Association between atherogenic index of plasma and new-onset stroke in individuals with different glucose metabolism status: insights from CHARLS.

BACKGROUND: Circulating atherogenic index of plasma (AIP) levels has been proposed as a novel biomarker for dyslipidemia and as a predictor of insulin resistance (IR) risk. However, the association between AIP and the incidence of new-onset stroke, particularly in individuals with varying glucose metabolism status, remains ambiguous. METHODS: A total of 8727 participants aged 45 years or older without a history of stroke from the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. The AIP was calculated using the formula log [Triglyceride (mg/dL) / High-density lipoprotein cholesterol (mg/dL)]. Participants were divided into four groups based on their baseline AIP levels: Q1 (AIP ≤ 0.122), Q2 (0.122 < AIP ≤ 0.329), Q3 (0.329 < AIP ≤ 0.562), and Q4 (AIP > 0.562). The primary endpoint was the occurrence of new-onset stroke events. The Kaplan-Meier curves, multivariate Cox proportional hazard models, and Restricted cubic spline analysis were applied to explore the association between baseline AIP levels and the risk of developing a stroke among individuals with varying glycemic metabolic states. RESULTS: During an average follow-up of 8.72 years, 734 participants (8.4%) had a first stroke event. The risk for stroke increased with each increasing quartile of baseline AIP levels. Kaplan-Meier curve analysis revealed a significant difference in stroke occurrence among the AIP groups in all participants, as well as in those with prediabetes mellitus (Pre-DM) and diabetes mellitus (DM) (all P values < 0.05). After adjusting for potential confounders, the risk of stroke was significantly higher in the Q2, Q3, and Q4 groups than in the Q1 group in all participants. The respective hazard ratios (95% confidence interval) for stroke in the Q2, Q3, and Q4 groups were 1.34 (1.05-1.71), 1.52 (1.19-1.93), and 1.84 (1.45-2.34). Furthermore, high levels of AIP were found to be linked to an increased risk of stroke in both pre-diabetic and diabetic participants across all three Cox models. However, this association was not observed in participants with normal glucose regulation (NGR) (p > 0.05). Restricted cubic spline analysis also demonstrated that higher baseline AIP levels were associated with higher hazard ratios for stroke in all participants and those with glucose metabolism disorders. CONCLUSIONS: An increase in baseline AIP levels was significantly associated with the risk of stroke in middle-aged and elderly individuals, and exhibited distinct characteristics depending on the individual's glucose metabolism status.

Antitumor effects of Cypaliuruside F from Cyclocarya paliurus on HepG2 cells.

An undescribed dammarane triterpenoid saponin Cypaliuruside F was isolated from the leaves of Cyclocarya paliurus in our preliminary study. The MTT assay, flow cytometry, cell scratch, and DAPI staining were used to detect the antitumor effects of Cypaliuruside F on HepG2 cells. Subsequently, network pharmacology and molecular docking analysis were used to analyse the key targets of Cypaliuruside F against HCC. In addition, a Western blot was performed to determine the effects of Cypaliuruside F on the expression of key proteins in HepG2 cells. The experimental results indicated that the damarane triterpenoid saponin Cypaliuruside F from Cyclocarya paliurus inhibits the proliferation of HepG2 cells by inducing apoptosis and cell cycle arrest. These changes may promote the apoptosis of HepG2 cells by inhibiting the expression of mTOR, STAT3, and Bcl-2 while activating Bax.

AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

Neuroprotective effects of Aucubin against cerebral ischemia-reperfusion injury.

