This review synthesizes evidence from recent clinical and mechanistic studies published between 2015 and 2024 to provide updated insights into the prevention and management of adverse drug reactions (ADRs) associated with first-line anti-tuberculosis drugs (ATDs)-namely isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB)-which are essential for tuberculosis (TB) treatment but frequently cause significant ADRs that threaten therapeutic success. We examine four major toxicities: hepatotoxicity (primarily from INH and RIF, mediated by oxidative stress, mitochondrial dysfunction, and cytochrome P450 induction); peripheral neuropathy (driven by INH-induced pyridoxine depletion and EMB-related copper chelation leading to optic and axonal damage); central nervous system (CNS) toxicity (notably INH-induced seizures due to GABAergic disruption); and myelosuppression (mainly RIF- or PZA-related, involving oxidative injury to hematopoietic stem cells and impaired DNA synthesis). Key risk factors include advanced age, malnutrition, pre-existing organ dysfunction, and pharmacogenetic variations (eg, NAT2 acetylator status). Management strategies emphasize protocol-driven monitoring-including baseline and serial liver function tests (LFTs), complete blood counts (CBC), neurologic exams, and monthly visual assessments for EMB-and graded interventions based on severity thresholds (eg, temporary discontinuation if ALT >3× upper limit of normal (ULN) with symptoms or >5× ULN asymptomatic), alongside targeted therapies such as pyridoxine for neuropathy and N-acetylcysteine for hepatotoxicity. Proactive measures, including pretreatment risk stratification, patient education, and multidisciplinary coordination, are critical to optimizing adherence and outcomes. Effective management of first-line anti-TB drug toxicity requires mechanism-informed monitoring, individualized interventions, and proactive patient education to maintain treatment adherence and improve global TB outcomes.

To systematically evaluate the efficacy and safety of mesenchymal stem cell (MSC) therapy for patients with Multiple System Atrophy (MSA) by synthesising available clinical trial evidence and clarifying signals of disease modification.

The use of animal-derived reagents in biomedical research poses challenges for reproducibility due to batch-to-batch variability and inter-species differences, along with ethical concerns related to their origin. In pursuing a human-relevant in vitro model, an animal-free and defined cell culture process is preferred to improve relevance and reproducibility. We investigated the use of serum replacement (SR) consisting of human hepatocyte-derived proteins in cell culture and recombinant antibodies with a plant-derived blocking solution (animal-free blocker, AFB) in immunocytochemical staining of cells. Human serum (HS) instead of animal-derived serum was used in this study for comparison with SR. We showed that bone marrow stem/stromal cells (BMSCs) maintain their proliferation capacity and cell-specific morphology in SR-supplemented medium, whereas human umbilical vein endothelial cells (HUVECs) show compromised growth under similar conditions. In a more complex co-culture, BMSCs + HUVECs formed a stable vascular network in SR-supplemented medium. In immunocytochemical staining, we compared the performance of recombinant antibodies with animal-derived antibodies and an AFB solution with a bovine serum albumin (BSA)-based blocking solution. Adipose stem/stromal cells (ASCs) showed their typical spindle-shaped morphology when stained with recombinant antibodies against alpha-smooth muscle actin (αSMA) in both AFB and BSA-based blocking solutions. We detected partial non-specific binding of recombinant antibodies and animal-derived antibodies against β-tubulin III in ASC. In contrast, we did not observe non-specific binding on these neuronal antibodies in HUVECs in any tested condition. While protocol optimization depends on the cell type used, our findings indicate that animal-derived materials can reliably be replaced.

Ly-1 antibody reactive clone gene (Lyar) is involved in the regulation of embryonic stem cell (ESC) self-renewal. To explore the specific role of Lyar in cell cycle progression and embryonic differentiation, we generated Lyar knockout (KO) mouse ESC (mESC) lines using CRISPR/Cas9, and investigated the effects of Lyar deficiency on mESC proliferation, cell cycle, apoptosis and multi-lineage differentiation. We found that Lyar deficiency reduces proliferation, increases apoptosis, and elevates p53 and p21 protein expression. The impaired mESC proliferation is associated with the increased apoptosis and cell cycle progression defect, which is driven by p53-p21 pathway activation. In embryoid body (EB) formation assay, loss of Lyar led to significant downregulation of most germ layer-specific markers in KO mESC clones, including mesoderm (Gsc, T), endoderm (Gata4, Sox17) and ectoderm marker Pax6. These findings confirm that Lyar is required for cell cycle progression, proliferation, and lineage-specific marker expression during early differentiation, demonstrating that Lyar may serve as a critical regulatory factor in stem cell biology.

