Huntington's disease (HD) is an inherited illness. 3-Nitropropionic acid (3-NPA) is a recognized neurotoxin that resembles symptoms similar to HD in laboratory animals and neuroinflammation via the activation of high mobility group box-1 (HMGB1)/Toll-like receptor-4 (TLR-4)/nuclear factor-κB (NF-κB) signaling cascade. Rifampicin (RIF) and probucol (PROB) have been shown to inhibit proposed pathway. The primary aim of this study is to investigate the impact of RIF and PROB on the HMGB1/TLR-4/NF-κB signaling cascade in 3-NPA-induced neurotoxicity. Molecular docking and molecular dynamics simulation (100 ns) were employed to assess target-binding affinity. In vivo investigation employed either sex Wistar rats. 3-NPA (10 mg/kg i.p.) was administered along with PROB (10, 20, and 40 mg/kg p.o.) and RIF (20, 40, and 80 mg/kg i.p.) for 21 days, and assessed in terms of percentage change in body weight, behavioral activities (narrow beam walk, open field test, and rotarod), quantitative real time polymerase chain reaction (qRT-PCR) (caspase-3, Bax, and Bcl-2), neuroinflammatory markers (tumor necrosis factor-alpha, interleukin-1β, and interleukin-6), Western blotting (HMGB1 and NF-κB), and immunohistochemistry (IHC) [pTLR-4]. In silico studies demonstrated that both drugs have good binding affinity and stability with different targets. In vivo investigation revealed that administration of both RIF and PROB significantly rescued 3-NPA-induced behavioral alterations, modulation of HMGB1/TLR-4/NF-κB signaling, apoptotic markers, and neuroinflammation. Both RIF and PROB showed protective effects by inhibiting HMGB1 through TLR-4, thereby further inhibiting HMGB1-mediated downstream signaling axis and apoptosis. Hence, our findings suggest that RIF and PROB may have ability to mitigate 3-NPA-induced neurotoxicity via HMGB1/TLR-4/NF-κB signaling pathway.

Early revascularization and contemporary medical management for myocardial infarction (MI) have significantly improved patients' survival and performance. However, despite significant advances in MI therapies, several challenges remain in improving cardiac recovery and optimizing long-term clinical outcomes, including persistent cardiomyocyte loss, adverse ventricular remodeling, and subsequent cardiac complications. These have prompted increasing exploration of regenerative approaches for MI, which focus on repairing, regenerating, and/or replacing damaged myocardial tissue to restore cardiac structure and function. This includes stem cell-based therapies, cell-free approaches, gene therapy, tissue engineering, and blood-based regenerative strategies. While significant progress has been made in both preclinical and clinical studies of these regenerative therapies, further research is required to optimize their therapeutic efficacy. This review provides a summary of the recent advances, clinical progress, and translational limitations of some of the commonly investigated regenerative therapies for MI.

Indeterminate thyroid nodules classified as Bethesda III (atypia of undetermined significance) and Bethesda IV (follicular neoplasm) remain a diagnostic challenge because cytomorphology alone cannot reliably distinguish benign from malignant disease. Molecular testing has emerged as an adjunct to cytological, sonographic, and clinical assessment to refine preoperative risk stratification and inform management. This narrative review critically summarizes current evidence for major commercially available molecular platforms, including the Afirma Gene Expression Classifier, Afirma Genomic Sequencing Classifier (GSC), ThyroSeq v3, and ThyGeNEXT[®]/ThyraMIR[®], with emphasis on diagnostic performance, clinical utility, limitations, and contemporary practice integration. In pivotal validation studies, Afirma GSC demonstrated a sensitivity of 91%, specificity of 68%, positive predictive value (PPV) of 47%, and negative predictive value (NPV) of 96%, whereas ThyroSeq v3 demonstrated a sensitivity of 94%, specificity of 82%, PPV of 66%, and NPV of 97%. In a blinded multicenter validation study of Bethesda III/IV nodules, ThyGeNEXT/ThyraMIR demonstrated prevalence-adjusted sensitivity of 95%, specificity of 90%, PPV of 75%, and NPV of 97% at a standardized disease prevalence of 30%. These estimates should not be interpreted as direct head-to-head comparisons because studies differ in population characteristics, disease prevalence, reference standards, assay generation, and classification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Clinical-utility evidence indicates that molecular testing can influence decisions regarding surveillance and surgery and may reduce potentially avoidable diagnostic operations, although the magnitude of benefit varies across assays and clinical settings. The Bethesda System for Reporting Thyroid Cytopathology supports selective molecular testing when results are expected to meaningfully influence management. Molecular testing should therefore be regarded as an adjunct to integrated risk assessment rather than a stand-alone determinant of management, with results interpreted alongside cytological, sonographic, clinical, patient-specific, and institutional factors.

