This study investigates the mechanism by which Xintong Granules improve myocardial ischemia-reperfusion injury(MIRI) through the regulation of gut microbiota and their metabolites, specifically short-chain fatty acids(SCFAs). Rats were randomly divided based on body weight into the sham operation group, model group, low-dose Xintong Granules group(1.43 g·kg~(-1)·d~(-1)), medium-dose Xintong Granules group(2.86 g·kg~(-1)·d~(-1)), high-dose Xintong Granules group(5.72 g·kg~(-1)·d~(-1)), and metoprolol group(10 mg·kg~(-1)·d~(-1)). After 14 days of pre-administration, the MIRI rat model was established by ligating the left anterior descending coronary artery. The myocardial infarction area was assessed using the 2,3,5-triphenyltetrazolium chloride(TTC) staining method. Apoptosis in tissue cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay. Pathological changes in myocardial cells and colonic tissue were observed using hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), creatine kinase MB isoenzyme(CK-MB), and cardiac troponin T(cTnT) in rat serum were quantitatively measured using enzyme-linked immunosorbent assay(ELISA) kits. The activities of lactate dehydrogenase(LDH), creatine kinase(CK), and superoxide dismutase(SOD) in myocardial tissue, as well as the level of malondialdehyde(MDA), were determined using colorimetric assays. Gut microbiota composition was analyzed by 16S rDNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry(GC-MS). The results show that Xintong Granules significantly reduced the myocardial infarction area, suppressed cardiomyocyte apoptosis, and decreased serum levels of pro-inflammatory cytokines(TNF-α, IL-1β, and IL-6), myocardial injury markers(CK-MB, cTnT, LDH, and CK), and oxidative stress marker MDA. Additionally, Xintong Granules significantly improved intestinal inflammation in MIRI rats, regulated gut microbiota composition and diversity, and increased the levels of SCFAs(acetate, propionate, isobutyrate, etc.). In summary, Xintong Granules effectively alleviate MIRI symptoms. This study preliminarily confirms that Xintong Granules exert their inhibitory effects on MIRI by regulating gut microbiota imbalance and increasing SCFA levels.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Myocardial Reperfusion Injury/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Humans ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/genetics* ; Malondialdehyde/metabolism*

OBJECTIVE: To investigate the variability of bone metabolism levels among different populations and its association with knee osteoarthritis (KOA) pain. METHODS: A total of 50 people (control group) who participated in physical examination from January 2023 to June 2023 were selected, including 26 males and 24 females, wtih a mean aged of (52.14±9.04) years old ranging 41 to 65 years old. The other 50 patients with knee osteoarthritis(case group) who attended the outpatient clinic of the Orthopedics and Traumatology Department in the same time period, including 19 males and 31 females, with a mean age of (53.60±7.76) years old ranging 40 to 65 years. The two groups of Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC) and bone metabolism markers, such as 25-hydroxy-cholecalciferol[25(OH)D], β-isomerized typeⅠcollagen C-telopeptide breakdown products (β-CTX), total typeⅠprocollagen N-terminal propeptide (t-PINP), osteocalcin (OC), parathormone (PTH) levels were compared. Pearson correlation analysis was used to compare the correlation between two groups of bone metabolism related markers and WOMAC. RESULTS: The WOMAC score of the case group (39.90±2.34) was higher than that of the control group (3.60±0.57), with significant difference (P<0.05). There was no significant difference between the two groups of 25 (OH)D, β-CTX and PTH (P>0.05). The t-PINP and OC of the case group were (62.90±52.40) and (19.88±10.15) ng·ml-1, respectively, and those of the control group were (38.86±10.82) and (14.90±3.62) ng·ml^-1, respectively;the t-PINP and OC of the case group were higher than those of the control group, with significant difference (P<0.05). Pearson correlation analysis showed that t-PINP was positively correlated with WOMAC pain score in the case group (r²=0.045, P<0.01). CONCLUSION Bone metabolism levels in the serum of patients with knee osteoarthritis are different from those of healthy people, and the difference between OC and t-PINP is the most obvious, and the concentration of t-PINP levels is positively correlated with pain symptoms in patients with KOA. However, the specific mechanism of correlation between the bone metabolism levels of patients with KOA and their pain symptoms needs to be further elucidated by basic experimental research as well as by enlarging the samples.
Humans ; Female ; Male ; Middle Aged ; Osteoarthritis, Knee/metabolism* ; Aged ; Adult ; Bone and Bones/metabolism* ; Pain/etiology* ; Biomarkers/metabolism*