AIMS: To study the role of Aucubin (AU) in cerebral ischemia-reperfusion injury and investigate the potential mechanisms. METHODS: For the in vitro experiment, primary microglia were cultured and stimulated by Lipopolysaccharides (LPS) and treated with AU. Male C57/BL6J mice were used and middle cerebral artery occlusion (MCAO) model was performed to induce cerebral ischemia-reperfusion injury. For the short-term effects, mice administrated with AU (40 mg/kg) for 3 days after MCAO were evaluated for the infarct volume and neurological deficits. The neuroinflammatory factors and microglia activation were determined by Real-time PCR, western blot and immunofluorescence staining. For the long-term effects, MCAO mice were injected daily with AU (5 mg/kg or 10 mg/kg) for 28 days. Behavior tests were used to assess the neurological deficits of MCAO mice, and white matter integrity was determined by myelin basic protein (MBP) staining and black-gold staining. RESULTS: AU suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release, and downregulated the NF-κB and MAPK pathways in primary microglia. In addition, AU attenuated ischemic injury and inhibited the neuro-inflammatory response in MCAO mice. Moreover, AU induced prolonged improvements in sensorimotor function and memory function following MCAO, and preserved white matter integrity in the long-term experiments. CONCLUSIONS: AU protected against ischemic injury, which might be correlated with the downregulation of NF-κB and MAPK signaling pathways. Furthermore, AU alleviated cognitive impairment after stroke and restored white matter integrity. Our data indicated that AU might be a potential compound for the treatment of stroke and post-stroke cognitive impairment.

Association between corticosteroid use and 28-day mortality in septic shock patients with gram-negative bacterial infection: a retrospective study.

Purpose: Although corticosteroids are recommended in the 2021 Surviving Sepsis Campaign (SSC) guidelines, evidence with respect to their effects on short-term mortality remains conflicting. We conducted this study to identify whether corticosteroids alter 28-day mortality in septic shock patients with gram-negative bacterial infection. Materials and methods: A total of 621 patients with septic shock and gram-negative bacterial culture results were identified from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Propensity score matching (PSM) was performed, and Kaplan-Meier survival curve analyses with log-rank tests were used to determine the relationship between corticosteroid use and the risk of 28-day mortality. Subgroup analyses were conducted to assess whether the conclusions were stable and reliable. Results: Corticosteroid administration was associated with increased 28-day mortality in septic shock patients with gram-negative bacterial infection (log-rank test P = 0.028). The incidence of Stage 2 or 3 AKI and the rate of hospital mortality were higher among patients who received corticosteroids. The incidence of Stage 2 or 3 AKI in the early period significantly mediated the relationship between corticosteroid use and 28-day mortality [P =0.046 for the average causal mediation effect (ACME)]. Interaction tests indicated that the effect of corticosteroid use was maintained in patients with a neutrophil-to-lymphocyte ratio (NLR) of <20 (P-value for interaction = 0.027). Conclusion: Systemic corticosteroid use could be harmful in septic shock patients with gram-negative bacterial infection, especially in patients with relatively low NLR.

Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice.

Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/ß-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aß) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aß levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aß phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.

MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.

Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer's disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-ß levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.

Prevalence and distribution of acute gastrointestinal illness in the community of China: a population-based face-to-face survey, 2014-2015.

BACKGROUND: The true incidence of acute gastrointestinal illness in China is underrecognized by surveillance systems. The aims of this study were to estimate the incidence and prevalence of self-reported AGI in the community of China, and to investigate sociodemographic and epidemiological determinants of AGI. METHODS: We conducted a 12-months cross-sectional population-based survey in eight provinces of China during 2014-2015. The survey determined the prevalence and incidence of acute gastrointestinal illness (AGI) in the total permanent resident population in China according to the census of the population in 2010. The random multilevel population sample was stratified by geographic, population, and socioeconomic status. We used a recommended case definition of AGI, with diarrhea (three loose or watery stools) and/or any vomiting in a four-week recall. A face-to-face survey was conducted by selecting the member in the household with the most recent birthday. RESULTS: Among 56,704 sampled individuals, 948 (1,134 person-time) fulfilled the case definition; 98.5% reported diarrhea. This corresponds to 2.3% (95% CI:1.9%-2.8%) of an overall standardized four-week prevalence and 0.3 (95% CI: 0.23-0.34) episodes per person-year of annual adjusted incidence rate. There was no significant difference between males and females. The incidence rates were higher among urban residents, and in the spring and summer. In the whole study period, 50% of the cases sought medical care, of which 3.9% were hospitalized and 14.3% provided a biological sample for laboratory identification of the causative agent. Children aged 0-4 and young adults aged 15-24, people living in rural areas and people who traveled frequently had higher prevalence of AGI. CONCLUSION: Results showed that AGI represents a substantial burden in China, and will contribute to the estimation of the global burden of AGI. Complemented with data on the etiologies of AGI, these estimates will form the basis to estimate the burden of foodborne diseases in China.

