Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression

Fibroblast activation protein(Fap)is a serine protease that degrades denatured type I collagen,α2-antiplasmin and FGF21.Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin(Oln).Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis(RA).However,whether Fap plays a critical role in osteoarthritis(OA)remains poorly understood.Here,we found that Fap is significantly elevated in osteoarthritic synovium,while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice.Mechanistically,we found that Fap degrades denatured type II collagen(Col II)and Mmp13-cleaved native Col II.Intra-articular injection of r Fap significantly accelerated Col II degradation and OA progression.In contrast,Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA.Genetic deletion of Oln significantly exacerbated OA progression,which was partially rescued by Fap deletion or inhibition.Intra-articular injection of r Oln significantly ameliorated OA progression.Taken together,these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

Molecular phylogenetics and population demographic history of Amphioctopus fangsiao,inferred from mitochondrial and microsatellite DNA markers

Amphioctopus fangsiao(Cephalopoda:Octopodidae)is an important commercial species in the coastal waters of China.In recent years,however,the resource of A.fangsiao have declined because of habitat destruction and overfishing.To analyze the genetic variations of A.fangsiao caused by the fluctuation of resources,the population genetic structure of nine sampling locations collected from the Bohai Sea to the South China Sea were investigated,using mtDNA COI fragments and microsatellite DNA.The results of F-statistics,AMOVA,STRUCTURE and PCA analyses showed three phylogeographic clades(Clades A,B and C),revealing limited genetic exchange between north and south populations.These clades diverged in 2.23(Clades A and B)and 3.67(Clades A,B and C)million years ago,during the dramatic environmental fluctuations,such as sea level and temperature changes,have exerted great influence on the survival distribution pattern of global organisms.Our results for low genetic connectivity among A.fangsiao populations provide insights into the development of management strategies,that is,to manage this species as separate management unit.

Scutellarin alleviates complete freund’s adjuvant-induced rheumatoid arthritis in mice by regulating the Keap1/Nrf2/HO-1 pathway

Scutellarin(SCU)is a herbal flavonoid glucuronide with multiple pharmacological activities,including antioxidant,anti-inflammation,vascular relaxation,anti-platelet,and myocardial protection.However,the effect of SCU on complete Freund’s adjuvant(CFA)-induced rheumatoid arthritis(RA)had not been studied.In this study,we investigated the beneficial effects of SCU in the CFA-induced RA mice model and the anti-arthritic activity was evaluated by paw edema.Enzyme-linked immunosorbent assay(ELISA)was carried out to evaluate the plasma levels of immunoglobulin(Ig)G,IgE,tumor necrosis factor(TNF)-α,interleukin(IL)-1β,IL-6,receptor activator of nuclear factor-κB ligand(RANKL),and osteoprotegerin(OPG).Histological slides were prepared from the harvested paws of mice to determine the pathological changes in the joints.The proportions of T helper type 1(Th1)and T helper type 2(Th2)cells of CD4+T lymphocyte subsets were analyzed by flow cytometry.The expression of Kelch-like ECHassociated protein 1(Keap1),nuclear factor erythroid 2-related factor 2(Nrf2),and heme oxygenase-1(HO-1)was analyzed using real-time quantitative PCR(RT-qPCR)and western blotting assays.The present study demonstrated that SCU prevented CFA-induced RA,and inhibited the expression of inflammation factors,IgG,IgE,TNF-α,IL-1β,and IL-6.While SCU also reduced the RANKL level,it increased OPG expression in RA mice.The Th1/Th2 ratio was significantly lower in mice treated with SCU.Additionally,HO-1 expression was reduced while the expression of Keap1 and Nrf2 was elevated following SCU treatment.Results provide preliminary evidence to employ SCU in arthritis treatment which might be related to the regulation of Th1/Th2 balance and the Keap1/Nrf2/HO-1 pathway.

Discussion on the Application Effect of Simplified Vacuum Sealing Drainage(VSD)in the Treatment of Chronic Refractory Wounds

Objective:To analyze the effect of simplified vacuum sealing drainage(VSD)in the treatment of chronic refractory wounds.Methods:A total of 90 patients with chronic refractory wounds treated from May 2022 to May 2023 were randomly divided into groups.The simplified VSD treatment was employed in group A,and conventional treatment was employed in group B,and the wound healing of both groups were compared.Results:Group A showed better wound healing compared to group B,P<0.05;the wound healing rate,wound healing duration,visual analog scale(VAS)score,wound dressing times and other indicators in group A were better than those in group B,P<0.05.The SF-36 score of group A was higher than that of group B,P<0.05;the complication rate of chronic refractory wounds in group A was no different from that in group B,P>0.05.Conclusion:Simplified VSD treatment is effective in treating patients with chronic refractory wounds,and it reduces the number of wound dressing changes and promote wound healing.

