Biomedicines最新文献

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy-apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer.

Polycystic Ovary Syndrome (PCOS) is characterized by a self-perpetuating vicious cycle between insulin resistance (IR) and hyperandrogenism (HA). While lifestyle management remains the internationally recommended first-line treatment, current clinical management, primarily relying on combined oral contraceptives and metformin, offers symptomatic relief or "masking" of the phenotype but fails to adequately disrupt this core pathophysiological loop, while also carrying potential intergenerational safety concerns. This review systematically evaluates the paradigm shift toward mechanism-based precision medicine. First, we analyze emerging precision-targeted therapies that intervene in specific pathological nodes: (1) metabolic regulators (e.g., GLP-1RAs, SGLT2i, and brown adipose tissue (BAT) activators) that target systemic glucotoxicity and the novel "BAT-Ovarian axis"; (2) neuroendocrine modulators (e.g., NK3R antagonists) that act as negative modulators of the hyperactive GnRH pulse generator; and (3) innovative androgen synthesis inhibitors (e.g., Artemisinins) that utilize a degradation-at-source mechanism. Complementing these, we explore the strategic value of Natural Products through the lens of "Network Pharmacology", highlighting their ability to restore systemic homeostasis via multi-target modulation. Finally, we address critical translational challenges, specifically the need to establish long-term reproductive and offspring safety, providing a roadmap for developing true disease-modifying treatments for PCOS. Distinct from reviews limited to isolated therapeutic modalities, this article uniquely bridges current clinical management with emerging organ-specific precision targets and natural product networks.

Steroidal compounds lie at the crossroads of inflammation and cancer, where modulation of common signaling pathways creates opportunities for dual-action therapeutic intervention. Accumulating evidence indicates that their anti-inflammatory and antitumor activities are frequently interconnected, reflecting shared molecular mechanisms that regulate immune signaling, oxidative stress, cell proliferation, and apoptosis. This review provides a critical and comparative analysis of major classes of bioactive steroids-including furanosteroids, neo-steroids, aromatic steroids, α,β-epoxy steroids, peroxy steroids, cyanosteroids, nitro- and epithio steroids, halogenated steroids (fluorinated, chlorinated, brominated, iodinated), and steroid phosphate esters-with emphasis on their dual anti-inflammatory and anticancer potential. More than one thousand steroidal metabolites derived from plants, fungi, marine organisms, bacteria, and synthetic sources are surveyed. While the majority exhibit either anti-inflammatory or antineoplastic activity alone, only a limited subset displays potent activity in both domains. Comparative evaluation highlights the structural features that favor dual functionality, including epoxide, peroxide, nitrile, nitro, halogen, and phosphate ester moieties, as well as rearranged or heteroatom-enriched steroidal frameworks. Where available, biological data from in vitro and in vivo assays (IC₅₀ values, enzyme inhibition, cytokine modulation, and antiproliferative effects) are summarized and critically compared. Special attention is given to rare natural metabolites-such as polyhalogenated marine steroids, phosphorylated sterols, and heteroatom-containing derivatives-as well as synthetic analogues designed to enhance cytotoxic or immunomodulatory efficacy. Mechanistically, steroids exhibiting dual activity commonly modulate convergent signaling pathways, including NF-κB, JAK/STAT, MAPK, PI3K/AKT, redox homeostasis, and apoptosis regulation. Collectively, these findings underscore the potential of structurally optimized steroids as multifunctional therapeutic agents and provide a framework for the rational design of next-generation anti-inflammatory and anticancer drugs.

Background: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition influenced by both genetic and non-genetic factors, although the underlying pathomechanisms remain unclear. We systematically analyzed microRNA (miRNA) expression and associated functional pathways in ASD to evaluate their potential as prenatal/postnatal, diagnostic, and prognostic biomarkers. Methods: Peripheral blood mononuclear cells from 12 Sicilian patients with ASD (eight with normal cognitive function) and 15 healthy controls were analyzed using small RNA sequencing. Differential expression analysis was performed with DESeq2 (|fold change| ≥ 1.5; adjusted p ≤ 0.05). Functional enrichment and network analyses were conducted using Ingenuity Pathway Analysis, focusing on Diseases and Biofunctions. Results: 998 miRNAs were differentially expressed in ASD, 424 upregulated and 553 downregulated. Enriched pathways were primarily associated with psychological and neurological disorders. Network analysis highlighted three principal interaction clusters related to inflammation, cell survival and mechanotransduction, synaptic plasticity, and neuronal excitability. Four miRNAs (miR-296-3p, miR-27a, miR-146a-5p, and miR-29b-3p) emerged as key regulatory candidates. Conclusions: The marked divergence in miRNA expression between ASD and controls suggests distinct regulatory patterns, thus reinforcing the central involvement of inflammatory, autoimmune, and infectious mechanisms in ASD, mediated by miRNAs regulating S100 family genes, neuronal migration, and synaptic communication. However, rather than defining a predictive biomarker panel, this study identified candidate miRNAs and regulatory networks that may be relevant to ASD pathophysiology. As such, further validation in appropriately powered cohorts with predictive modeling frameworks are warranted before any biomarker or diagnostic implications can be inferred.