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Triterpenoids in cosmetic raw materials have attracted much attention due to their various skin-care effects such as anti-inflammatory, antioxidant, and moisturizing properties, showing broad application prospects. However, the conventional methods such as chemical synthesis and plant extraction for obtaining triterpenoid have problems like poor sustainability, which limit their application in large-scale production. In recent years, with the development of synthetic biology and metabolic engineering, yeast synthesis of compounds has provided a green and sustainable alternative for the production of triterpenoids. This article reviews the research progress in the synthesis of triterpenoids and their derivatives in the cosmetic field and elaborates on the two main synthesis pathways (mevalonate and methylerythritol phosphate pathways) and their advantages and limitations in different microbial hosts. In addition, this article introduces the current status of the synthesis of triterpenoids and their derivatives in yeast, discusses the current strategies for increasing the yield, and looks ahead to the future development directions, aiming to promote the applications of triterpenoids in the cosmetic field.
Triterpenes/metabolism* ; Cosmetics/chemistry* ; Metabolic Engineering/methods* ; Saccharomyces cerevisiae/genetics* ; Synthetic Biology

Overtraining is a condition characterized by various functional disorders or pathological states caused by continuous fatigue, which occurs after a persisting imbalance between training-related load and physical function and recovery. Generally speaking, it’s a state of imbalance between training and recovery, exercise and exercise performance, and stress and stress tolerance. Overtraining can cause various phenotypic changes or pathological remodeling, such as decreased skeletal muscle strength and exhaustive exercise endurance, skeletal muscle fatigue damage and dysfunction, skeletal muscle atrophy and loss, skeletal muscle glycogen depletion, skeletal muscle soreness and stiffness, skeletal muscle glucose intolerance, inattention, memory decline, anxiety, depression, abnormal emotions and behaviors, sleep disorders, cognitive function impairment, poor appetite, weight loss, liver/heart fat deposition, compensatory increase of liver/heart insulin signaling and glycogen storage, cardiac pathological hypertrophy, exercise-induced arrhythmias, myocardial fibrosis, ectopic and visceral fat deposition, and increased risk of injury. Unfortunately, its underlying mechanism is largely unclear. Recently, the enrichment of molecular and cellular signal pathway theory offers us a new explanatory paradigm for revealing its internal mechanisms. Based on the traditional explanation mechanisms and molecular and cellular signal pathway theory, we thoroughly analyzed the key mechanisms of health damage caused by overtraining from the perspective of oxidative stress, mitochondrial quality control disorder, inflammatory response, endoplasmic reticulum stress, cell apoptosis, and so forth. Specifically, overtraining-induced excessive reactive oxygen species (ROS) leads to serious oxidative stress damage in organisms at least via depressing Kelch like ECH associated protein 1(Keap1)/nuclear factor erythroid-2-related factor (Nrf2)/antioxidant response element (ARE) antioxidant pathway and activating p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Overtraining induces mitochondrial quality control disorder and mitochondrial dysfunction, and thus triggers health impairment through inhibiting mitochondrial biogenesis and fusion, stimulating mitochondrial fission, and over-activating autophagy/mitophagy. Overtraining can also produce muscle, skeletal and joint trauma, then circulating monocytes are abundantly activated by injury-related cytokines, and in turn generate large quantities of proinflammatory IL-1β, IL-6, TNF‑α, causing systemic inflammation and inflammatory health injury. Overtraining induces excessive pathological endoplasmic reticulum stress (ERS) and severe health damage via PERK-eIF2α, IRE1α-XBP1 and ATF6 pathways which activated by proinflammatory signals. Overtraining also induces excessive apoptosis and harmful health consequences via Bax/Bcl2-Caspase 3-mediated mitoptosis which activated by oxidative stress and inflammation or even CHOP and Caspase 12-dependent ERS apoptosis. Nonetheless, it should be importantly emphasized that oxidative stress and inflammation are the central and pre-emptive mechanisms of overtraining and its health damage. Although the efficient strategies for preventing and controlling overtraining are scientifically and reasonably arranging and planning training intensity, training volume, and recovery period, as well as accurately assessing and monitoring physical function status in the early stage, yet various anti-inflammatory, anti-oxidant, anti-apoptotic, or anti-aging drugs such as curcumin, astaxanthin, oligomeric proanthocyanidins, silibinin, hibiscus sabdariffa, dasatinib, quercetin, hydroxytyrosol, complex probiotics, astragalus polysaccharides, semaglutide and fasudil also have an irreplaceable positive effect on preventing overtraining and its relevant health damage via depressing oxidative stress, mitochondrial quality control disorder, proinflammatory signals, endoplasmic reticulum stress, apoptosis and so on. We hope that this review can help us further grasp the features, mechanisms and regularity of overtraining, and provide an important reference for athletes and sports fan to conduct scientific training, improve training effectiveness, extend exercise lifespan, and promote physical and mental health.