Increased ICU mortality in septic shock patients with hypo- or hyper- serum osmolarity: A retrospective study.

Background: While many factors that are associated with increased mortality in septic shock patients have been identified, the effects of serum osmolarity on the outcomes of ICU patients with septic shock have not yet been studied. Methods: The present study was designed to examine the association of serum osmolarity with ICU 28-day mortality in ICU patients with septic shock. Adult patients diagnosed with septic shock from the MIMIC-IV database were selected in this study. The serum osmolarity was calculated synchronously according to the serum concentrations of Na+, K+, glucose, and urea nitrogen. Results: In the present study, a significant difference was observed between the 28-day mortality of septic shock patients with hypo-osmolarity, hyper-osmolarity, and normal osmolarity (30.8%, 34.9%, and 23.0%, respectively, p < 0.001), which were detected at ICU admission. After propensity score matching (PSM) for basic characteristics, the relatively higher mortality was still observed in the hypo-osmolarity and hyper-osmolarity groups, compared to normal osmolarity group (30.6%, 30.0% vs. 21.7%, p = 0.009). Furthermore, we found that transforming the hyper-osmolarity into normal osmolarity by fluid therapy on day 2 and 3 decreased this mortality. Conclusion: The serum osmolarity disorder is markedly associated with increased 28-day mortality in septic shock patients.

Vascular invasion and lymph node metastasis mediate the effect of CA242 on prognosis in hilar cholangiocarcinoma patients after radical resection.

Background: Carbohydrate antigen 242 has been clinically used as a diagnostic biomarker for pancreatic cancer. However, the prognostic role of CA242 in hilar cholangiocarcinoma (HCCA) has not been identified. Also, it remains unclear to what extents the vascular invasion and lymph node metastasis mediate the effect of serum CA242 on prognosis. Objective: This study aimed to investigate whether vascular invasion and lymph node metastasis mediate the relationship between CA242 levels and clinical prognosis in HCCA patients after radical resection. Methods: Data of 234 HCCA patients who accepted radical resection from March 2008 to December 2014 were analyzed. Vascular invasion and lymph node metastasis were assessed by postoperative pathological examinations. Mediation analysis was performed to study the potential causal relationship between CA242 and overall survival (OS) and relapse-free survival (RFS). Survival analysis was performed using the Kaplan-Meier method. Results: Among 234 HCCA patients, 104 patients (44.4%) with normal CA242 levels (≤ 20 IU/ml) had significantly better OS (p=0.004) and RFS (p=0.001) than those 130 patients (55.6%) with elevated CA242 levels (>20 IU/ml). The logistic analysis showed that elevated CA242 was an independent risk factor for vascular invasion (p=0.006) and lymph nodes metastasis (p=0.040). The causal mediation analysis indicated that the vascular invasion (p=0.012 for OS; p=0.036 for RFS) and lymph nodes metastasis (p=0.024 for OS; p=0.014 for RFS) played significant roles in mediating the effect of serum CA242 on OS and RFS. Conclusion: Serum elevated CA242 could be a novel marker for prognosis prediction in HCCA patients. Vascular invasion and lymph node metastasis mediated the relationship between CA242 and clinical prognosis.

Transcriptomic Profile Identifies Hippocampal Sgk1 as the Key Mediator of Ovarian Estrogenic Regulation on Spatial Learning and Memory and Aß Accumulation.

