Leishmaniasis is a neglected tropical disease caused by infection with the protozoan parasite Leishmania and it is a significant global health problem. The disease has a wide clinical spectrum, from tegumentary leishmaniasis (TL) that encompasses cutaneous (CL), mucosal (ML) and cutaneous-diffuse (CDL) forms, to the potentially fatal systemic visceral leishmaniasis (VL). Neurological manifestations are not generally considered as classical clinical signs or symptoms of leishmaniasis, but in this review, we present evidence that this is a false assumption. We examine brain involvement in human and canine leishmaniasis and the contribution of animal models for studying cerebral Leishmania infection. Clinical descriptions of brain involvement are presented, and evidence of Leishmania invasion of the central nervous system. Notably, evidence for brain involvement comes from considerable studies in the dog and covers aspects of disruption of the blood-brain and blood-cerebrospinal fluid barriers and the nature of the inflammatory response.

This study isolated and screened a multifunctional plant-growth-promoting bacterium, Bacillus sp. G52, from the rhizosphere soil of Gannan navel oranges. Through pot experiments and genomic analysis, the growth-promoting effects and molecular mechanisms of strain G52 on navel orange seedlings were systematically evaluated. The results showed that strain G52 could secrete indole-3-acetic acid (IAA, yield: 18.68 ± 0.81 mg/L), siderophores (yield: 47.10 ± 1.03%), and phosphate-solubilizing substances (91.85 ± 4.94 mg/L) while also exhibiting ACC deaminase activity and ammonia production. Pot experiments demonstrated that inoculation with G52 significantly increased seedling height (12.51%), stem diameter (10.97%), biomass (27.87% in shoots, 41.13% in roots), and chlorophyll content (37.40% increase in total chlorophyll). Additionally, G52-treated seedlings showed enhanced antioxidant enzyme activities (SOD, POD, CAT), indicating improved stress resistance. Genomic analysis revealed that G52 carries functional genes related to IAA synthesis (e.g., trpA-trpF) and siderophore production (e.g., ent gene cluster), further confirming the molecular basis of its growth-promoting potential. Phylogenetic analysis indicated a 99.7% similarity between G52 and Bacillus velezensis. This study provides a theoretical foundation for developing multifunctional Bacillus-based biofertilizers, contributing to sustainable agricultural development.

Cytochrome C (Cyt C) is a central mediator of intrinsic apoptosis, whereas its heme-free precursor, apocytochrome C (APO-Cyt C), competitively inhibits this process. Sodium aescinate (SA), a natural triterpene saponin, is known to facilitate the endosomal escape of protein drugs. We initially aimed to investigate the effects of enhancing endosomal escape efficiency on protein activity through the combination of SA and Cyt C. However, this study investigates an cytotoxicity observed when APO-Cyt C is combined with SA and aims to elucidate the underlying molecular mechanism. Contrary to its established anti-apoptotic function, APO-Cyt C, when co-administered with a non-toxic concentration of SA, induced potent, caspase-dependent mitochondrial apoptosis in cancer cells. This pro-apoptotic switch was not primarily triggered by BCL-2 family protein modulation, ROS generation, or calcium overload. Instead, the primary mechanism is the induction of excessive and lethal autophagy. SA was found to induce lysosomal membrane damage, evidenced by Galectin-9 recruitment, which initiates lysophagy. The addition of APO-Cyt C significantly amplified the autophagic flux, leading to decreased p62 levels and enhanced LC3-II turnover. Mechanistically, this synergy is driven by a dual impact on the AKT-mTOR-TFEB pathway: APO-Cyt C treatment decreased mTOR phosphorylation, while the combination promoted the nuclear translocation of the autophagy regulator, TFEB. Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death. This study reveals a novel therapeutic strategy wherein an anti-apoptotic protein is converted into a potent pro-apoptotic agent. The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy.

Methylmalonic acidemia and propionic acidemia are inherited organic acidemias resulting from deficiencies in the enzymes methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Impaired activity of these enzymes leads to the accumulation of propionyl-CoA and methylmalonyl-CoA metabolites in tissues and biological fluids. The two disorders share similar clinical features, most notably severe neurological involvement. In the absence of early diagnosis and appropriate treatment, affected individuals may develop irreversible neurological injury, progress to coma, and, in severe cases, death. In this scenario, this review presents some findings from studies in patients, cells and animal models, evidencing that oxidative stress and inflammation plays a crucial role in the pathophysiology of methylmalonic acidemia and propionic acidemia. Furthermore, it allows us to understand the profile of oxidative stress and new perspectives for the treatment of these diseases. Decreased antioxidant defenses, as well as increased levels of markers of inflammation, oxidative damage to lipids, proteins and DNA were observed in animal models, cells and patients, possibly due to the increase in the production of reactive species caused by the accumulated metabolites. The literature also indicates that the use of specific antioxidants may provide benefits by improving the oxidative profile. Based on this evidence, it is widely accepted that oxidative stress and inflammation contribute to severe neurological damage in patients with methylmalonic acidemia and propionic acidemia.