Gait speed is a key indicator for diagnosing sarcopenia, validated by both the European Working Group on Sarcopenia in Older People in 2018 and the Asian Working Group on Sarcopenia in 2019 for assessing physical performance. While global data link vitamin D to physical performance, regional sex-stratified evidence in East Asian populations remains limited. This study aims to validate and confirm the association between gait speed and vitamin D levels in a middle-aged and older population in Taiwan. This cross-sectional investigation focused on community-dwelling residents. Participants were assigned to vitamin D sufficiency (≥30 ng/mL), insufficiency (<30 ng/mL and ≥ 20 ng/mL), and deficiency (<20 ng/mL) defined by the American Endocrine Society and International Osteoporosis Foundation criteria. Analyses included Student's t-tests, analysis of variance (ANOVA), Chi-square test and sex-stratified multiple linear regression. A total of 396 participants (164 men and 232 women) were recruited, with a mean age of 65.18 ± 8.75 years; mean serum vitamin D concentration of 28.25 ± 9.45 ng/mL; and mean gait speed of 0.91 ± 0.23 m/s. A positive association between gait speed and 25(OH)D (p = 0.047), and a negative association between gait speed and age (p < 0.001) and body mass index (BMI) (p = 0.005) were observed in men. Conversely, in women, gait speed was negatively associated with age (p < 0.001), BMI (p = 0.010), hypertension (p = 0.027), and diabetes mellitus (p = 0.009). This study demonstrated a positive association between gait speed and serum 25(OH)D levels in middle-aged and older men.

Falls impose a major public health burden on middle-aged and older adults. Coexisting cardiovascular disease (CVD) and arthritis further increases fall risk, yet targeted prediction models remain scarce, especially in Chinese populations. We analyzed 633 China Health and Retirement Longitudinal Study participants aged ≥45 years with comorbid CVD and arthritis at the 2015 baseline. Seven predictors were selected through univariate analysis, LASSO logistic regression (LR), and clinical review. Eight machine-learning algorithms were compared. Among models with an area under the receiver operating characteristic curve (AUC) ≥0.72, the model with the highest specificity was preferred to reduce false-positive referrals. A geographically defined holdout group (n = 110) from different provincial-code regions, but within the same CHARLS source population, was treated as a geographic split-sample rather than independent external validation. Performance was assessed using AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), F1-score, calibration, decision-curve analysis, precision-recall curves, and SHapley Additive exPlanations (SHAP). During cumulative follow-up, 296 participants (46.8%) reported at least one fall. Random forest (RF) and LR achieved similar internal-validation AUCs (0.730 vs. 0.729); RF was selected because of higher specificity. Internally, RF showed 87.5% specificity, 37.7% sensitivity, 70.3% PPV, 64.2% NPV, and an F1-score of 0.491. Its AUC in the geographic holdout sample was 0.735. Despite similar AUCs, sensitivity and specificity differed substantially between samples, suggesting limited regional stability of the fixed threshold. SHAP identified fall history, ankle pain, activities of daily living impairment, and sleep duration as the most influential predictors. The RF model showed moderate discrimination and a conservative, high-specificity profile. However, its low internal sensitivity means it should not be used alone to rule out falls or as a diagnostic tool. Pending independent validation and regional threshold calibration, it may serve only as adjunctive stratification within a stepped assessment pathway and should not replace routine clinical fall-risk screening.

Biological age describes how a person is aging on molecular, cellular, and physiological levels. At the present time, biological age is not something that can be fully quantified and aging itself is far too complicated to be captured by a single layer of information. As such, it is relegated to being an abstract and somewhat vague idea. In this sense, biological age is remarkably similar to health. Health, like biological age, is not well defined and too multifarious to be summarized with a single biomarker. Given their similarities, it is intriguing to consider whether or not biological age and health are synonyms. Indeed, these two ideas can be cleanly swapped with each other in a variety of scenarios. If someone appears uniquely vigorous and capable for their chronological age, that person can be described as either quite healthy or being biologically youthful. However, there are situations where biological age and health diverge from each other. It is possible, for instance, to have a short healthspan but a long lifespan. While biological age is otherwise comparable to health as an abstract idea, it is possible that biological age and health will be confidently quantifiable in the future. Indeed, such quantification may be unlocked by the integration of multimodal data and artificial intelligence. In such a scenario, biological age offers a clear advantage over health in that it operates on a more intuitive, familiar scale as opposed to an artificially created index.