Protein S-palmitoylation is a highly conserved posttranslational lipid modification that occurs on cysteine residues and critically influences protein maturation, subcellular localization, trafficking, and stability. Owing to its unique reversibility and dynamic nature, S-palmitoylation plays a pivotal role in cancer. This review comprehensively summarized the expression profiles and distribution of key cancer-related S-palmitoylation enzymes in recent years. Importantly, we highlight the specific mechanisms by which the dual states of palmitoylation and depalmitoylation function as a dynamic regulatory axis during the transformation of cancer cells into cancer stem cells and during the transition from a normal tissue environment to a tumor microenvironment. Furthermore, we discussed emerging therapeutic strategies targeting S-palmitoylation, including the development of specific inhibitors and competitive blockade of substrate-binding sites, which offer additional insights into the translational potential of S-palmitoylation as a therapeutic target for cancer.

Neuroendocrine tumors (NETs) have traditionally been considered rare; however, an increasing incidence has been observed in recent years. Although often indolent, these tumors can exhibit malignant behavior. Our case of a left intrahepatic duct NET in a young woman highlights this rare presentation and underscores the need for heightened clinical awareness.

Bone loss is the most common skeletal complication of childhood acute lymphoblastic leukemia (ALL) and seriously affects the long-term survival quality of children. However, the mechanisms behind bone loss are complicated and need to be elucidated. This study seeks to examine the principal parameters influencing the osteogenic development of bone marrow mesenchymal stem cells (BMSCs) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) experiencing bone loss, and to identify viable ways for alleviating bone loss.

Glioblastoma multiforme (GBM) is an aggressive, therapy-resistant brain tumor with limited treatment options. Epidermal growth factor receptor (EGFR) drives GBM pathogenesis. Here, we investigate ZYH005 (Z5), a brain-penetrant DNA intercalator with low systemic toxicity, as a novel therapeutic agent. Z5 potently inhibits the proliferation of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) in vitro and suppresses tumor growth in orthotopic GSCs-derived mouse models, significantly prolonging survival without apparent toxicity. Mechanistically, Z5 exerts potent anti-GBM activity through a dual mechanism: DNA intercalation-induced damage and targeted inhibition of EGFR. By specifically inhibiting EGFR at E762, Z5 not only enhances DNA damage by suppressing the DNA damage response in the nucleus but also disrupts the interaction between nuclear EGFR and WEE1, leading to impaired WEE1/CDC2 signaling and G2/M checkpoint failure. Extranuclearly, Z5 further enhances its anti-GBM efficacy by inhibiting the canonical EGFR downstream pathways, mTOR, and ERK. These combined actions lead to cell cycle arrest and mitotic catastrophe. Our findings establish Z5 as a promising clinical candidate for classical GBM, employing a unique dual mechanism that overcomes EGFR-targeted and DNA-damaging therapy limitations by synergistically targeting DNA and EGFR with high efficacy, advancing understanding of EGFR-WEE1 biology, and supporting clinical development.

Mitochondria are nanoscale organelles essential for cellular metabolism and redox regulation, making them a compelling target for regenerative therapeutics. Analysis of wound-edge tissues from pediatric patients with chronic non-healing ulcers revealed marked metabolic insufficiency and impaired regenerative signaling, underscoring an unmet clinical need for mitochondrial-based interventions. Here, we show that topically applied mesenchymal stem cell-derived mitochondria (MSC-mt), functioning as naturally derived nanoscale organelles, markedly accelerate wound closure in a murine full-thickness skin injury model. MSC-mt enhanced angiogenesis, collagen deposition, and fibroblast survival while reducing oxidative stress and apoptosis. Mechanistically, their cytoprotective effects occur primarily through extracellular scavenging of reactive oxygen species (ROS), independent of cellular internalization. Excessive immobilization of MSC-mt within a thermosensitive hydrogel compromised their efficacy, emphasizing the importance of mitochondrial mobility and microenvironmental access. Under high oxidative stress, internalized MSC-mt activated PINK1-Parkin-mediated mitophagy, indicating a context-dependent intracellular quality-control response. These findings position MSC-mt as a cell-free, organelle-level nano-therapeutic that operates through a dual extracellular-intracellular mechanism and emphasize the importance of delivery strategies that preserve mitochondrial functionality and spatial freedom.

