This paper explored the specific mechanism of ginsenoside Rg_1 in regulating mitochondrial fusion through the neurogenic gene Notch homologous protein 1(Notch1) pathway to alleviate hypoxia/reoxygenation(H/R) injury in HL-1 cells. The relative viability of HL-1 cells after six hours of hypoxia and two hours of reoxygenation was detected by cell counting kit-8(CCK-8). The lactate dehydrogenase(LDH) activity in the cell supernatant was detected by the lactate substrate method. The content of adenosine triphosphate(ATP) was detected by the luciferin method. Fluorescence probes were used to detect intracellular reactive oxygen species(Cyto-ROS) levels and mitochondrial membrane potential(ΔΨ_m). Mito-Tracker and Actin were co-imaged to detect the number of mitochondria in cells. Fluorescence quantitative polymerase chain reaction and Western blot were used to detect the mRNA and protein expression levels of Notch1, mitochondrial fusion protein 2(Mfn2), and mitochondrial fusion protein 1(Mfn1). The results showed that compared with that of the control group, the cell activity of the model group decreased, and the LDH released into the cell culture supernatant increased. The level of Cyto-ROS increased, and the content of ATP decreased. Compared with that of the model group, the cell activity of the ginsenoside Rg_1 group increased, and the LDH released into the cell culture supernatant decreased. The level of Cyto-ROS decreased, and the ATP content increased. Ginsenoside Rg_1 elevated ΔΨ_m and increased mitochondrial quantity in HL-1 cells with H/R injury and had good protection for mitochondria. After H/R injury, the mRNA and protein expression levels of Notch1 and Mfn1 decreased, while the mRNA and protein expression levels of Mfn2 increased. Ginsenoside Rg_1 increased the mRNA and protein levels of Notch1 and Mfn1, and decreased the mRNA and protein levels of Mfn2. Silencing Notch1 inhibited the action of ginsenoside Rg_1, decreased the mRNA and protein levels of Notch1 and Mfn1, and increased the mRNA and protein levels of Mfn2. In summary, ginsenoside Rg_1 regulated mitochondrial fusion through the Notch1 pathway to alleviate H/R injury in HL-1 cells.
Ginsenosides/pharmacology* ; Receptor, Notch1/genetics* ; Signal Transduction/drug effects* ; Mice ; Animals ; Mitochondrial Dynamics/drug effects* ; Mitochondria/metabolism* ; Cell Line ; Reactive Oxygen Species/metabolism* ; Oxygen/metabolism* ; Cell Hypoxia/drug effects* ; Cell Survival/drug effects* ; Membrane Potential, Mitochondrial/drug effects* ; Humans

Oral submucous fibrosis (OSF), characterized by excessive deposition of extracellular matrix (ECM) that causes oral mucosal tissue sclerosis, and even cancer transformation, is a chronic, progressive fibrosis disease. However, despite some advancements in recent years, no targeted antifibrotic strategies for OSF have been approved; likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined. In this review, we briefly introduce the epidemiology and etiology of OSF. Then, we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors, secretion function, and activation of ECM-producing myofibroblasts. In addition, we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF. Finally, we summarize strategies to interrupt key mechanisms that cause OSF, including modulation of the ECM, inhibition of inflammation, improvement of vascular disturbance. This review will provide potential routes for developing novel anti-OSF therapeutics.
Humans ; Oral Submucous Fibrosis/immunology* ; Extracellular Matrix/metabolism* ; Myofibroblasts

Background::Hepatic ischemia-reperfusion injury (HIRI) remains a common complication during liver transplantation (LT) in patients. As a key downstream effector of the Hippo pathway, Yes-associated protein (YAP) has been reported to be involved in various physiological and pathological processes. However, it remains elusive whether and how YAP may control autophagy activation during ischemia-reperfusion.Methods::Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation. Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation. Results::Autophagy was activated in the post-perfusion liver grafts during LT in patients, and the expression of YAP positively correlated with the autophagic level of hepatocytes. Liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI ( P <0.05). YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models ( P <0.05). Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine. In addition, inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species ( P <0.05). Moreover, the regulation of autophagy by YAP during HIRI was mediated by AP1 (c-Jun) N-terminal kinase (JNK) signaling through binding to the transcriptional enhanced associate domain (TEAD). Conclusions::YAP protects against HIRI by inducing autophagy via JNK signaling that suppresses the apoptosis of hepatocytes. Targeting Hippo (YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.

