Although skeletal muscle decline is implicated in cardiometabolic diseases, the precise mechanistic pathways and the prognostic superiority of relative over absolute handgrip strength for cardiometabolic multimorbidity (CMM) remain incompletely quantified. This nationally representative cross-sectional study included 6,839 middle-aged and older Chinese adults from the 2015 China Health and Retirement Longitudinal Study. We evaluated the associations of relative handgrip strength (RHGS) and absolute grip strength with CMM using multivariable logistic and Poisson regressions. Causal mediation analysis was employed to dissect the pathways linking RHGS to CMM. Results demonstrated that a 1-standard deviation decrease in RHGS was robustly associated with a 68
Midkine (MDK) and thyroid hormone receptor beta (THRB) have each been implicated separately in metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). THRB drives hepatic fatty-acid beta-oxidation (FAO). We tested whether MDK and the THRB-linked FAO program are reciprocally related in human liver tissue. We analyzed two independent human cohorts on different platforms. TCGA-LIHC provided 374 tumor and 50 adjacent non-tumor RNA-seq samples. GSE164760 provided 53 NASH-HCC, 74 NASH, 29 non-tumoral NASH adjacent to HCC, 8 cirrhotic and 6 healthy microarray samples. We quantified MDK, THRB and a curated 21-gene hepatic FAO composite score. Tests included Mann-Whitney, Spearman, Kruskal-Wallis, Jonckheere-Terpstra and genome-wide correlation with Benjamini-Hochberg correction. MDK was higher in tumor tissue in both cohorts (TCGA-LIHC p = 1.0 × 10-24, GSE164760 p = 8.1 × 10-13). The FAO composite was correspondingly lower (p = 7.0 × 10-10 and p = 7.1 × 10-6). THRB itself was lower in GSE164760 (p = 3.9 × 10-3) but not in TCGA-LIHC (p = 0.509). MDK correlated negatively with THRB and with the FAO composite in both cohorts. The strongest association was MDK versus FAO composite (rho=-0.45 in each cohort). Within-group analysis showed that the THRB to FAO composite correlation persisted in almost every subgroup. The MDK correlations weakened in three smaller subgroups. Across the five GSE164760 disease states, MDK, THRB and the FAO composite each differed significantly (Kruskal-Wallis p < 10−5) and each followed a significant monotonic trend (Jonckheere-Terpstra one-sided p < = 1.5 × 10-3). A reciprocal MDK-high and FAO-low transcriptional signature is reproducible across two independent human cohorts and across the MASH-to-HCC spectrum. These human tissue data support THRB agonism as a candidate therapeutic rationale in MASH-HCC that warrants prospective validation.
A mixture of lactonic and acidic sophorolipids exerted concentration-dependent cytotoxicity against human breast ductal adenocarcinoma (MCF-7) cells, with an IC₅₀ of 82.54 µg/mL as determined by resazurin assay. Phase-contrast microscopy revealed morphological alterations including cell swelling, loss of adhesion, and impaired membrane integrity. Flow cytometry analysis demonstrated cell cycle arrest in the S phase, mitochondrial membrane depolarization, and a predominance of necrosis-like cell death at higher concentrations. Transcriptional profiling by RT-qPCR identified overexpression of CDKN1A, GADD45A, ERN1, and BBC3, alongside repression of ACTB and GAPDH, indicating activation of DNA damage and stress-response pathways, endoplasmic reticulum stress, structural collapse, and metabolic dysfunction. Collectively, these findings demonstrate that sophorolipids induce mitochondrial and endoplasmic reticulum stress, culminating in homeostatic failure and cell death in MCF-7 cells, positioning these biosurfactants as promising candidates for the development of natural antiproliferative therapies.
Piper methysticum G. Forst., commonly known as Kava, is a culturally significant shrub native to the Pacific islands, including Fiji, Vanuatu, and Tonga. Flavokawain A is one of the primary non-kavalactone constituents found within its rhizomes. This review aims to provide a comprehensive and critical evaluation of the current state of research on Flavokawain A. Specifically, it aims to elucidate the diverse molecular mechanisms and signaling networks that drive its pharmacological effects, while assessing its viability as a multi-targeted therapeutic candidate for diverse diseases. Flavokawain A exhibits profound therapeutic potential across a spectrum of pathological conditions, including malignancy, chronic inflammation, myocardial infarction, and neurodegenerative disorders such as Alzheimer’s disease. Evidence from in silico, in vitro and in vivo models suggests that Flavokawain A’s efficacy is rooted in its ability to modulate key signaling hubs, notably the TGF-β1, NF-κB, PI3K/AKT, and Nrf2 pathways, as well as regulatory proteins like PRMT5, CDK2, and SKP2. These multi-target interactions underpin Flavokawain A’s potent antioxidant, anti-apoptotic, and anti-inflammatory properties, positioning it as a promising candidate for multifactorial disease management. FKA represents a versatile, multi-targeted potential therapeutic scaffold with a robust pharmacological profile. Its demonstrated anti-fibrotic, anti-inflammatory, and anti-proliferative activities across diverse disease models underscore its clinical potential. However, bridging the gap from bench to bedside requires rigorous translational studies and clinical trials to validate its safety, bioavailability, and therapeutic efficacy in human populations.
External factors such as oxidative stress and ultraviolet (UV) radiation increase reactive oxygen species (ROS) and cause the skin to age faster. Recently, peptides have been frequently preferred in nanoformulation development to prevent these effects. This study aimed to develop a nanoemulsion formulation of Syn-Ake peptide that reduces wrinkles by affecting neurotransmitters and to evaluate its efficacy by in silico and in vitro methods. In this context, the anti-aging activity of Syn-Ake peptide was evaluated by molecular docking and MD simulation. Then, nanoemulsion formulations of the peptide were produced using ultrasonic homogenization method and stability and characterization studies were conducted. The in vitro safety of the formulation was evaluated by genotoxicity and cytotoxicity studies. The cell regenerative effect of the formulation was evaluated by scratch test. Additionally, the protective effect of its formulation against H2O2-UV-induced skin damage was evaluated at both the cellular and DNA levels. Finally, the antioxidant activity and the collagenase inhibitory activity of the formulation was evaluated. Our findings showed that the peptide strongly interacted with p-38 MAPK and PI3K-AKT signalling pathways, as well as stromelysins and gelatinases. The most stable formulation was determined among the formulations developed with different production procedures. The formulation was determined to be non-genotoxic, cytocompatible and to have cell regenerative properties. It was also evaluated that the formulation was protective against H2O2-UV-based damage, showed antioxidant activity and collagenase inhibitory activity. The formulation of Syn-Ake peptide in nanoemulsion was evaluated to have promising potential as an anti-aging product candidate with a high efficacy and safety profile.
