.

Aging-associated β-cell senescence is a key driver of type 2 diabetes mellitus (T2DM). However, its associated molecular mechanisms remain poorly explored. This study identifies Chromobox 4 (CBX4), a Polycomb group protein with SUMO E3 ligase activity, as an essential regulator of β-cell aging and function. The results show that CBX4 expression progressively downregulates in both aged and diabetic pancreatic islets. Targeted deletion of Cbx4 in β-cell accelerates cellular senescence, impairs glucose tolerance, and compromises mitochondrial function. CBX4 interacts directly with the transcription factor NEUROD1 via its SUMO-interacting motif 1 (SIM1). CBX4 promotes SUMOylation of NEUROD1 at lysine 38 and drives its assembly into nuclear condensates via phase separation. These processes collectively antagonize NEDD4-mediated ubiquitination at the same site, stabilizing NEUROD1. The preserved NEUROD1 enhances Ins2 transcription and suppresses Camk2n1 expression, thus activating CaMKII signaling, promoting calcium influx, and maintaining mitochondrial bioenergetics. Furthermore, the study identifies STAT5A as a transcriptional regulator upstream of Cbx4. These findings reveal a STAT5A-CBX4-NEUROD1 signaling axis associated with β-cell aging in T2DM and suggest CBX4 as a promising therapeutic target to maintain β-cell function in metabolic disorders. As pancreatic β-cells age, CBX4 levels fall. Restoring CBX4 stabilizes the transcription factor NEUROD1 via SUMOylation and phase separation, counteracting its degradation to rejuvenate β-cell function and offering a new diabetes treatment avenue.

While the functional adaptation of β-cells during type 2 diabetes progression is well-established, the role of non-β islet cells remains largely unexplored. Utilizing single-cell RNA sequencing, we identified a substantial expansion of the macrophage population and a concomitant reduction in the proportion of mesenchymal stem cells (MSCs) within the islets of diabetic mice transitioning from metabolic compensation to decompensation. Under conditions of metabolic stress, macrophages extensively infiltrated the islets and adopted a pronounced pro-inflammatory phenotype. This phenotypic shift impaired β-cell glucose-stimulated insulin secretion and induced β-cell apoptosis. Simultaneously, macrophage-derived inflammatory factors, notably TNF-α, suppressed MSC proliferation and downregulated Wntless (Wls), thereby reducing extracellular Wnt transport. The resultant loss of Wls diminished MSCs' capacity to provide trophic support to β-cells and hindered the transition of macrophages to an anti-inflammatory phenotype. This self-perpetuating cycle establishes a chronic pro-inflammatory environment within the islets, culminating in β-cell functional deterioration and the onset of diabetes. Experimental intervention involving macrophage elimination and MSC administration was shown to disrupt this detrimental cycle, restoring β-cell function and glycemic control. Collectively, our findings reveal that macrophages and MSCs jointly govern β-cell adaptation through intricate paracrine crosstalk. Modulating these macrophage-MSC interactions holds significant therapeutic implications for maintaining β-cell integrity and underscores the considerable potential of MSC-based therapies for type 2 diabetes treatment.

The conversion of white adipose tissue (WAT) to brown adipose tissue (BAT) is a promising strategy for obesity treatment. It is previously identified βFaar as a conserved long noncoding RNA (lncRNA) regulator of islet β-cell function in individuals with obesity, but its effect on WAT browning is not well understood. In this study, it is discovered that βFaar expression in adipose tissue markedly decreases with the progression of obesity in both mice and humans. βFaar in adipose tissue reduces lipid droplet (LD) size in WAT and promotes a browning phenotype in inguinal WAT (iWAT), leading to the amelioration of high-fat diet (HFD)-induced obesity. These effects can be attributed to crosstalk between βFaar and proteins within the master regulatory pathways of LD formation and WAT browning, including RAS oncogene family 18 (RAB18) and interferon regulatory factor 4 (IRF4). Specifically, βFaar inhibits LD swelling by binding to RAB18 and promoting IRF4 nuclear translocation, increases uncoupling protein 1 (UCP1) transcription, and further induces iWAT browning by binding to karyopherin subunit alpha 6 (KPNA6). Together, these results demonstrate the critical roles of βFaar in regulating iWAT browning and preserving metabolic health; thus, βFaar may be a potential therapeutic target for management of obesity and related disorders.