7例生物潜能未定非典型神经纤维瘤的临床病理学特征

目的:探讨生物潜能未定非典型神经纤维瘤(atypical neurofibromatous neoplasm of uncertain biologic potential,ANNUBP)的临床病理特征、免疫表型、分子遗传学改变。方法:分析2014年12月至2020年8月收集于北京大学国际医院病理诊断为非典型或富于细胞性神经纤维瘤14例患者的临床资料,其中7例具有ANNUBP的特征,光镜观察肿瘤细胞形态、免疫表型特征、并进行总结。结果:ANNUBP中男性5例,女性2例,年龄14~44岁(平均年龄27岁,中位年龄27岁);6例位于腹膜后,1例位于头颈部,最大径4.5~21.5 cm,平均11.0 cm,界限较清。镜下肿瘤细胞可见细胞异型性、丰富密集、失去神经纤维瘤结构和/或核分裂像增加(>1/50 HPF和<3/10 HPF);其中4例多次复发,2例进展为恶性外周神经鞘膜瘤(malignant peripheral nerve sheath tumor,MPNST),1例无瘤生存,复发率85.71%(6/7),恶变率28.57%(2/7);S-100、SOX-10、H3K27Me3在7例中均弥漫强表达,1例CD34染色显示网状结构消失,Ki-67增殖指数<2%~5%。结论:ANNUBP是具有较高复发率和恶变率的肿瘤,术后应结予相应的辅助治疗,并密切随访,同时也应避免过度治疗;结合免疫组织化学,有助于其诊断和鉴别诊断。

A simple method of depressing numerical dissipation effects during wave simulation within the Euler model

Numerical wave tanks are widely-acknowledged tools in studying waves and wave-structure interactions. They can generate waves under realistic scales and offers more information on the fluid field. However, most numerical wave tanks suffer from issues known as the numerical dissipation and numerical dispersion. The former causes wave energy to be slowly dissipated and the latter shifts wave frequencies during wave propagation. This paper proposes a simple method of depressing numerical dissipation effects on the basis of solving Euler equations using the finite difference method(FDM). The wave propagation solutions are solved analytically taking into account the influence of the damping terms. The main idea of the method is to append a source term to the momentum equation, whose strength is determined by how strong the numerical damping effect is. The method is verified by successfully depressing numerical effects during the simulation of regular linear waves, Stokes waves and irregular waves. By applying the method, wave energy is able to be close to its initial value after long distance of travel.

石质文物风化成因分析及化学封护材料的研究

选择本地区部分焦山石刻,从物理因素、化学因素、生物因素以及人为因素等方面,分析了引起焦山石刻风化的原因。本文以丙烯酸酯为基料,甲基丙烯酸十二氟庚酯和二氧化硅为改性剂,制备了一种成膜性好、无色透明的氟硅丙烯酸酯封护材料。通过模拟抗风化试验,研究封护材料在焦山石刻上的抗风化能力。结果表明,经封护后,能保持石质文物原貌,且具有较好的耐水、耐酸碱性和较强的抗风化能力。

EHMT2 (G9a) activation in mantle cell lymphoma and its associated DNA methylation and gene expression

Objective:The function of euchromatic histone-lysine N-methyltransferase 2(EHMT2)has been studied in several cancers;however,little is known about its role in mantle cell lymphoma(MCL).Thus,this study aimed to characterize the significance and function of EHMT2 in MCL.Methods:EHMT2 expression in MCL and reactive hyperplasia(RH)were investigated by immunohistochemistry.Genome-wide analysis of DNA methylation was performed on EHMT2+MCL samples.The function of EHMT2 was determined by CCK&flow cytometry,and western blot assays.Gene expression profile analysis was performed before and after EHMT2 knockdown to search for EHMT2-regulated genes.Co-immunoprecipitation(Co-IP)experiments were conducted to identify the proteins interacting with EHMT2.Results:EHMT2 was expressed in 68.57%(24/35)of MCLs but not in any RHs.Genome-wide analysis of DNA methylation on EHMT2+MCLs revealed that multiple members of the HOX,FOX,PAX,SOX,and CDX families were hypermethylated or hypomethylated in EHMT2+MCLs.BIX0I294,a EHMT2 inhibitor,inhibited MCL cell growth and stalled cells in the G1 phase.Additionally,BIX01294 downregulated the expressions of cell cycle proteins,cyclin DI,CDK4,and P21,but upregulated the expressions of apoptosis-related proteins,Bax and caspase-3.Co-IP experiments revealed that EHMT2 interacted with UHRF1,HDAC1,and HDAC2 but not with HDCA3.After EHMT2 knockdown,multiple genes were regulated,including CD5 and CCND1,mostly enriched in the Tec kinase signaling pathway.In addition,several genes(e.g.,MARCH 1,CCDC50,HIP1,and WNT3)were aberrantly methylated in EHMT2+MCLs.Conclusions:For the first time,we determined the significance of EHMT2 in MCL and identified potential EHMT2-regulated genes.

