Among the numerous complications associated with diabetes, diabetic nephropathy is a prominent one. However, strategies to curb or mitigate the worsening of DN are still absent from the therapeutic arsenal. The administration of San-Huang-Yi-Shen capsules (SHYS) has led to substantial improvements in renal function, effectively slowing down the progression of diabetic nephropathy (DN). Nevertheless, the precise method by which SHYS impacts DN remains elusive. This research project entailed the development of a mouse model of DN. Subsequently, we explored the anti-ferroptotic mechanisms of SHYS, encompassing iron overload mitigation and the activation of the cystine/GSH/GPX4 pathway. In a final experimental step, GPX4 inhibitor (RSL3) and the ferroptosis inhibitor (ferrostatin-1) were employed to determine if the presence of SHYS could reduce diabetic neuropathy (DN) by curbing ferroptosis. Mice treated with SHYS exhibited improved renal function, reduced inflammation, and decreased oxidative stress, as evidenced by the results. Concurrently, SHYS therapy minimized iron overload and enhanced the expression of factors related to the cystine/GSH/GPX4 axis within renal tissue. Simultaneously, SHYS exhibited a similar therapeutic effect on DN to ferrostatin-1, and RSL3 could block the therapeutic and anti-ferroptotic effects of SHYS on DN. In closing, SHYS presents a possible solution to the issue of DN in mice. In addition, SHYS potentially prevents ferroptosis in DN through a reduction of iron overload and a heightened expression of the cystine/GSH/GPX4 pathway.
Modifying the gut microbiota through oral agents could potentially serve as a novel preventive or treatment strategy for Parkinson's disease. The pentacyclic triterpene acid maslinic acid (MA), while displaying GM-dependent biological activity when taken orally, has not yet been reported as effective against Parkinson's disease. Analysis of a classical chronic Parkinson's disease mouse model in this study showed that low and high doses of MA treatment successfully prevented dopaminergic neuronal loss. This was associated with improvements in motor functions, higher levels of tyrosine hydroxylase in the substantia nigra pars compacta (SNpc), and increased dopamine and its metabolite homovanillic acid in the striatum. Remarkably, the impact of MA in PD mice exhibited no dose-responsiveness, as beneficial effects were similar for both lower and higher MA doses. Low-dose MA treatment, as revealed by further mechanistic studies, showed a tendency to support the growth of probiotic bacteria in PD mice, consequently leading to elevated levels of serotonin, 5-hydroxyindoleacetic acid, and gamma-aminobutyric acid in the striatum. Cecum microbiota In Parkinson's disease (PD) mice, high-dose MA treatment did not influence the gut microbiota composition, but significantly decreased neuroinflammation, indicated by lower levels of tumor necrosis factor alpha and interleukin 1 in the SNpc; these effects were predominantly mediated by the presence of acetic acid, a product of microbial metabolism in the colon. To conclude, oral MA, administered at diverse doses, conferred protection from PD via distinct pathways associated with GM. Future investigations will concentrate on the signaling pathways mediating the interaction between varying doses of MA and GM, as our current study lacked a thorough examination of the underlying mechanisms.
The key risk factor of aging often plays a substantial role in the development of a range of diseases, including neurodegenerative diseases, cardiovascular diseases, and cancer. In the face of this, the responsibility for combating age-related diseases has become a global imperative. The identification of drugs that can extend both lifespan and healthspan is critically important. As a natural, nontoxic phytocannabinoid, cannabidiol (CBD) has been identified as a possible anti-aging drug candidate. A rising trend in scientific investigations showcases a possible connection between CBD and beneficial effects on healthy longevity. Within this work, we outline the effects of CBD on aging and examine the probable underlying mechanisms. The presented conclusions suggest a direction for future research into the impact of CBD on the aging process.
Traumatic brain injury (TBI), a pathology with profound societal consequences, impacts millions globally. Although scientific progress has been observed in improving traumatic brain injury (TBI) management recently, a targeted therapy for controlling post-mechanical trauma inflammation remains elusive. The lengthy and costly process of discovering and implementing new treatments highlights the clinical appeal of repurposing approved medications for different diseases. Tibolone, a medicament used for treating menopausal symptoms, acts by adjusting the activity of estrogen, androgen, and progesterone receptors, generating strong anti-inflammatory and antioxidant responses. Our present study explored the potential therapeutic role of tibolone metabolites, namely 3-Hydroxytibolone, 3-Hydroxytibolone, and 4-Tibolone, in TBI treatment via network pharmacology and network topology analysis. Results from our study demonstrate the estrogenic component, facilitated by the and metabolites, influencing synaptic transmission and cell metabolism. The metabolite may potentially be involved in regulating the inflammatory cascade following TBI. Among the molecular targets identified, KDR, ESR2, AR, NR3C1, PPARD, and PPARA are known to play crucial roles in the development of TBI. The predicted effect of tibolone metabolites is to modulate the expression of key genes involved in oxidative stress, inflammation, and cellular apoptosis. The potential of tibolone as a neuroprotective treatment for TBI warrants further investigation in future clinical trials. Nevertheless, additional research is crucial to validate the effectiveness and safety of this approach in traumatic brain injury patients.