Sepsis is a condition characterized by organ dysfunction resulting from the systemic inflammatory response triggered by an infection. Excessive inflammation and immunosuppression are intertwined, and severe cases may even develop into multiple organ failure. Studies have shown that indoleamine 2,3-dioxygenase 1-mediated tryptophan metabolism is involved in the occurrence and development of sepsis, and elevated plasma kynurenine levels and Kyn/Trp ratios are early indicators of sepsis development. In this paper, we provide a comprehensive summary of the role of IDO1 in the acute inflammatory phase of sepsis, late immunosuppression, and organ damage. This includes its regulation of inflammatory state, immune cell function, blood pressure, and other aspects. Additionally, we analyze preclinical studies on targeted IDO1 drugs. An in-depth understanding and study of IDO may help to understand the pathogenesis and clinical significance of sepsis and multiple organ damage from a new perspective and provide new research ideas for exploring its prevention and treatment methods.

BACKGROUND:Due to the mismatch between the design of the proximal femoral nail antirotation Asian version(PFNA-Ⅱ)and Asian population,extrusion of the proximal femoral intertrochanteric nail may occur in the treatment of femoral intertrochanteric fractures.The influence of the protruding length on the curative effect of the operation needs to be further discussed. OBJECTIVE:To quantitatively measure the protruding length of the proximal trochanter of the femur with intramedullary nail after PFNA-Ⅱ,and to analyze the effect of protruding length on the efficacy of PFNA-Ⅱ in the treatment of femoral intertrochanteric fractures. METHODS:Totally 68 patients with femoral intertrochanteric fractures treated with PFNA-Ⅱ internal fixation in the First Affiliated Hospital of Anhui Medical University were selected.The extramedullary process of the proximal trochanter of the femur was quantitatively measured on the anterior and posterior X-ray films of the hip joint within 6 months after operation.According to the existence of extrusion of the proximal trochanter intramedullary nail,the patients were divided into protruding group and non-protruding group.The data of sex,height,fracture type,length and diameter of the intramedullary nail,the position of screw blade in the femoral neck and protruding length of proximal greater trochanter were collected.The postoperative curative effect was judged by visual analog scale pain score and hip joint Harris score at 6 months after operation.The influence of protruding proximal trochanter of the PFNA-Ⅱ intramedullary nail on the operative effect was observed. RESULTS AND CONCLUSION:(1)There were significant differences in sexual characteristics between the protruding group and the non-protruding group(P=0.001).(2)According to AO/OTA classification,there were no significant differences in fracture type between the protruding group and the non-protruding group(P=0.289).(3)There was no significant difference in the length and diameter of the intramedullary nail between the two groups(P=0.067,P=1.000).(4)There was no significant correlation between the height of all patients and the length of the intramedullary nail(P=0.510),but there was a significant correlation between height and protruding length(P=0.034).There was no significant correlation between screw blade position and protruding length(P=0.968).(5)Six months after operation,there was no significant difference in the hip Harris score(P=0.373),but the visual analog scale pain score was significantly higher in the protruding group than that in the non-protruding group(P=0.000).(6)The results suggest that nail extrusion often occurs in the proximal greater trochanter when PFNA-Ⅱ is used in the treatment of intertrochanteric fractures in Asians.When the nail extended into the proximal soft tissue of the greater trochanter,patients complained of proximal greater trochanteric pain and the visual analog scale score of proximal greater trochanter pain in the patient was significantly higher than that in the non-protruding group.To be more suitable for the Asian population,we suggest that the PFNA-Ⅱ should be improved to further shorten the proximal nail end to obtain better clinical results of femoral intertrochanteric fracture fixation.