This study aims to investigate the relationship between serum levels of integrin alpha M (ITGAM), CX3CR1, and inducible nitric oxide synthase (iNOS) (microglial activation markers) and the development and severity of postoperative cognitive dysfunction (POCD) in elderly patients undergoing cardiopulmonary bypass (CPB). This observational study included 246 patients aged 60-80 years undergoing CPB. Serum levels of ITGAM, CX3CR1, and iNOS were measured preoperatively and early postoperatively (within 6 hours after surgery). Cognitive function was assessed preoperatively and 7 days postoperatively using the Montreal Cognitive Assessment and a comprehensive battery of neuropsychological tests. Receiver operating characteristic (ROC) analysis was employed to evaluate the predictive value of the biomarkers. Among the participants, 94 patients developed POCD, while 152 did not. Patients with POCD exhibited significantly higher early postoperative serum levels of ITGAM, CX3CR1, and iNOS compared to non-POCD patients. ROC analysis indicated moderate predictive accuracy for each biomarker individually (AUC: ITGAM = 0.78, CX3CR1 = 0.72, iNOS = 0.74), with a notable improvement when biomarkers were combined (AUC = 0.87). MoCA scores at 7 days postoperatively showed significant negative correlations with biomarker levels, while positive correlations were observed between biomarker levels and serum neuron-specific enolase, a marker of neuronal injury. Elevated postoperative serum levels of ITGAM, CX3CR1, and iNOS are strongly associated with the development and severity of POCD in elderly patients undergoing CPB. These biomarkers show promise as predictive tools for early identification of at-risk patients and may represent potential therapeutic targets for mitigating POCD by modulating microglial activation.

Chemotherapy remains a cornerstone in cancer treatment, yet its associated toxic effects, particularly pulmonary complications, pose significant clinical challenges. Chemotherapeutic agents, either alone or in combination, can induce severe pulmonary toxicity through mechanisms involving direct cytotoxicity, oxidative stress, and inflammatory responses. Drug-induced lung injuries, including interstitial pneumonitis, acute respiratory distress syndrome, and fibrosis, are commonly observed, with agents such as bleomycin, cyclophosphamide, and busulfan. Approximately 10% of patients undergoing chemotherapy experience pulmonary complications, necessitating effective management strategies. Emerging evidence suggests that natural products, particularly antioxidants and plant-derived compounds like ellagic acid, can mitigate chemotherapy-induced pulmonary toxicity by counteracting oxidative stress and inflammation. We aim to summarize the toxic implications of chemotherapeutic drugs on the respiratory system, elucidating the underlying pathophysiological mechanisms. It also explores potential therapeutic interventions, including natural products, to reduce pulmonary toxicity. A thorough understanding of overall mechanisms will aid in the advancement of targeted strategies to improve the efficacy of cancer treatment while minimizing adverse effects.

Mild cognitive impairment (MCI) lacks approved disease-modifying therapies. Classical multicomponent prescriptions may act on convergent neurobiological nodes. We combined network pharmacology with in vivo testing to evaluate Yizhi Dihuang Decoction (YZDHD). Constituents were curated from traditional chinese medicine systems pharmacology database and analysis platform (TCMSP) and high-throughput experiment- and reference-guided database of Traditional Chinese Medicine (HERB under blood-brain barrier-aware SwissADME criteria. Targets were inferred, intersected with MCI genes, organized into STRING and MCODE networks, and examined by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment. Structure-based docking evaluated ligand-protein interactions across network-identified hub targets and ranked complexes by predicted binding energy. Predictions were tested in a D-galactose mouse model using the Morris water maze and novel object recognition, hippocampal histology with hematoxylin and eosin and Nissl staining, transmission electron microscopy, and molecular readouts by Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR), including PI3K, p-AKT/AKT, p-mTOR/mTOR, LC3-II/LC3-I, and p62/SQSTM1. We identified 152 bioavailable compounds and 381 overlapping targets that converged on hub kinases including AKT1, PIK3CA, PIK3CD, and mTOR; docking supported feasible engagement. In vivo, YZDHD improved spatial learning and recognition memory, preserved hippocampal cytoarchitecture and mitochondrial integrity, increased LC3-II/LC3-I, decreased p62/SQSTM1, and reduced activation indices of AKT and mTOR. YZDHD ameliorates MCI-like deficits by rebalancing PI3K-AKT-mTOR signaling and restoring autophagy-related activity. Signals for mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1 (HIF-1), epidermal growth factor receptor (EGFR), and toll-like receptor 4 (TLR4) broaden the mechanistic hypothesis space and warrant targeted follow-up.