Limited treatment options exist for one of the most prevalent liver diseases, nonalcoholic fatty liver disease (NAFLD). Beyond that, the rate of occurrence of this phenomenon is increased to two times in type 2 diabetes mellitus (T2DM). Studies on the flavonoid Kaempferol (KAP) and its potential beneficial effects on non-alcoholic fatty liver disease (NAFLD) have been conducted, but more research is needed, especially in understanding its action in the context of diabetes. An in-depth exploration was conducted into how KAP affects NAFLD in the context of T2DM, and the underlying mechanisms involved, both in laboratory settings and using live subjects. Oleic acid-induced HepG2 cells experienced a significant decrease in lipid accumulation upon KAP treatment, as determined by in vitro investigations using concentrations of 10⁻⁸ to 10⁻⁶ molar. In addition, using the db/db mouse model of T2DM, we found that KAP (50 mg/kg) meaningfully reduced lipid buildup and mitigated liver damage. Studies employing both in vitro and in vivo models demonstrated that KAP's impact on hepatic lipid accumulation is mediated by Sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) signaling. KAP treatment activated Sirt1 and AMPK, consequently elevating the expression of the fatty acid oxidation-related protein, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), and diminishing the expression of lipid synthesis enzymes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein 1 (SREBP1). Additionally, the curative influence of KAP on lipid buildup was nullified by siRNA-mediated suppression of either Sirt1 or AMPK. These findings, taken together, suggest a possible therapeutic role for KAP in NAFLD co-occurring with T2DM, a role mediated by the modulation of hepatic lipid accumulation via activation of the Sirt1/AMPK pathway.
GSPT1 (G1 to S phase transition 1) is the necessary release factor for the conclusion of translation termination. The oncogenic driver GSPT1, prevalent in several cancer types, is viewed as a promising candidate for cancer therapy. Two selective GSPT1 degraders, having entered clinical trials, remain without clinical use approval. We synthesized a set of novel selective GSPT1 degraders, and compound 9q, specifically, exhibited potent GSPT1 degradation in U937 cells, achieving a DC50 of 35 nM, with good selectivity in proteomic profiling analysis. Compound 9q's mechanism of action, as researched through mechanistic studies, has been found to involve the degradation of GSPT1 through the ubiquitin-proteasome system. Compound 9q's GSPT1 degradation activity was strongly associated with its antiproliferative effects on U937, MOLT-4, and MV4-11 cells, reflected by IC50 values of 0.019 M, 0.006 M, and 0.027 M, respectively. conventional cytogenetic technique In U937 cells, a dose-dependent relationship was found between compound 9q treatment and G0/G1 phase arrest and apoptosis.
To investigate the underlying mechanisms in a cohort of hepatocellular carcinoma (HCC) patients, paired tumor and adjacent nontumor DNA samples underwent whole exome sequencing (WES) and microarray analysis to identify somatic variants and copy number alterations (CNAs). A study was conducted to determine the relationship between tumor mutation burden (TMB) and copy number alteration burden (CNAB) with clinicopathologic variables, specifically Edmondson-Steiner (E-S) grading, Barcelona-Clinic Liver Cancer (BCLC) stages, recurrence rates, and patient survival. In 36 analyzed cases, whole-exome sequencing (WES) revealed variations in the TP53, AXIN1, CTNNB1, SMARCA4 genes; additionally, amplifications of the AKT3, MYC, and TERT genes were observed, as well as deletions in CDH1, TP53, IRF2, RB1, RPL5, and PTEN genes. A significant portion, roughly eighty percent, of the observed cases displayed genetic defects within the p53/cell cycle control, PI3K/Ras, and -catenin pathways. In 52 percent of the instances, a germline variant of the ALDH2 gene was discovered. Metabolism inhibitor Significantly greater CNAB levels were measured in patients with a poor prognosis, specifically those with E-S grade III, BCLC stage C, and recurrence, compared to patients with a good prognosis, identified by grade III, stage A, and no recurrence. A comprehensive analysis of a large cohort of cases, correlating genomic profiles with clinicopathological classifications, could offer insights into diagnostic interpretation, prognostication, and targeted intervention strategies for affected genes and pathways.