Male factors contribute to approximately half of all infertility cases globally, with heat stress recognized as a major environmental determinant of impaired male reproductive function. Extensive research indicates that heat stress disrupts spermatogenesis through multiple pathways, including testicular oxidative stress (OS), compromise of the blood-testis barrier, and dysregulation of the spermatogonial stem cell niche. As global temperatures rise, the prevalence of heat-induced reproductive impairment is increasing, underscoring the urgent need to identify safe and effective interventions that target the underlying oxidative damage. L-citrulline demonstrates significant potential in the field of male reproductive protection. However, existing reviews primarily focus on general discussions of antioxidants, lacking a systematic analysis of the specific mechanisms of L-citrulline. This review systematically synthesizes current knowledge on the molecular mechanisms of heat stress-induced oxidative injury in male gametes. Particular emphasis is placed on the multifaceted protective role of L-citrulline, which acts through synergistic mechanisms involving modulation of the arginine-nitric oxide (NO) pathway, preservation of mitochondrial homeostasis, restoration of autophagy flux, and suppression of apoptotic signaling. By integrating experimental and clinical evidence, this analysis aims to elucidate both the translational potential and the key scientific challenges of L-citrulline supplementation in male reproductive health. The review seeks to advance the translation of L-citrulline from basic research to clinical practice and to propose novel nutritional strategies for improving fertility outcomes in men exposed to heat stress.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Alcohol-related Liver Disease (MetALD) exhibit systemic immune abnormalities. Given that such immune dysregulation is closely linked to the skeletal complications frequently observed in MASLD and MetALD, we sought to comprehensively characterize the bone marrow hematopoietic compartment and its link to osteoclastogenesis.

Male infertility due to spermatogenic failure remains a global challenge. While in vitro spermatogenesis (IVS) offers potential for fertility preservation, recapitulating the complex, species-specific testicular niche remains a formidable task. This review evaluates IVS progress and bottlenecks across rodents, primates, domestic animals, and humans.

Boerhavia elegans has long-held medicinal importance, yet its comprehensive phytochemical and biological characterization remains limited. This study provides the first integrated analysis combining HPLC, GC-MS, and molecular docking to correlate the chemical composition of B. elegans with its antioxidant and cytotoxic activities across different plant parts and solvent systems. Antioxidant assays revealed that polar leaf extracts exhibited the highest activity, with a DPPH IC50 value of 16.73 μg/mL. The methanolic stem extract showed the greatest phenolic content (25.89 mg GAE/100 mg), and the methanolic seed extract had the highest flavonoid yield (6.717 mg QE/100 mg). Ethyl acetate favored flavonoid extraction from the stem (18.29 mg QE/100 mg), while diethyl ether was most effective for the roots (10.21 mg QE/100 mg). UHPLC-DAD identified 15 phenolic compounds with detection limits ranging from 0.47 to 2.20 μg/mL. Cytotoxicity assays demonstrated strong inhibitory effects, with the methanol leaf extract showing 82.5% inhibition of HepG2 cells and the ethyl acetate root extract inhibiting 83.55% of MCF-7 cells. The hexane leaf extract produced the highest inhibition (88.8%) of MDA-MB-231 cells. GC-MS analysis revealed bioactive molecules such as phytol, stigmasterol, and hexadecanoic acid, which were further validated by molecular docking interactions with vimentin and BCL-2 proteins, suggesting potential anticancer mechanisms.

The purpose of the study was to discuss the role of molecular imaging in stem cells (SCs) therapy and SC tracking with the special focus on nuclear medicine (NM) applications.

Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.

An experimental study on scaffold characterization and animal study.