Hypertriglyceridaemia (HTG) is a common and well-established aetiology of acute pancreatitis (AP). Although the underlying pathophysiology of hypertriglyceridaemic pancreatitis (HTGP) is complex, some animal models of HTAP have been successfully reproduced by repeated caerulein injections based on HTAP. However, most of the current HTGP models are critically dependent on the "two-attack" of cholecystokinin analogue, which may not be consistent with the fact of HTGP aetiologies due to ignored the initial effects of HTG in the development of HTGP. Here, we showed that HTGP could be induced by HTG independently, the HTGP mice with the typical characteristics and typical complications of pancreatitis. We found that the HTGP mice with mild pancreatic oedema, but the necrosis and immune cell infiltration were extensive. In addition, the immune cell infiltration and immune dysregulation that widely observed in HTGP patients were well reproduced in this model, including innate and adaptive immune cells. Our results suggest that the murine HTGP model independently induced by HTG could recapitulate the pathological and immunological profiles of HTGP in the clinic. More importantly, the model generated by this method could sustain a prolonged, non-life-threatening course of the disease and is suitable for research into the underlying mechanisms and for application to the preclinical evaluation of HTGP drugs.

BACKGROUND:To explore Ubiquitin D (UBD) and autophagy in hepatocellular carcinoma (HCC) and the key role of Olaparib targeting UBD in treating HCC. RESEARCH DESIGN AND METHODS:Bioinformatics analysis was conducted to study UBD expression in HCC tissues. qRT-PCR and Western blot measured UBD mRNA/protein levels, autophagy markers, and Gln metabolism proteins in HCC tissues. Cellular thermal shift assay (CETSA) confirmed Olaparib-UBD interaction. A xenograft tumor model was established to observe tumor growth in mice, with qRT-PCR and western blot used to measure UBD expression levels in tumor tissues and Immunohistochemistry (IHC) used to assess expression of Microtubule-associated protein light chain 3 (LC3), sequestosome 1 (P62), solute carrier family 1 member 5 (SLC1A5), and glutaminase (GLS). RESULTS:UBD was highly expressed in HCC tissues (p = 7.6e-11). UBD could negatively regulate autophagy levels by activating Gln metabolism. Olaparib could target and downregulate UBD expression, promoting HCC cell autophagy by regulating Gln metabolism pathways. Olaparib treatment in xenograft mice overexpressing UBD significantly reduced tumor growth (p < 0.05), inhibited Gln metabolism pathways, and enhanced HCC cell autophagy. CONCLUSIONS:Olaparib targeted UBD to promote autophagy in HCC by inhibiting Gln metabolism pathways.

BACKGROUND:Diabetic kidney disease (DKD) represents a common microvascular complication associated with diabetes. Research suggests that lipid accumulation contributes to lipotoxicity, exacerbating kidney injury in DKD. Quercetin (QCT), a flavonoid derived from specific fruits and vegetables, has shown potential in mitigating DKD progression; however, its precise protective mechanisms remain to be explored. PURPOSE:This study aimed to explore the effects of quercetin (QCT) on lipid accumulation in DKD and elucidate the underlying mechanisms. METHODS:The pathological and molecular changes associated with DKD were examined through histological, biochemical, and transcriptomic analyses in DKD mice and cell models treated with QCT. Bioinformatics analysis was conducted to identify key targets of QCT in DKD treatment. Molecular docking, cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were utilized to confirm the interaction of QCT and the identified targets. Moreover, PPARA/PPARG inhibitors and si-UCP1 were co-incubated with QCT in DKD cell models to assess their regulatory roles. RESULTS:QCT significantly improved renal function, reduced lipid deposition, and mitigated renal fibrosis in DKD mice. Peroxisome proliferator-activated receptors alpha and gamma (PPARA and PPARG) were identified as critical targets of QCT in DKD treatment. Inhibition of PPARA and PPARG in HK-2 cells reduced the protective effects of QCT. Transcriptomic analysis revealed that QCT activated the PPARA/PPARG-UCP1 axis, enhancing fatty acid oxidation, decreasing reactive oxygen species (ROS) production, and alleviating lipotoxicity. CONCLUSIONS:QCT ameliorated renal injury in DKD by improving lipid accumulation via the PPARA/PPARG-UCP1 axis, highlighting its potential as a therapeutic option for DKD treatment.