FBXW7 regulates epithelial barrier impairment in human bronchial epithelial cells in vitro by targeting apoptosis signal-regulating kinase1 via the p38 pathway

Bronchial asthma is a common chronic inflammatory disease characterized by airway hyperresponsiveness(AHR),inflammatory cell infiltration,and airway remodeling.F-box/WD repeat-containing protein 7(FBXW7),an E3 ubiquitin ligase,is required for various endothelial functions,such as cell migration,inflammation,and endothelial integrity.This study aimed to investigate the role of FBXW7 in lipopolysaccharide(LPS)-induced epithelial barrier impairment in bronchial epithelial cells in vitro.By using lentivirus-based technology,FBXW7 was overexpressed or silenced(24 h)in human bronchial epithelial(16HBE)cells,which were treated with LPS or not(24 h).Immunoprecipitation(IP)detection and Western blot analysis were used to evaluate the interaction of target proteins.Cell permeability was measured using transepithelial electrical resistance and FITC dextran flux(48 h).IL-1β,IL-18 and TNF-αin cell supernatants were measured using ELISA(48 h).The results showed that LPS stimulation suppressed FBXW7 expression in a time-and dose-dependent manner.LPS exposure decreased cell proliferation,elevated IL-1β,IL-18 and TNF-α,increased epithelial permeability,and p38 phosphorylation.These LPS-induced changes were partly compromised by FBXW7 overexpression.Similar to LPS stimulation,FBXW7 knockdown increased epithelial permeability and levels of inflammatory cytokines and p38 phosphorylation,which were,in part,blocked by apoptosis signal-regulating kinase(ASK)1 knockdown or p38 pathway inhibition.IP and Western blot analysis showed that FBXW7 interacted with ASK1.ASK1 expression was inversely associated with FBXW7 expression.FBXW7 overexpression markedly enhanced ASK1 ubiquitination.These data revealed that FBXW7 counter against inflammation and protects epithelial barrier integrity in bronchial epithelial cells by promoting ubiquitination-mediated degradation of ASK1 via the p38 pathway.

PIP, Not FiO₂Regulates Expression of MMP-9 in the Newborn Rabbit VILI with Different Mechanical Ventilation Strategies

Background: Results from experimental and clinical studies have shown that mechanical ventilation or/and hyperoxia may aggravate a pre-existing lung injury or even cause lung injury in healthy lungs by affecting the expression of MMP-9, but the MMP-9 effects are controversial. How are MMP-9 regulated when multicausative factors of injury such as different FiO2, PIP, and respiratory time (RT) impose simultaneously on lungs? Methods: Newborn New Zealand white rabbits were randomly allocated to an unventilated air control group or to one of the 2 × 3 × 3 ventilation strategies by using a factorial design, with different FiO2, PIP, and RT. Then, lung wet-to-dry ratio (W/D), lung histopathology scores, transmission electron microscope, and cells in BALF were analyzed in these different groups. MMP-9 levels were studied by immunohistochemistry and ELISA. Results: MMP-9 levels were significantly different among 3 PIP ventilation regimes (F = 7.215) and MPIP group was the highest among 3 PIP groups. The lung histopathology score in 100% oxygen was significantly higher than in 45% oxygen group (F = 9.037) and MPIP group was the lowest among 3 PIP groups (F = 57.515) and RT 6 h was more serious than RT 1 h. MMP-9 positively correlated with monocytes, but negatively correlated with neutrophils and lung injury histopathology scores. Conclusions: Different PIP and FiO2 exert simultaneously on newborn lung in newborn rabbits ventilation, only mechanical stretch stimulation affects MMP-9 synthesis. Advisable mechanical stretch can promote MMP-9 expression and has protective role in lung in VILI. HPIP causes barotraumas and LPIP induces atelectrauma.