Diminished ovarian reserve (DOR), affecting more than 10% of reproductive-aged women, leads to impaired fertility and systemic health disturbances. Baozhu Granule, a novel Chinese herbal formulation, has shown potential ovarian-protective effects in preliminary studies. This exploratory clinical trial aimed to investigate the efficacy and safety of Baozhu Granule in patients diagnosed with DOR. In this prospective, single-arm, open-label trial, 134 women aged 18-45 years with confirmed DOR were enrolled. Participants received Baozhu Granule (20 g, twice daily) orally for 12 consecutive weeks. The primary outcome was the recovery rate of ovarian reserve, assessed by antral follicle count and serum biomarkers. Secondary outcomes included menstrual recovery and changes in the Kupperman menopausal index (KMI). Evaluations were performed at baseline and after 12 weeks of treatment. Of the 134 enrolled patients, 108 completed the full treatment course; 20 of these were unable to attend the final visit (Visit 3) due to COVID-19 restrictions. Among the 88 patients evaluable at Visit 3, 68.2% showed recovery of ovarian reserve. Menstrual recovery was reported in 45.9% of patients, and 42.9% showed alleviation of menopausal symptoms (reduction in KMI). Subgroup analyses indicated that younger age, detectable anti-Müllerian hormone levels, and lower baseline follicle-stimulating hormone levels were associated with higher rates of ovarian reserve and menstrual recovery. Specifically, the overall recovery rate was 85.2% at 12 weeks of observation. No serious adverse events were reported throughout the study period. In this exploratory study, Baozhu Granule was associated with improvements in ovarian reserve, restoration of menstrual cyclicity, and relief of menopausal symptoms in women with DOR, with a favorable safety profile. These preliminary findings suggest its potential as a therapeutic option for DOR; however, further randomized controlled trials are needed to confirm these results.

Metformin use may be associated with reduced risk of all-cause mortality as well as prevent the onset of diseases of aging, namely cardiovascular diseases (CVD), cancer, and dementia. We systematically reviewed recent studies to determine whether metformin can promote healthspan in people with type 2 diabetes mellitus (T2DM). A comprehensive literature search was conducted using Medline, Embase, and Scopus for randomized controlled trials (RCTs) and cohort studies evaluating the effect of metformin on the incidence of all-cause mortality. Publications investigating metformin's effects on CVD, cancer or dementia were included. Search was restricted to English-only publications between 2016 and 2021. Full-text review, data extraction, and assessment of risk of bias using the Newcastle-Ottawa Scale were undertaken. Of 130 articles reviewed, 27 met the inclusion criteria. All 27 studies are observational cohorts, and no RCTs met the inclusion criteria, so causality cannot be inferred. No RCTs met the inclusion criteria. Five studies investigated the effects of metformin on all-cause mortality, 17 on the incidence of cancer, 3 on CVD, and 4 on dementia. Data heterogeneity precluded meta-analysis. Included studies were of high quality with NOS scores of 6-9. Metformin use in individuals with T2DM was associated with reduced risk of all-cause mortality, incidence of CVDs, and dementia. Metformin was associated with a reduced risk of prostate cancer but otherwise effects varied with cancer type and remain inconclusive.