Cadmium exposure is a known disruptor of ovarian redox homeostasis and steroidogenesis, with clinically relevant implications for fertility and pregnancy outcomes. We hypothesized that date seed extract (DS), rich in antioxidant constituents, and low-dose gamma radiation (LDR) could synergistically counteract Cd-induced ovarian toxicity. (1) To assess whether DS and/or low-dose γ-radiation mitigate Cd-induced oxidative stress, inflammatory signaling, and impairment of steroidogenesis; (2) to determine whether the combination of DS + LDR offers superior protection relative to single treatments; and (3) to evaluate whether biochemical improvements translate to preservation of ovarian histology. The present study highlights the combinatorial approach (DS + LDR) as a potential, novel intervention for reducing Cd-associated gonadotoxicity. Forty-eight female Swiss albino rats were allocated to eight groups (n = 6): Control; DS; R; DS + R; Cd; Cd + DS; Cd + R; Cd + DS + R. Treatments were administered for 21 days (DS) and 2 weeks (Cd exposure) with ongoing γ-radiation where indicated. Outcomes included: (i) oxidative stress markers (SOD, GSH); (ii) steroidogenic axis components (StAR, CYP11A1, 3β-HSD, 17β-HSD) at the ovarian level; (iii) hormonal profiles (e.g., estrogen, progesterone, and relevant gonadotropins); (iv) inflammatory signaling (NF-κβ); and (v) histopathology of ovarian sections. Cd exposure caused a significant decline in ovarian antioxidants (SOD, GSH) and a reduction in steroidogenic enzyme expression, accompanied by hormonal disturbances and prominent NF-κβ-driven inflammatory changes. Histologically, Cd induced cortical and follicular disruption with increased degenerative changes. DS and LDR mitigated these effects, with the combination DS + LDR showing the most robust rescue: antioxidant defenses and steroidogenic enzyme expression nearly normalized, hormonal levels stabilized, NF-κβ signaling reduced, and ovarian architecture preserved. Statistical significance was achieved for most endpoints (p < 0.05) and trends supported additive or synergistic benefits for DS + LDR. The combination of DS and low-dose γ-radiation offers superior protection against Cd-induced ovarian toxicity by restoring redox balance, downregulating inflammatory pathways, normalizing steroidogenesis, and preserving ovarian histology. These findings support further exploration of DS + R as a potential therapeutic strategy to mitigate heavy metal-related reproductive damage.

Bone-muscle diseases, such as osteoporosis, rheumatoid arthritis, sarcopenia and cachexia, represent a growing global health concern, particularly among aging populations and older adults. These multifactorial disorders are characterized by progressive decline in bone density and muscle mass, increasing the chances of immobility and eventually disability. Such manifestations are driven by a complex molecular crosstalk between bones and muscles. This review highlights the key role of the irisin-sclerostin-inflammation triad in the pathophysiology of musculoskeletal degeneration. Irisin is a myokine induced by exercise. It is associated with osteogenesis and muscle regeneration. Sclerostin is an osteocyte-derived Wnt antagonist, inhibits bone formation and is linked to impaired muscle regeneration. Inflammatory mediators such as TNF-α and IL-6 drive muscle catabolism and bone resorption through the NF-κB and STAT3 signaling pathways. Dysregulation of this triad accelerates musculoskeletal degeneration, particularly in chronic diseases and aging. We described the correlation between these diseases and mediators with age and gender. Additionally, we discussed current and emerging therapeutic strategies targeting these mediators, including anti-sclerostin antibodies for high-risk osteoporosis, cytokine/JAK-pathway inhibitors for inflammatory disease, and structured resistance/weight-bearing exercise as a cornerstone intervention. We highlighted assay standardization needs, proposed human-focused models, and outlined priorities for precision, combination strategies targeting the triad in bone-muscle wasting disorders.