A novel biological sources consistency evaluation method reveals high level of biodiversity within wild natural medicine:A case study of Amynthas earthworms as"Guang Dilong"

For wild natural medicine,unanticipated biodiversity as species or varieties with similar morphological characteristics and sympatric distribution may co-exist in a single batch of medical materials,which affects the efficacy and safety of clinical medication.DNA barcoding as an effective species identification tool is limited by its low sample throughput nature.In this study,combining DNA minibarcode,DNA metabarcoding and species delimitation method,a novel biological sources consistency evaluation strategy was proposed,and high level of interspecific and intraspecific variations were observed and validated among 5376 Amynthas samples from 19 sampling points regarded as"Guang Dilong"and 25 batches of proprietary Chinese medicines.Besides Amynthas aspergillum as the authentic source,8 other Molecular Operational Taxonomic Units(MOTUs)were elucidated.Significantly,even the subgroups within A.aspergillum revealed here differ significantly on chemical compositions and biological activity.Fortunately,this biodiversity could be controlled when the collection was limited to designated areas,as proved by 2796"decoction pieces"samples.This batch biological identification method should be introduced as a novel concept regarding natural medicine quality control,and to offer guidelines for in-situ conservation and breeding bases construction of wild natural medicine.

Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation

Ketone bodies have beneficial metabolic activities,and the induction of plasma ketone bodies is a health promotion strategy.Dietary supplementation of sodium butyrate(SB)is an effective approach in the induction of plasma ketone bodies.However,the cellular and molecular mechanisms are unknown.In this study,SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2),a rate-limiting enzyme in ketogenesis,to promote ketone body production in hepatocytes.SB administrated by gavage or intraperitoneal injection significantly induced bloodβ-hydroxybutyrate(BHB)in mice.BHB production was induced in the primary hepatocytes by SB.Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis.However,the alteration was mostly observed in mitochondrial proteins with 41%down-and 65%up-regulation,respectively.Succinylation status of HMGCS2 protein was altered by a reduction at two sites(K221 and K358)without a change in the protein level.The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice.The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver.The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis.The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.

Implantable and biodegradable closed‐loop devices for autonomous electrotherapy

Implantable electronic devices as a valuable biomedical tool are used to treat chronic diseases.However,traditional pacemakers exist a serious risk of complications.A biodegradable,closed‐loop sensor‐actuator system is developed for cardiac rhythm monitoring.This system could achieve autonomous electrotherapy.

Regulation of microbiota–GLP1 axis by sennoside A in diet-induced obese mice

Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet(HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR(homeostatic model assessment for insulin resistance) and glucose tolerance test(GTT). SA restored plasma level of glucagon-like peptide 1(GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids(SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.

NF-κB/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis

The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In this study,the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1(HDAC1)in hepatocytes.The activity was supported by the phenotypes of P50 knockout(P50-KO)mice and P65 knockout(P65-KO)mice.Hepatic steatosis was reduced in the P50-KO mice,but not in the P65-KO mice.The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells.Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells.A decrease in sterol-regulatory element binding protein lc(SREBP1 c)protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown.The decrease was associated with an increase in succinylation of SREBP1 c protein.The study suggests that P50 stabilizes HDAC1 to support the SREBP1 c activity in hepatic steatosis in the pathophysiological condition.Interruption of this novel pathway in the P50-KO,but not the P65-KO mice,may account for the difference in hepatic phenotypes in the two lines of transgenic mice.

A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models

Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.

Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis:a randomized,double-blind,placebo-controlled phase 2 trial

Rheumatoid arthritis(RA)is an aggressive autoimmune arthritis,and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects.Low-dose interleukin-2(Ld-IL2)is potentially a therapeutic approach to further improve the disease.This randomized,double-blind,placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA.Patients were randomly assigned(1:1)to receive Ld-IL2,defined as a dose of 1 million IU,or placebo in a 12-week trial with a 12-week follow-up.Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks(a total of 7 doses),followed by a 2-week break.All patients received a stable dose of methotrexate(MTX).The primary outcomes were the proportion of patients achieving the ACR20,DAS28-ESR<2.6,and the change from baseline in CDAI or SDAI at week 24.Secondary endpoints included other clinical responses and safety.The primary outcomes were achieved in the perprotocol population.The improvements from baseline in CDAI and SDAI were significantly greater across time points for the LdIL2+MTX group(n=17)than for the placebo+MTX group(n=23)(P=0.018 and P=0.015,respectively).More patients achieved ACR20 response in the Ld-IL2+MTX group than those in the placebo+MTX group at week 12(70.6%vs 43.5%)and at week 24(76.5%vs 56.5%)(P=0.014).In addition,low Treg and high IL-21 were associated with good responses to Ld-IL2.Ld-IL-2 treatment was well-tolerated in this study.These results suggested that Ld-IL2 was effective and safe in RA.ClinicalTrials.gov number:NCT 02467504.