Objective:To assess the prognostic impact of frailty on elderly inpatients with heart failure.Methods:This prospective cohort study enrolled 121 in elderly patients with heart failure from Beijing Hospital, the General Hospital of the People's Liberation Army, and Beijing Tsinghua Changgung Hospital between September 2018 and April 2019.Patients were assessed for frailty using the Fried frailty phenotype and categorized into frail and non-frail groups.Follow-ups were conducted at 3-, 6-, and 12-months post-enrollment through clinic visits or phone calls to record adverse events.Composite endpoints include all-cause mortality and rehospitalization duo to deterioration of heart failure.Results:The study included 121 patients with an average age of 78.0±7.4 years, of whom 71(58.7%)were male and 57(47.1%)were classified as frail.Compared to the non-frail group, the frail group had lower estimated glomerular filtration rates[49.5±20.7 ml/(min·1.73m 2) vs.(64.0±27.1)ml/(min·1.73m 2)], lower scores in Basic Activities of Daily Living[5.0(4.0, 6.0) vs.6.0(5.0, 6.0)], Instrumental Activities of Daily Living[2.0(1.3, 7.8) vs.7.0(5.0, 8.0)], and Mini-Mental State Examination[26.0(16.0, 28.0) vs.27.0(22.3, 29.0)], all P<0.05.They also experienced longer hospital stays[10.5(6.0, 18.8)days vs.8.0(6.0, 11.8)days, P=0.008].During the follow-up period, the incidence of composite endpoint events was significantly higher in the frail group(43.9% vs.25.0%, P=0.029).Kaplan-Meier survival analysis demonstrated that the one-year incidence of composite endpoint events was significantly higher in the frail group( P=0.013).Multivariable Cox regression analysisindicated that frailty was an independent risk factor for composite endpoint events( HR=2.201, 95% CI: 1.089-4.447, P=0.028). Conclusions:Frailty is an independent risk factor for poor outcomes in elderly hospitalized patients with heart failure and should be considered a crucial factor in clinical assessment and treatment strategies.

Objective:To investigate the impact of ionizing radiation(IR)on the structure and function of the testis and pro-vide some strategies for the prevention and treatment of IR-induced damage(IRD).Methods:Using radiation dose simulation,se-men analysis,hormone testing,electron microscopy and single-cell transcriptome sequencing,we assessed and analyzed a case of IRD.We established a mouse model of IRD to validate the results of single-cell sequencing,and investigated the specific biological mecha-nisms of IRD and potential strategies for its intervention.Results:IR at 1-2 Gy significantly reduced sperm concentration and mo-tility,which gradually recovered after 12 months but the percentage of morphologically normal sperm remained low.It also caused im-balanced levels of various steroid hormones,decreased testosterone and dehydroepiandrosterone sulfate,increased progesterone,prolac-tin,luteinizing hormone,and follicle-stimulating hormone.Electron microscopy revealed damages to the testis structure,including loss of germ cells,atrophy of the seminiferous tubules,nuclear membrane depression of the spermatocytes,mitochondrial atrophy and de-formation,and reduction of mitochondrial cristae.Single-cell sequencing indicated significant changes in the function of the Leydig cells and macrophages and disrupted lipid-related metabolic pathways after IRD.Administration of L-carnitine to the mouse model im-proved lipid metabolism disorders and partially alleviated IRD to the germ cells.Conclusion:Ionizing radiation can cause disorders of testicular spermatogenesis and sexual hormones and inhibit lipid metabolism pathways in Leydig cells and macrophages.Improving lipid metabolism can alleviate IRD to germ cells.