Polycomb repressive complex 1 (PRC1) is a multisubunit, evolutionarily conserved epigenetic regulator critical to numerous biological processes. Being a core component of the canonical PRC1 subunit within the Polycomb group protein complex, Chromobox4 (CBX4), a SUMO E3 ligase, can bind to H3K27me3 and recruit PRC1. This ligase regulates the SUMOylation of various proteins and permits their post-translational modification under different physiological conditions. CBX4 has been reported to regulate the development of senescence and various diseases in vivo. This review delves into the physiological functions and action mechanisms of CBX4 across different tissues and cells, particularly focusing on its primarily roles in migration, cellular senescence, metabolic dysregulation, inflammation development, and tumor proliferation. Targeting CBX4 offers a therapeutic potential for delaying cell senescence and suppressing tumor growth.

Introduction & Objective: Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. Macrophages accumulate in the adipose tissue and surround the dying or dead adipocytes like corona, which is witnessed to be the contributors to inflammation and obesity-induced insulin resistance. In this study, we aimed to identify key microRNA that regulates inter-cellular communication between lipid-overloaded adipocytes and macrophages, ultimately leading to adipose tissue inflammation and insulin resistance. Methods: RNA sequencing was performed to analyze the adipocyte tissue of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). We found progressive increase of microRNA-802 (miR-802) expression in adipose tissue with the development of dietary obesity in obese mice and humans. Then, the mechanism of miR-802 regulating adipose function was investigated by flow cytometric analysis, mouse metabolic studies, magnetic resonance imaging, and animal energy metabolism monitoring system. Results: Our findings validated miR-802 increasing prior to macrophage accumulation. Adipose tissue-specific knockout of miR-802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific miR-802 overexpression in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, miR-802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3, which translated into strong recruitment and M1-like polarization of macrophages. Conclusion: We established that miR-802 expression is an inflammatory signal in adipocytes, and this effect occurs through sensitization of the NF-kB signaling pathway. Collectively, our data raise the possibility that manipulation of miR-802 action axis represents therapeutic potential for adipose inflammation treatment. Disclosure Y. Yang: None. F. Zhang: None. L. Jin: None. Funding National Natural Science Foundation of China (82373925,82070801); Natural Science Foundation of Jiangsu Province (BK20221520, BK20200569); The Fundamental Research Funds for the Central Universities (2020M671661,2632023GR07)

Metastasis is the major cause of breast cancer mortality, with angiogenesis and tumor-released exosomes playing key roles. However, the communication between breast cancer cells and endothelial cells and its role in tumor metastasis remains unclear. Here, we characterize a long noncoding RNA, RPPH1, which is upregulated in breast cancer tissues and positively associated with poor prognosis. Hypoxia microenvironment upregulates the expression of RPPH1 in breast cancer cells, and promotes its packaging into exosomes through hnRNPA1, leading to the maintenance of stemness and aggressive traits in cancer cells and angiogenesis in endothelial cells. The function of cellular and exosomal RPPH1 was confirmed in the MMTV-PyMT mouse model, in which ASO-RPPH1 therapy effectively inhibited tumor progression and metastasis. Mechanistically, RPPH1 protects IGF2BP2 from ubiquitination-induced degradation, stabilizes N6-methyladenosine (m6A)-modified FGFR2 mRNA, and activates the PI3K/AKT pathway. Our research unveils the role of RPPH1 in breast cancer metastasis and highlights its potential as a therapeutic target.

Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

The use of mesenchymal stem cells (MSCs) is recognized as a promising strategy for the treatment of androgenetic alopecia (AGA). However, the underlying mechanism remains to be explored. Here, we evaluated the therapeutic effects and potential mechanisms of the use of human umbilical cord mesenchymal stem cells (hUCMSCs) in dihydrotestosterone (DHT)-induced AGA models in vivo and in vitro. Intradermal transplantation of hUCMSCs was performed in AGA model mice and therapeutic effects were evaluated using histological and immunofluorescence staining. Transwell assays were used for co-culture of hUCMSCs and dermal papilla cells (DPCs), and communication was assessed using RT-qPCR, immunofluorescence, and apoptosis analysis. Interactions between DPCs and hair follicle stem cells (HFSCs) were investigated using RT-qPCR, EdU assays, and cell cycle analysis. Treatment of AGA mice with hUCMSCs promoted hair growth, HFs density, skin thickness, and anagen phase activation, while inhibiting DPCs apoptosis, and promoting HFSCs proliferation. In vitro, hUCMSCs activated Wnt/β-catenin signaling in DPCs via Wntless (Wls), while stimulating growth factor secretion and HFSCs proliferation. Blocking β-catenin degradation with MSAB increased DPCs apoptosis, reduced growth factor secretion, and retarded HFSCs proliferation. hUCMSCs promoted hair regeneration in AGA model mice. This was found to be dependent on reducing DPCs apoptosis, thereby relieving the inhibitory effects of DPCs on the growth of HFSCs. The activation of the Wnt/β-catenin signaling pathway was shown to play a crucial role in the promotion of hair growth by hUCMSCs in AGA mice.

AbstractAdipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found thatmicroRNA-802(miR-802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend ofmiR-802preceded the accumulation of macrophages. Adipose tissue-specific knockout ofmiR-802lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression ofmiR-802in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically,miR-802activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokine and SREBP1, which translated into strong recruitment and M1-like polarization of macrophages. Our findings indicate thatmiR-802endows adipose tissue with the ability to recruit and polarize macrophages, which underscoresmiR-802as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

Background Dihydrotestosterone-induced androgen receptor activation and nuclear translocation was identified as the key event in androgen alopecia, which led to dermal papilla cell damage and hair growth cycle arrest. Inhibiting androgen receptor activation or nuclear translocation thus represents a potential therapeutic strategy for reducing dermal papilla cell damage and treating androgen alopecia. Purpose To evaluate the effects of obacunone androgen alopecia and explore the potential underlying mechanisms. Methods The effects of obacunone on androgen receptor activation and changes in the properties of dermal papilla cells were investigated. Meanwhile, the effects of obacunone on transforming growth factor-β-induced hair follicle stem cell damage and on androgen alopecia mice induced by dihydrotestosterone were evaluated. Results Obacunone can competitively bind to androgen receptors with dihydrotestosterone, thereby alleviating the androgen receptor dimerization and nuclear translocation. The negative effects of dihydrotestosterone on dermal papilla cell apoptosis, senescence, and cycle arrest were alleviated by obacunone. Obacunone also counteracted the proliferation and apoptosis of transforming growth factor-β-mediated hair follicle stem cells. In mice with androgen alopecia, treatment with obacunone promoted mice hair growth and inhibited TGF-β/smad signaling. Conclusion Thus, inhibiting androgen receptor dimerization was found to be an effective strategy for alleviating androgen alopecia. Obacunone follows a novel mechanism and holds potential as a drug candidate for androgen alopecia through inhibition of the dimerization of the androgen receptor. This targeting strategy may provide a new avenue for the development of new drugs different from the existing therapeutic approaches.