The liver is essential for maintaining metabolic functions, detoxification, and homeostasis. It is crucial to recognize any malfunction in patients with liver disease/failure. To better understand disease pathology, a combination of clinical investigation and emerging technologies, such as organoid models, provides powerful tools for advancing disease studies. There are limitations in animal models, and conventional twodimensional (2D) cultures have hindered accurate modeling of liver physiology and pathology. Liver organoids, three-dimensional, self-organizing structures produced using pluripotent or adult stem cells, have increased prominence as advanced in vitro systems that recapitulate the architecture, cellular heterogeneity, and functionality of native liver tissue. This review explores the formation and cellular sources of liver organoids, such as multi-type cell and single-type cell systems, and highlights the role of engineered extracellular matrices and bioactive signaling pathways in their formation. We further address the integration of advanced technologies, for example, CRISPR/Cas9, viral transduction, three-dimensional (3D) bioprinting, and a liver-on-achip platform, which have revolutionized the customization and application of liver organoids. Their utility in drug screening, modeling liver diseases, such as genetic, infectious, and fibrotic conditions, and also applications in regenerative medicine are discussed. Liver organoids depict a transformative tool for understanding liver tissue pathophysiology, screening therapeutics, advancing personalized medicine, and tissue engineering.

Exposure to silver nanoparticles (AgNPs) poses potential health risks. Epigenetic alterations are increasingly recognized as a critical mechanistic bridge between environmental stressors and adverse toxicological outcomes. Here, we demonstrate that exposure to noncytotoxic concentrations of AgNPs induces significant genome-wide alterations in DNA hydroxymethylation in mouse embryonic stem cells, which primarily is mediated by TET dioxygenase-dependent pathways. Further investigation shows that AgNPs activate TETs through a reactive oxygen species (ROS)-dependent manner, independent of the Ag+ ion. Our findings provide evidence that AgNPs disrupt TET-mediated DNA demethylation and reveal a novel epigenetic mechanism by which nanoparticles perturb DNA methylation homeostasis during early embryonic development.

The study outlines principles and workflows for a comprehensive extractables and leachables qualification trial of microcarriers for use in a cell therapy application. Styrene-based MCs were qualitatively and quantitatively analyzed in accordance with USP 〈665〉, followed by a kinetic investigation. Extractables data were fitted to an algorithm to enable reconstructive modeling of dynamic experimental data for both stable and degradable extractables. In a subsequent step, the temporal exposure to process equipment-related leachables (PERLs) was modeled for MCs used in a hypothetical cell therapy application with partial and continuous medium exchange. The results demonstrated that, in a dynamic environment, the release of PERLs from MCs in a perfused system does not influence product quality at levels that would pose a patient safety risk. Furthermore, process concentrations remain significantly below exposure levels that could have detrimental effects on therapeutic human cells. This demonstrates the benefits of perfused systems, or systems with partial medium exchange, as the washout effect dominates PERL release rates. PERL concentrations in such dynamic systems will always be significantly lower than PERL equilibrium concentrations under static, stagnant conditions.

Remote ischemic postconditioning (RIPC) confers neuroprotection in ischemic stroke partly via promoting angiogenesis and neurogenesis, but its precise molecular mechanisms remain unclear; here, we investigated the role of the secreted guidance protein Netrin-4 (NTN4) and its upstream regulator hypoxia-inducible factor 1α (HIF-1α) in mediating RIPC's reparative effects, using endothelial-specific Ntn4 knockout (KO) mice subjected to transient middle cerebral artery occlusion (MCAO) and RIPC, alongside in vitro assays with brain microvascular endothelial cells (BMECs) and neural stem cells (NSCs) and molecular interaction analyses, including DNA pull-down and chromatin immunoprecipitation (ChIP), finding that RIPC significantly upregulated NTN4 expression in the ischemic penumbra of MCAO mice, that endothelial-specific Ntn4 knockout abolished RIPC's protective effects-impairing neurological recovery, angiogenesis and neurogenesis, which were rescued by recombinant NTN4 administration, that NTN4 promoted BMEC proliferation and tube formation via an integrin β1-PI3K/AKT pathway while conditioned medium from Ntn4-overexpressing BMECs enhanced NSC neuronal differentiation through an integrin β1-MAPK/ERK axis, and that RIPC stabilised HIF-1α, which directly bound the Ntn4 promoter to drive its transcription, collectively establishing that RIPC orchestrates brain repair by stabilising HIF-1α to transcriptionally activate endothelial NTN4, which signals through integrin β1 to drive parallel PI3K/AKT and MAPK/ERK pathways for angiogenesis and neurogenesis, highlighting this axis as a key therapeutic target in stroke.