Comprehensive lipidomics in apoM^(-/-) mice reveals an overall state of metabolic distress and attenuated hepatic lipid secretion into the circulation

Apolipoprotein M(apoM) participates in both high-density lipoprotein and cholesterol metabolism. Little is known about how apo M affects lipid composition of the liver and serum. In this study, we systemically investigated the effects of apo M on liver and plasma lipidomes and how apo M participates in lipid cycling, via apo M knockout in mice and the human SMMC-7721 cell line. We used integrated mass spectrometry-based lipidomics approaches to semiquantify more than 600 lipid species from various lipid classes, which include free fatty acids, glycerolipids, phospholipids, sphingolipids, glycosphingolipids, cholesterol, and cholesteryl esters(CEs), in apo M^(-/-)mouse. Hepatic accumulation of neutral lipids, including CEs, triacylglycerols, and diacylglycerols, was observed in apo M^(-/-)mice;while serum lipidomic analyses showed that, in contrast to the liver, the overall levels of CEs and saturated/monounsaturated fatty acids were markedly diminished. Furthermore, the level of Apo B-100 was dramatically increased in the liver, whereas significant reductions in both Apo B-100 and low-density lipoprotein(LDL) cholesterol were observed in the serum of apo M^(-/-)mice, which indicated attenuated hepatic LDL secretion into the circulation. Lipid profiles and proinflammatory cytokine levels indicated that apo M^(-/-)leads to hepatic steatosis and an overall state of metabolic distress. Taken together, these results revealed that apo M knockout leads to hepatic steatosis, impaired lipid secretion, and an overall state of metabolic distress.

Effect of soil crust on evaporation and dew deposition in Mu Us sandy land,China

The development of soil crust on sandy land may affect the surface hydrological process.This paper investigates the process of evaporation and dew deposition influenced by different soil surface types which were dominated by sand,primitive biotic crust,and advanced biotic crust,respectively,in the south fringe of Mu Us sandy land in Northwest China from July to September of 2006.The experimental results indicate that the advanced biotic crust could increase evaporation and dew deposition compared to the primitive biotic crust and bare sand although the differences between them were not significant.The average evaporation from advanced biotic crust,primitive biotic crust and sand was 6.8,6.6,and 6.5 mm/d,respectively,and water content is around 16.2%in the condition of initially identical soil.The average dew amount on advanced biotic crust was 0.116 mm/d with extreme 0.05 and 0.24 mm/d.The average values on primitive biotic crust and sand were 0.105 and 0.101 mm/d,respectively,with extreme 0.04 and 0.21 mm/d for both treatments.Also,the dew deposition on advanced biotic crust seemed stable and might rest for a longer time than that on primitive biotic crust and sand.The results suggest that the advanced biotic crust possibly facilitates evaporation and dew deposition.Therefore,the development of biotic crust may potentially enhance the hydrological circulation in the upper sand layer in sandy land.

Mitochondrial protein IF1 is a potential regulator of glucagon-like peptide(GLP-1) secretion function of the mouse intestine

IF1(ATPIF1) is a nuclear DNA-encoded mitochondrial protein whose activity is inhibition of the F1Fo-ATP synthase to control ATP production.IF1 activity remains unknown in the regulation of GLP-1 activity.In this study,IF1 was examined in the diet-induced obese mice using the gene knockout(If1-KO) mice.The mice gained more body weight on a high fat diet without a change in food intake.Insulin tolerance was impaired,but the oral glucose tolerance was improved through an increase in GLP-1 secretion.The KO mice exhibited an improved intestine structure,mitochondrial superstructure,enhanced mitophagy,reduced apoptosis and decreased adenine nucleotide translocase 2(ANT2) protein in the intestinal epithelial cells together with preserved gut microbiota.The data suggest that GLP-1 secretion was enhanced in the obese If1-KO mice to preserve glucose tolerance through a signaling pathway of ANT2/mitochondria/L-cells/GLP-1/insulin.IF1 is a potential mitochondrial target for induction of GLP-1 secretion in L-cells.