AIM To study the protective effects and mechanism of pueraria isoflavones on myocardial injury in ovariectomized rats.METHODS Thirty-six rats were randomly divided into the sham operation group,the model group,the estradiol valerate group(0.1 mg/kg)and the low,medium and high dose pueraria isoflavones groups(55,110,220 mg/kg).In contrast to the rats of the sham operation group having their small pieces of adipose tissue removal around the ovaries,rats of the other groups had their bilateral ovaries excised,followed by the 16-week corresponding oral drug administration 2 weeks later at a once daily frequency for,6 days a week.At the end of the 16th week,the rats had their hemodynamics[systolic pressure(SBP),diastolic pressure(DBP),mean pressure(MBP),left ventricular systolic pressure(LVSP),left ventricular diastolic pressure(LVMP),and the maximum rate of increase and decrease of left ventricular pressure during isovolumic contraction(±dp/dtmax)]detected by PowerLab;their cardiac pathological changes observed by HE staining;their levels of creatine kinase(CK),lactate dehydrogenase(LDH),total cholesterol(TC),triglyceride(TG),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C)and glucose(Glu)in plasma detected by biochemical analyzer;their myocardial level of adenosine triphosphate(ATP)detected by colorimetry;their mRNA expressions of glucose transporter 4(GLUT4),lactate dehydrogenase A(LDHA),carnitine palmitoyl transferase-1(CPT-1α),acyl coenzyme A carboxylase(ACC),liver kinase B1(LKB1),adenylate-activated protein kinase(AMPK)and peroxisome proliferator-activated receptor γ coactivator factor 1α(PGC-1α)detected by RT-qPCR;and their myocardial expressions of energy metabolism related proteins LKB1,p-AMPK/AMPK and PGC-1α detected by Western blot.RESULTS Compared with the model group,the pueraria isoflavones groups displayed decreased levels of SBP,DBP,MBP,LVSP,LVMP(P＜0.05,P＜0.01);increased-dp/dtmax(P＜0.05,P＜0.01);improved myocardial fibrinolysis,gap widening and inflammatory infiltration caused by ovariectomy;decreased activities of LDH and CK(P＜0.05);increased myocardial ATP level(P＜0.05,P＜0.01);decreased levels of TC,TG,LDL-C and Glu(P＜0.05,P＜0.01);increased HDL-C level(P＜0.05,P＜0.01);increased myocardial mRNA expressions of GLUT4,LDHA,CPT-1α,ACC,LKB1,AMPK and PGC-1α(P＜0.05,P＜0.01);and increased protein expressions of myocardial LKB1,p-AMPK/AMPK and PGC-1α(P＜0.05,P＜0.01).CONCLUSION Pueraria isoflavones are protective to myocardial injury in ovariectomized rats,and the mechanism may lie in the improvement of energy metabolism-related myocardial proteins via LKB1/AMPK/PGC-1α signaling pathway.

Aim To investigate the effects of ber-bamine on behavioral changes in LPS-induced chronic neuroinflammation model mice and the related mecha-nisms.Methods By injecting lipopolysaccharide in-traperitoneally for seven days in a row,berbamine was given intraperitoneally as a treatment;the behavioral studies of mice in each group were identified;Nissen staining was used to observe the changes in the patho-logical morphology of the mouse hippocampus and the expression levels of inflammation-related proteins.These procedures established a mouse neuroinflamma-tion model.Results The number of neurons in the model group's hippocampal CA1 and CA3 regions was significantly smaller than that in the control group.In the water maze experiment,as the number of training days grew,the model group's escape latency increased and its retention time in the target quadrant dropped.The immobilization period of the model group mice in-creased during the forced swimming exercise.Serum levels of inflammatory factors such as IL-1β,IL-6,and TNF-α levels were also higher.The hippocampus tis-sue of the mice in the model group had higher levels of NLRP3,ASC,caspase-1,IL-18,ROCK1,ROCK2 ex-pression,and RHOA.When compared to the model group,the administration of berbamine was a therapy intervention.In the meantime,with the number of training days increased,the target quadrant lag time increased and the escape latency gradually decreased.Additionally,the model group's mice spent less time resting during forced swimming,and the serum inflam-matory factors TNF-α,IL-1β,and IL-6 decreased in mouse hippocampal tissues.Lastly,the expression lev-els of NLRP3,caspase-1,ASC,IL-1β,ROCK1,ROCK2,and RHOA all decreased in mouse hippocam-pal tissue.Conclusions The mechanism of action of berbamine,which improves lipopolysaccharide-induced depressive-like behaviors and modifies learning memory in mice,may include the NLRP3 and RHOA/ROCK signaling pathways.