Trichinosis is a global food-borne zoonotic parasitic disease caused by Trichinella spiralis(T.spiralis),which causes serious harm to animal production,and the public health safety of humans and animals.T.spiralis has a complex devel-opment history,and its entire life cycle is completed in the same host.To coexist with the host,it has evolved various immune escape mechanisms for avoiding immune clearance by the host,thus establishing long-term chronic infection.In this study,to aid in understanding the pathogenic mechanism of T.spiralis,the immune escape mechanism of Trichinella is discussed from three aspects:the molecular role of antigens in various stages,the immune regulatory effect on the host,and the formation of cysts to generate immune isolation.

Objective:To study the early predictors of refractory septic shock (RSS) in neonates.Methods:From July 2020 to December 2021, clinical data of neonates with septic shock admitted to the Neonatal Department of our hospital were retrospectively reviewed. According to the maximum septic shock score (SSS) during clinical course, the neonates were assigned into RSS group and non-RSS group. Perinatal data, laboratory results and hemodynamic parameters at diagnosis were compared between the two groups. Multiple logistic regression analysis was used to identify independent risk factors of RSS and septic shock-related death. Receiver operating characteristic (ROC) curve was constructed to evaluate the early predictors of poor prognosis.Results:A total of 130 neonates were enrolled, including 54 in RSS group and 76 in non-RSS group. Compared with the non-RSS group, the RSS group had significantly lower pH, base excess (BE), stroke volume index (SVI), cardiac output (CO) and cardiac index (CI).Meanwhile, the RSS group had significantly higher mean arterial pressure (MAP) to CI ratio (MAP/CI) and SSS [including bedside SSS (bSSS), computed SSS (cSSS) and modified version of cSSS (mcSSS)] (all P<0.05). Multiple logistic regression analysis showed that increased MAP/CI was an independent predictor of RSS. The cut-off value of MAP/CI was 11.6 [sensitivity 62%, specificity 87%, positive predictive value (PPV) 79% and negative predictive value (NPV) 77%], with an area under the curve (AUC) of 0.734. Increased mcSSS was an independent predictor of septic shock-related death. The cut-off value of mcSSS was 5.8 (sensitivity 83%, specificity 72%, PPV 21% and NPV 97%), with an AUC of 0.845. Conclusions:Increased MAP/CI (≥11.6) and mcSSS (≥5.8) may be early predictors of RSS and septic shock-related death in neonates.

Objective: To investigate the clinical and biological characteristics of familial platelet disorder (FPD) with germline Runt-related transcription factor (RUNX) 1 mutations. Methods: Patients diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with RUNX1 mutations from February 2016 to December 2021 in Wuhan No.1 Hospital underwent pedigree analysis and were screened for gene mutations (somatic and germline). Patients diagnosed with FPD with germline RUNX1 mutations were enrolled and evaluated in terms of clinical characteristics and biological evolution. Bioinformatics analysis was used to assess the pathogenicity of mutations and to analyze the effect of mutated genes on the function of the corresponding protein. Results: Germline RUNX1 mutations were detected in three out of 34 patients suffering from MDS/AML who had RUNX1 mutations. A pedigree of FPD with RUNX1 (RUNX1-FPD) c.562A>C and RUNX1 c.1415T>C mutations was diagnosed, and the mutations were of patrilineal origin. Bioinformatics analysis indicated that the locus at positions 188 and 472 in the AML-1G type of RUNX1 was highly conserved across different species, and that variations might influence functions of the proteins. The mutations were evaluated to be highly pathogenic. Of the nine cases with germline RUNX1 mutations: two patients died due AML progression; one case with AML survived without leukemia after transplantation of hemopoietic stem cells; four patients showed mild-to-moderate thrombocytopenia; two cases had no thrombocytopenia. During the disease course of the proband and her son, mutations in RUNX1, NRAS and/or CEBPA and KIT appeared in succession, and expression of cluster of differentiation-7 on tumor cells was enhanced gradually. None of the gene mutations correlated with the tumor were detected in the four cases not suffering from MDS/AML, and they survived until the end of follow-up. Conclusions: RUNX1-FPD was rare. The mutations c.562A>C and c.1415T>C of RUNX1 could be the disease-causing genes for the family with RUNX1-FPD, and these mutations could promote malignant transformation. Biological monitoring should be carried out regularly to aid early intervention for family members with RUNX1-FPD.
Humans ; Female ; Germ-Line Mutation ; Core Binding Factor Alpha 2 Subunit/genetics* ; Pedigree ; Blood Platelet Disorders/complications* ; Leukemia, Myeloid, Acute/genetics*