Identification of natural compounds that delay aging and prevent age-related neurodegeneration is a key goal in gerontology. Fucoxanthin, a marine-derived xanthophyll, exhibits potent antioxidant properties, yet its effects on organismal aging and specific molecular mechanisms remain underexplored. Here, we investigated the pro-longevity and neuroprotective effects of fucoxanthin using Caenorhabditis elegans. Fucoxanthin supplementation significantly extended the mean lifespan of wild-type nematodes by 12.1% and improved health span, as evidenced by delayed age-related motility decline and enhanced resistance to oxidative stress. Notably, this lifespan extension occurred without compromising reproductive fitness. Genetic analysis revealed that the beneficial effects of fucoxanthin require the FOXO transcription factor DAF-16 and the autophagy-essential gene bec-1. Furthermore, fucoxanthin treatment increased autophagic flux and upregulated the expression of SKN-1/Nrf2-dependent detoxification genes, hsp-16.2 and gst-4. In nematode models of Alzheimer's and Parkinson's disease, fucoxanthin significantly ameliorated Aβ-induced paralysis and protected against dopaminergic neurodegeneration and α-synuclein accumulation in a DAF-16-dependent manner. Collectively, our findings demonstrate that fucoxanthin acts as a multitarget geroprotector that promotes healthy aging through the coordinated activation of DAF-16 and autophagy, suggesting its potential as a therapeutic intervention for age-related decline.

Huntington's disease (HD) is an inherited hyperkinetic movement disorder allied with chorea, cognitive impairment, and psychological disorders. Nerolidol (NRD) is a natural sesquiterpene alcohol obtained from many plants that has been shown to display neuroprotective properties. The current study focused on investigating the mechanism behind the neuroprotective role of NRD against 3-nitropropionic acid (3-NP)-induced neurotoxicity in experimental animals. Initial prediction was carried out through computational modeling (in silico), followed by a series of in vitro and in vivo experiments utilizing batteries of behavioral and molecular tests. Molecular docking was performed using Schrödinger (Maestro 2.0) to further explore NRD's neuroprotective capacity against 3-NP-induced neurotoxicity in SH-SY5Y cell lines and rats. For the in vivo study, 24 adult Wistar rats were randomly divided into four different groups, while NRD (50 and 100 mg/kg) was chosen to study their neuroprotective impact against HD-like symptoms utilizing different behavioral, biochemical, and histopathological parameters. In silico studies demonstrated that NRD has a high binding affinity for active sites of targeted enzymes, while in vitro data showed that NRD can counteract the neurotoxic effects of 3-NP in SH-SY5Y cells. NRD therapy (50 and 100 mg/kg) significantly improved motor activity, levels of malondialdehyde and glutathione, and histopathological changes. The findings revealed that NRD offers antioxidant and neuroprotective effects against 3-NP-induced neurotoxicity. The observed results indicated that NRD may exert its effects by activating the Nrf2 and heme oxygenase-1 pathways. Thus, it is suggested that it may be employed as an alternative treatment to fight against neurotoxicity.

Sarcopenia attenuates independence and mobility in older adults, and scalable nonpharmacological interventions are needed. This trial evaluated whether a 12-week exercise program improves activities of daily living, muscle mass and strength, physical performance, and systemic inflammation in older adults with sarcopenia. In this 12-week randomized controlled trial, adults aged 60-75 years with sarcopenia were randomized 1:1 to a control group or an exercise group. The exercise group performed postprandial multicomponent training (37 min/session, 3 days/week), combining resistance and aerobic exercise. Outcomes were measured at baseline and at week 12. The primary endpoint was the Modified Barthel Index (MBI). Secondary endpoints were Appendicular Skeletal Muscle Mass Index (ASMI), handgrip strength, the 6-minute walk test (6MWT), the Timed Up and Go Test (TUGT), and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Of 224 enrolled participants, 120 were randomized and 94 were analyzed (control, n = 49; exercise, n = 45). At week 12, the exercise group showed higher MBI (68.89 ± 9.60 vs. 62.02 ± 10.35; p = 0.001), ASMI (6.074 ± 0.904 vs. 5.295 ± 0.739 kg/m[2]; p < 0.001), and handgrip strength (22.78 ± 5.02 vs. 19.95 ± 4.25 kg; p = 0.009); better 6MWT (395.6 ± 55.6 vs. 363.7 ± 53.8 minutes; p = 0.005), shorter TUGT (6.76 ± 1.41 vs. 7.66 ± 1.55 seconds; p = 0.005), and lower IL-6 (45.21 ± 10.66 vs. 53.73 ± 10.99 pg/mL; p < 0.001) and TNF-α (38.09 ± 8.64 vs. 45.45 ± 8.07 pg/mL; p < 0.001) compared with the control group. These findings suggested that a 12-week regular exercise program improved functional independence, muscle health, mobility, and inflammatory status in older adults with sarcopenia.