This review explores the role of extracellular matrix (ECM) in adipose tissue highlighting its composition, regulation, and impact on obesity and insulin resistance. The ECM in adipocytes is a dynamic entity and highly organized network composed of structural proteins which provide mechanical support for cells and tissues and regulate cellular signaling. ECM modifiers, such as matrix metalloproteinases and tissue inhibitors of metalloproteinases, coordinate ECM remodeling to allow the expansion of adipocytes. Furthermore, ECM receptors like integrins and CD44 mediate adipocytes-microenvironment interactions, affecting the inflammatory process resulting in insulin resistance. The ECM components are posttranslational being modified by an array of remodeling enzymes, such as lysyl oxidase and prolyl-4-hydroxylase, to regulate ECM integrity. While excessive ECM deposition and fibrosis urge physical constraints on adipocyte expansion, ECM remodeling emerges as a denominator linking obesity and insulin resistance associated with vascular dysfunction and severe inflammation emphasizing the role of ECM in metabolic diseases.

Silent mating type information regulation 2 homolog (SIRT1), a key protein involved in cellular regulation, exhibits altered expression in breast cancer. The study aimed to assess serum Sirtuin 1 level, investigate SIRT1 gene polymorphisms, and examine their association with breast cancer. One hundred seventy-two breast cancer patients and 78 healthy age-matched females were included in the study. Genetic variants of the SIRT1 gene were identified using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism/Sanger Sequencing and serum SIRT1 levels using Enzyme-Linked Immuno Sorbent Assay. Serum SIRT1 levels were significantly higher in breast cancer patients [0.822 (0.72-0.96)] than controls [0.752 (0.66-0.86)], p = 0.0027. Subgroup analyses revealed notable increases in Human epidermal growth factor receptor 2-positive (p = 0.0016), hormone-positive (p = 0.0232), and Triple Negative Breast Cancer groups (p = 0.4426) compared to the control group. The SIRT1 levels were also significantly associated with breast cancer (p = 0.0252). SIRT1 exhibited an Area Under Curve (AUC) of 0.618, with 58% sensitivity and specificity at a cutoff of 0.797, showing poor discriminative ability. rs141528984 had a significant difference in allele frequency between patient group and control group (OR = 3.48, 95% CI: 1.896-6.516), p < 0.0001. There were no significant associations between SIRT1 gene polymorphisms and serum Sirtuin 1 levels in breast cancer patients. The proliferation marker Ki67 showed a significant association (p = 0.0428) with specific SIRT1 variants, rs777323664, rs757804740, and rs184282868. SIRT1 levels are elevated in breast cancer patients indicate its potential as a diagnostic marker. Mutant alleles of rs141528984 were more common in controls compared to case group, indicating its protective function. Ki67 expression was associated with rs777323, rs757804740, and rs1842828683 which may contribute to tumor aggressiveness.

Bruton's tyrosine kinase (BTK) plays a pivotal role in intracellular signaling within B-cells, governing development, differentiation, and survival, and is an integral target in treating B-cell malignancies and autoimmune disorders. The impact on B-cell receptor, Toll-like receptor, and chemokine receptor pathways establishes its therapeutic interest. This review integrates existing studies on BTK functional roles in immunology and BTK inhibitors (BTKis) targeting. Literature was ascertained by searching prominent databases such as PubMed, Embase, Web of Science and Google scholar for BTK's molecular biology, the history of BTKis and their clinical significance. The review addresses mechanisms of resistance, particularly the C481S mutation, which impedes covalent inhibition but is abrogated by non-covalent BTKis like pirtobrutinib, including BTK's application in autoimmune and inflammatory disorders, and discusses the importance of further long-term safety and efficacy in chronic diseases. BTK inhibitors have proven to be an essential part of targeted therapy for B-cell cancer, and continuing advances are addressing challenges like drug resistance and side effects. However, major challenges like the emergence of novel resistance mutations, the need for accurate biomarkers to direct therapy, and the continuing challenge of controlling drug-associated toxicities and maintaining costs under control still pertain. Ongoing research is essential to fully realize the therapeutic potential of BTK inhibitors and integrate them into personalized regimens for cancer and immune diseases alike.

ABSTRACTIn Alzheimer's disease (AD), the interaction between many AD‐relevant proteins, including amyloid precursor protein (APP) and tau, with the cysteine protease caspase‐3 (Cas3) enhances AD pathogenesis. Searching for effective Cas3 inhibitors, we turned to the sensor calbindin‐D28K (D28K) which specifically inhibits Cas3. The specific D28K conformation that elicits Cas3 inhibition remains elusive. To shed more light on this D28K conformation, we investigated likely environmental regulators. Recently, evidence of pH imbalance in aging brains has been implicated in AD pathologies. Using pull‐down assays, Cas3 inhibition assays, and molecular docking, we identified pH as a critical regulator for tuning the strength of D28K's inhibitory actions and subsequently identified Loop4 in Cas3 as the structural element targeted by D28K.