OBJECTIVE: This study aimed to investigate the association between fruit and vegetable intake and arterial stiffness. METHODS: We conducted a cohort-based study comprising 6,628 participants with arterial stiffness information in the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project. A semi-quantitative food-frequency questionnaire was used to assess baseline (2007-2008) and recent (2018-2021) fruit and vegetable intake. We assessed changes in fruit and vegetable intake from 2007-2008 to 2018-2021 in 6,481 participants. Arterial stiffness was measured using the arterial velocity-pulse index (AVI) and arterial pressure-volume index (API). Elevated AVI and API values were defined according to diverse age reference ranges. RESULTS: Multivariable-adjusted linear regression models revealed that every 100 g/d increment in fruit and vegetable intake was associated with a 0.11 decrease in AVI ( B= -0.11; 95% confidence interval [ CI]: -0.20, -0.02) on average, rather than API ( B = 0.02; 95% CI: -0.09, 0.13). The risk of elevated AVI (odds ratio [ OR] = 0.82; 95% CI: 0.70, 0.97) is 18% lower in individuals with high intake (≥ 500 g/d) than in those with low intake (< 500 g/d). Furthermore, maintaining a high intake in the past median of 11.5 years of follow-up was associated with an even lower risk of elevated AVI compared with a low intake at both baseline and follow-up ( OR = 0.64; 95% CI: 0.49, 0.83). CONCLUSION Fruit and vegetable intake was negatively associated with arterial stiffness, emphasizing recommendations for adherence to fruit and vegetable intake for the prevention of arterial stiffness.
Humans ; Vascular Stiffness ; Fruit ; Vegetables ; Atherosclerosis ; China

Aim To observe the effect of epimedium on the proliferation and stem cell-like character expression of breast cancer cells, and investigate the relationship between the inhibition of stem cell-like character and miR-148a by epimedium, and its molecular mechanism. Methods After treatment with different concentrations of epimedium, cell viability and population dependence were detected by MTT assay and colony formation assay; the breast cancer stem cell-derived mammosphere formation was examined by Mammosphere assay; the expression levels of CD44,ALDH-1, Oct4,BMIl and EpCAM were detected by qPCR; the protein expression levels of EpCAM, SOX4, ZO-1, E-cadherin and vimentin were detected by Western blot; the protein localization of EpCAM was observed by im-munofluorescence assay; the effect of epimedium on migration was detected by wound healing assay. The miR-148a mimic was transfected into MDA-MB-231 cells, and the effects of epimedium on stem-like character expression of transfected MDA-MB-231 cells were observed. Results Epimedium significantly inhibited the proliferation and population dependence of MDA-MB-231 cells (P < 0.05 ), and reduced the breast cancer stem cell-derived mammosphere formation; compared with control group, epimedium significantly decreased mRNA levels of CD44, ALDH-1, Oct4, BMI1 and EpCAM (P <0.05) ,decreased protein contents of EpCAM, SOX4 and Vimentin (P < 0.05 ), up-regulated the protein expression of ZO-1 and e-cadherin ( P <0.05) ,and decreased the migration ability of MDA-MB-231 cells (P < 0.05). Epimedium up-regulated the expression of miR-148a in MDA-MB-231 cells (P <0.01). YYH + miR-148a mimic group significantly inhibited stem-like character expression and EMT process of breast cancer MDA-MB-231 cells compared with control group (P <0.05). Conclusions Epimedium can inhibit the proliferation of MDA-MB-231 cells, which may be related to the up-regulation of miR-148a, decrease of stem-like character expression of breast cancer cells,and inhibition of EMT.