Previous studies have shown that ovarian estrogens are involved in the occurrence and pathology of Alzheimer's disease (AD) through regulation on hippocampal synaptic plasticity and spatial memory; however, the underlying mechanisms have not yet been elucidated at the genomic scale. In this study, we established the postmenopausal estrogen-deficient model by ovariectomy (OVX). Then, we used high-throughput Affymetrix Clariom transcriptomics and found 143 differentially expressed genes in the hippocampus of OVX mice with the absolute fold change ≥ 1.5 and P < 0.05. GO analysis showed that the highest enrichment was seen in long-term memory. Combined with the response to steroid hormone enrichment and GeneMANIA network prediction, the serum and glucocorticoid-regulated kinase 1 gene (Sgk1) was found to be the most potent candidate for ovarian estrogenic regulation. Sgk1 overexpression viral vectors (oSgk1) were then constructed and injected into the hippocampus of OVX mice. Morris water maze test revealed that the impaired spatial learning and memory induced by OVX was rescued by Sgk1 overexpression. Additionally, the altered expression of synaptic proteins and actin remodeling proteins and changes in CA1 spine density and synapse density induced by OVX were also significantly reversed by oSgk1. Moreover, the OVX-induced increase in Aß-producing BACE1 and Aß and the decrease in insulin degrading enzyme were significantly reversed by oSgk1. The above results show that multiple pathways and genes are involved in ovarian estrogenic regulation of the function of the hippocampus, among which Sgk1 may be a novel potent target against estrogen-sensitive hippocampal dysfunctions, such as Aß-initiated AD.

Steroid receptor coactivator-1: The central intermediator linking multiple signals and functions in the brain and spinal cord.

The effects of steroid hormones are believed to be mediated by their nuclear receptors (NRs). The p160 coactivator family, including steroid receptor coactivator-1 (SRC-1), 2 and 3, has been shown to physically interact with NRs to enhance their transactivational activities. Among which SRC-1 has been predominantly localized in the central nervous system including brain and spinal cord. It is not only localized in neurons but also detectable in neuroglial cells (mainly localized in the nuclei but also detectable in the extra-nuclear components). Although the expression of SRC-1 is regulated by many steroids, it is also regulated by some non-steroidal factors such as injury, sound and light. Functionally, SRC-1 has been implied in normal function such as development and ageing, learning and memory, central regulation on reproductive behaviors, motor and food intake. Pathologically, SRC-1 may play a role in the regulation of neuropsychiatric disorders (including stress, depression, anxiety, and autism spectrum disorder), metabolite homeostasis and obesity as well as tumorigenesis. Under most conditions, the related mechanisms are far from elucidation; although it may regulate spatial memory through Rictor/mTORC2-actin polymerization related synaptic plasticity. Several inhibitors and stimulator of SRC-1 have shown anti-cancer potentials, but whether these small molecules could be used to modulate ageing and central disorder related neuropathology remain unclear. Therefore, to elucidate when and how SRC-1 is turned on and off under different stimuli is very interesting and great challenge for neuroscientists.

Mechanisms Underlying the Inhibition of KV1.3 Channel by Scorpion Toxin ImKTX58.

Voltage-gated KV1.3 channel has been reported to be a drug target for the treatment of autoimmune diseases, and specific inhibitors of Kv1.3 are potential therapeutic drugs for multiple diseases. The scorpions could produce various bioactive peptides that could inhibit KV1.3 channel. Here, we identified a new scorpion toxin polypeptide gene ImKTX58 from the venom gland cDNA library of the Chinese scorpion Isometrus maculatus Sequence alignment revealed high similarities between ImKTX58 mature peptide and previously reported KV1.3 channel blockers-LmKTX10 and ImKTX88-suggesting that ImKTX58 peptide might also be a KV1.3 channel blocker. By using electrophysiological recordings, we showed that recombinant ImKTX58 prepared by genetic engineering technologies had a highly selective inhibiting effect on KV1.3 channel. Further alanine scanning mutagenesis and computer simulation identified four amino acid residues in ImKTX58 peptide as key binding sites to KV1.3 channel by forming hydrogen bonds, salt bonds, and hydrophobic interactions. Among these four residues, 28th lysine of the ImKTX58 mature peptide was found to be the most critical amino acid residue for blocking KV1.3 channel. SIGNIFICANCE STATEMENT: In this study, we discovered a scorpion toxin gene ImKTX58 that has not been reported before in Hainan Isometrus maculatus and successfully used the prokaryotic expression system to express and purify the polypeptides encoded by this gene. Electrophysiological experiments on ImKTX58 showed that ImKTX58 has a highly selective blocking effect on KV1.3 channel over Kv1.1, Kv1.2, Kv1.5, SK2, SK3, and BK channels. These findings provide a theoretical basis for designing highly effective KV1.3 blockers to treat autoimmune and other diseases.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

Antidepressant-Like Effect and Mechanism of Ginsenoside Rd on Rodent Models of Depression.