Background: Even though there have been improvements in antimicrobial and supportive therapies, sepsis and septic shock are still major causes of death in intensive care units. Early prognostic stratification is very important for helping doctors make decisions. Platelet-derived indices may provide useful, low-cost indicators that signify both inflammatory activation and coagulation irregularities. This study looked at how well different platelet-based ratios could predict death in the hospital from sepsis. Materials and Methods: We performed a prospective observational study spanning one year in a tertiary ICU, enrolling 114 adult patients diagnosed with sepsis or septic shock. Upon admission, four platelet-related biomarkers were measured: the C-reactive protein-to-platelet ratio (CPR), the platelet-to-lymphocyte ratio (PLR), the platelet-to-white blood cell ratio (PWR), and the platelet-to-creatinine ratio (PCR). Logistic regression models and receiver operating characteristic (ROC) analyses were employed to assess predictive accuracy. Results: Compared to survivors, non-survivors (n = 39) had much higher CRP levels and CPR values, alongside lower platelet and lymphocyte counts. The CPR index showed the best ability in differentiating between non-survivors and survivors (AUC 0.757), with a best cutoff of 0.886. In simplified multivariate models, CPR was still an independent predictor of death in the hospital (OR 1.98; 95% CI 1.22-3.21), whereas PLR and PWR were not. PCR showed a non-significant trend toward lower values in not survivors. Conclusions: CPR is a strong and clinically viable predictor of early mortality in sepsis, outperforming other platelet-based indices. Derived from routine laboratory parameters, CPR serves as a valuable adjunct for initial risk stratification in the ICU. To further confirm its prognostic role and incorporation into current scoring systems, large-scale multicenter studies with longitudinal measurements are warranted to validate its prognostic utility and integration into existing scoring systems.

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial-mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24^- fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit.

Background/Objectives: Allergic rhinitis (AR) is a complex immune-mediated disorder characterized by defective regulatory mechanisms. Emerging evidence suggests that impaired immune tolerance mediated by regulatory B cell (Breg) plays a pivotal role in AR pathogenesis. This study investigates the therapeutic potential of Der p1 allergen-modified dendritic cells (DC) in enhancing Breg-mediated immunotherapy and explores novel mechanisms underlying AR immunomodulation. Methods: Breg and the inflammatory cytokines were detected before and after allergen immunotherapy (AIT) in AR patients. Dust mite gene-derived dendritic cells were used to induce Breg. AR mice were treated with Der p1-DCs, and changes in Breg and related inflammatory indicators, as well as the impact of the IL-10/STAT pathway on DC vaccine treatment, were observed. Results: Following 6-month AIT, AR patients exhibited significant alleviation of nasal symptoms alongside restored peripheral Breg and Treg. In vitro co-culture of Der p1-DC-induced Bregs with CD4⁺CD25^-T cells revealed that IL-10 blockade markedly increased Th cell. In AR murine models, intraperitoneal Der p1-DC administration suppressed allergic symptoms, upregulated nasal mucosal IL-10 expression, and attenuated STAT3 phosphorylation via IL-10 overexpression. Conclusions: AIT establishes immune tolerance through Breg-mediated regulatory mechanisms, while Der p1-DCs potently induce Breg differentiation and drive tolerance induction via the IL-10/STAT3 signaling axis.