The immunoregulatory role of mesenchymal stem cells (MSCs) in inflammation is heterogeneous and can exhibit anti-inflammatory or proinflammatory properties depending on the microenvironment. We herein observed that the activation of Toll-like receptor 3 (TLR3) by polyinosinic : polycytidylic acid (poly(I : C)) stimulation facilitated the transformation of adipose-derived stem cells (ADSCs) into an anti-inflammatory phenotype. The enhanced anti-inflammatory properties were assessed in a taurocholate-induced pancreatitis model. The results demonstrated that poly(I : C) pretreated ADSCs exhibited enhanced anti-inflammatory properties than untreated ADSCs in taurocholate-induced pancreatitis. Mechanistically, poly(I : C)-treated ADSCs showed increased production and secretion of interleukin-10 (IL-10), which demonstrates a potent ability to alleviate inflammatory signaling cascades in acinar cells. Simultaneously, the heightened anti-inflammatory effects of poly(I : C)-treated ADSCs in pancreatitis were associated with the regulation of macrophage classical/alternative transformation, thereby mitigating inflammatory factor-mediated damage to the pancreatic acinar cell. We propose that TLR3 activation by poly(I : C) is an effective strategy to enhance the anti-inflammatory properties of MSCs, which offers a valuable consideration for improving the therapeutic efficacy of MSCs in inflammatory diseases.

Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.

Osteoarthritis (OA) is considered to be a highly heterogeneous disease with progressive cartilage loss, subchondral bone remodeling, and low-grade inflammation. It is one of the world's leading causes of disability. Most conventional clinical treatments for OA are palliative drugs, which cannot fundamentally cure this disease. The stromal vascular fraction (SVF) from adipose tissues is a heterogeneous cell population. According to previous studies, it contains a large number of mesenchymal stem cells, which have been used to treat OA with good therapeutic results. This safe, simple, and effective therapy is expected to be applied and promoted in the future. In this paper, the detailed pathogenesis, diagnosis, and current clinical treatments for OA are introduced. Then, clinical studies and the therapeutic mechanism of SVF for the treatment of OA are summarized.

Pancreatic β-cell adapt to compensate for increased metabolic demand during obesity. Although the microRNA (miRNA) pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated β-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly-A tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity.

糖尿病是当今世界上最常见且普遍的慢性代谢性疾病之一,对于肾脏、心脑血管、神经、眼睛等均有极大的危害性.目前糖尿病主要包括以下四种:1型糖尿病、2型糖尿病、妊娠期糖尿病和特殊类型糖尿病.2017年我国糖尿病患病率持续上升至17.2％,其中2型糖尿病(Type 2 diabetes mellitus,T2DM)比例高达90％以上,因此糖尿病也已成为实施健康中国战略,提升健康水平亟待攻克的难题.肥胖是一种由环境、遗传、饮食、年龄等多种因素相互作用而引起的一种机体代谢紊乱综合征,也是糖尿病发生的重要诱因.T2MD患者和许多肥胖患者都表现出胰岛素刺激的葡萄糖吸收和利用的效率下降,胰岛β细胞出现代偿性增殖并增加总胰岛素的分泌水平从而达到稳定血糖的作用,这一现象被称为胰岛素抵抗(Insulin resistance,IR).胰岛素是通过其信号通路从而在机体中发挥调控作用,如果整个通路中的某一部分受到损害发生损伤,通路因此无法将上游信息正常传递至下游,胰岛素的调控作用将受到削弱甚至可能消失.当IR发生时,若通路受损,胰岛素无法调控全身葡萄糖稳态.随着IR的发展,当胰腺不能提供过量的胰岛素时,就会导致全身葡萄糖稳态的严重失衡,这将会诱发T2MD以及许多代谢性疾病.近年来已有大量以IR病理机制为主题的研究被报道,文章聚焦于以肥胖及胰岛素信号通路受损为主的IR诱导机制,整理并阐述了相关研究进展,以期为未来的进一步研究提供思路与依据.