Background: There is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study. Objective: This study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd. Methods: In this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors. Results: Our data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2. Conclusion: Our results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.

Imperatorin inhibits mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and alleviates neuroinflammation in ischemic stroke.

AIMS: Microglia-mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post-stroke neuroinflammation is not fully understood. METHODS: Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT-PCR, ELISA, and Western blot. The activation of MAPK and NF-κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume. RESULTS: Imperatorin suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF-κB pathways might contribute to the protective effects of imperatorin. CONCLUSIONS: Imperatorin downregulated MAPK and NF-κB signaling pathways and exerted anti-inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke.

Exploring the Therapeutic Mechanism of Tingli Dazao Xiefei Decoction on Heart Failure Based on Network Pharmacology and Experimental Study.

BACKGROUND: Tingli Dazao Xiefei decoction (TDXD) has been shown to have a therapeutic effect on heart failure (HF). Nevertheless, its molecular mechanism for treating HF is still unclear. MATERIALS AND METHODS: TDXD and HF targets were collected from the databases, and protein-protein interaction (PPI) analysis and enrichment analysis were performed on the overlapping targets. Then, AutoDock was employed for molecular docking. Finally, we used the left anterior descending coronary artery (LAD) ligation to induce HF model rats for in vivo experiments and verified the effect and mechanism of TDXD on HF. RESULTS: Network pharmacological analysis showed that the main active components of TDXD in treating HF were quercetin, kaempferol, beta-carotene, isorhamnetin, and beta-sitosterol, and the core targets were IL-6, VEGFA, TNF, AKT1, and MAPK1. Multiple gene functions and signaling pathways were obtained by enrichment analysis, among which inflammation-related, PI3K/Akt, and MAPK signaling pathways were closely related to HF. Furthermore, the molecular docking results showed that the core targets had good binding ability with the main active components. Animal experiments showed that TDXD could effectively improve left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS), decrease left ventricular internal diastolic diameter (LVIDd) and left ventricular internal systolic diameter (LVIDs), reduce the area of myocardial fibrosis, and decrease serum BNP, LDH, CK-MB, IL-6, IL-1ß, and TNF-α levels in HF rats. Meanwhile, TDXD could upregulate the expression of Bcl-2, downregulate the expression of Bax, and reduce cardiomyocyte apoptosis. At the same time, it was verified that TDXD could significantly decrease the expression of PI3K, P-Akt, and P-MAPK. Captopril showed similar effects. CONCLUSIONS: Combining network pharmacological analysis and experimental validation, this study verified that TDXD could improve cardiac function and protect against cardiac injury by inhibiting the activation of PI3K/Akt and MAPK signaling pathways.

Long-term environmental cadmium exposure induced serum metabolic changes related to renal and liver dysfunctions in a female cohort from Southwest China.

Cadmium (Cd), a toxic heavy mental, has been reported to be correlated with increased incidences of multiple diseases. Only a few studies have paid attention to screen the urine metabolites related to long-term environmental Cd exposure in humans. Research on the Cd exposure-related serum metabolic alternations and biological mechanisms linking Cd exposure to adverse health risks in humans is scanty. In this study, we investigated the serum Cd exposure-related metabolic alternations in a cohort of 101 non-smoking females (two polluted groups and one control group) and 18 Cd exposure-related metabolites were identified. A total of 16 clinical indicators of renal and hepatic functions and bone health were measured. Five health effect biomarkers including serum creatinine, alkaline phosphatase, total bilirubin, direct bilirubin and albumin to globulin ratio that are related to impaired renal and hepatic functions showed significant differences among the three groups and had close correlations with Cd levels. We identified intermediate metabolites that were associated with both Cd exposure and health effect biomarkers using a "meet-in-the-middle" approach. Fourteen Cd exposure-related metabolites in the metabolism of glycerophospholipids, sphingolipids, arachidic acid, linoleic acid and amino acids, were identified to be the intermediates of Cd exposure and the health effect biomarkers. Our findings provided evidence for the linkage of long-term environmental Cd exposure and the renal and hepatic insufficiency.