Background: Infection and consequent limb amputations are complications of severe peripheral artery disease, especially in diabetic patients. Risk factors and prognostic markers are of particular importance in defining patient care. Methods: This study included 99 peripheral artery disease (PAD) patients admitted for surgical intervention in the 2020-2021 time interval. The included subjects were stratified by type 2 diabetes mellitus (T2DM) diagnosis (present/absent). Protein, albumin concentrations, blood-count-derived inflammatory markers, and cultures from gangrenous wounds were assessed. In the group of severe cases, needing lower limb amputation (n = 31), homocysteine level, and related methylene tetrahydrofolate reductase (MTHFR) gene mutations were also investigated. Results: The mean age of patients was 68.36 ± 11.79 (SD) years and T2DM patients were significantly older (p = 0.0303). The measured inflammatory markers were at normal values in 20% of the subjects. In the cohort of infected patients, S. aureus, P. mirabilis, P. vulgaris, and S. agalactiae were the most commonly identified bacteria, with C. albicans prevailing as the most common fungal pathogen. The patient length of stay (LoS) was significantly longer in patients with pathological blood-count-derived biomarkers (p = 0.0283). A total of 58% of the severe cases presented hyperhomocysteinemia (mean 17.7 ± 10.6 (SD) μmol/L), and 19% of them presented homozygous mutation of the MTHFR gene (C677T), while 39% carried a heterozygous mutation. Compared to those with normal alleles, homocysteine levels were significantly higher in subjects with homozygous mutation (p = 0.0334). Discussion: Homozygous MTHFR mutation was associated with hyperhomocysteinemia. Blood-count-derived inflammatory markers may indicate an unfavorable outcome for PAD patients, guiding clinicians in identifying patients that are prone to complications.

Background/objectives: Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa, which has potential skeletal benefits through modulation of bone cell function and inflammatory signalling. However, evidence of its effects and mechanisms in bone health remains fragmented. This scoping review summarised the current findings on the impact of CBD on bone outcomes and its mechanisms of action. Methods: A systematic search of PubMed, Scopus, and Web of Science was conducted in October 2025 for original studies published in English, with the primary objective of examining the effects of CBD on bone health, regardless of study design. After applying inclusion and exclusion criteria, 24 primary studies were included. Data on model design, CBD formulation, treatment parameters, bone-related outcomes, and proposed mechanisms were extracted and analysed descriptively. Results: Among the studies included, eleven demonstrated beneficial effects of CBD on bone formation, mineralisation, callus quality, or strength; eleven showed mixed outcomes; and two demonstrated no apparent benefit. Previous studies have shown that CBD suppresses bone resorption by reducing osteoclast differentiation and activity while promoting osteoblast proliferation and matrix deposition. Mechanistically, CBD's effects involve activation of cannabinoid receptor 2, modulation of the receptor activator of nuclear factor-κB ligand/osteoprotegerin pathway, and regulation of osteoblastogenic and osteoclastogenic signalling through bone morphogenetic protein, Wnt, mitogen-activated protein kinase, nuclear factor-κB, and peroxisome proliferator-activated receptor signalling. The anti-inflammatory and antioxidant actions of CBD further contribute to a favourable bone microenvironment. Conclusions: Preclinical evidence suggests that CBD has a bone-protective role through multifaceted pathways that enhance osteoblast function and suppress osteoclast activity. Nevertheless, robust human trials are necessary to confirm its efficacy, determine its optimal dosing, and clarify its long-term safety.

Background/Objectives: Hemodynamic and neurohormonal factors, including renal perfusion and venous pressure, may affect diuretic response, which may be modulated by body position. This study aimed to assess whether supine versus upright positioning influences diuretic efficacy and neurohormonal activation during early decongestion in patients with AHF and reduced ejection fraction (HFrEF). Methods: This single-center, prospective, pilot randomized study enrolled 12 hospitalized patients with decompensated HFrEF receiving guideline-directed medical therapy. Participants were randomized (1:1) to remain in either the supine or upright/seated position during intravenous furosemide administration (1 mg/kg: half of the dose administered as a bolus, half as a 2-h infusion). Serial measurements of urine volume, electrolyte excretion, and neurohormonal biomarkers (renin, aldosterone, catecholamines) were performed at baseline, 2, and 6 h after diuretic administration. Results: No significant differences were found between supine and upright groups in total urine output, urine dilution, sodium excretion, or weight change after 6 h. There were no statistically significant differences in renin and aldosterone levels across subsequent timepoints; however, renin concentration tended to be higher in upright than in supine individuals. Interestingly, supine participants demonstrated greater urinary adrenaline concentration after furosemide administration, alone and after adjustment for urinary creatinine. Conclusions: No clinically meaningful differences were found between supine versus upright position patients with AHF, receiving neurohormonal blockade.