Pancreatic cancer is a hard-to-treat tumor with a poor prognosis. While traditional pancreatic cancer therapies can be effective, issues like cytotoxicity, low selectivity, and drug resistance still pose major challenges. Nanotechnology has shown promise in improving cancer diagnosis and treatment. Yttrium oxide nanoparticles (Y2O3-NPs), for example, have demonstrated potent selective cytotoxicity against triple negative breast cancer cells; but their effects on pancreatic cancer cells have not been explored. This study aimed to explore the impact of Y2O3-NPs on cell proliferation, DNA integrity, and oxidative stress in pancreatic cancer (PANC-1) and human skin fibroblast (HSF) cells. The cytotoxicity of Y2O3-NPs after 72 h were estimated using Sulforhodamine (SRB) cytotoxicity assay, while alkaline Comet assay was done to study genomic DNA integrity. Generation level of reactive oxygen species (ROS) and integrity of mitochondrial membrane potential were also analyzed. Apoptosis induction was investigated using Flow Cytometry and expression level of apoptotic (p53), anti-apoptotic (Bcl2) and mitochondrial (ND3) genes was measured using quantitative RTPCR. Our findings exhibited that Y2O3-NPs had strong selective cytotoxicity against PANC-1 cells with an IC50 value of 31.06 µg/ml, while having minimal effect on normal HSF cells (IC50 = 319.21 µg/ml). Treatment of PANC-1 cells with Y2O3-NPs at the IC50 concentration for 72 h significantly increased intracellular ROS levels and DNA damage, along with a notable reduction in mitochondrial membrane potential. Additionally, a significant rise in necrotic, early, and late apoptotic cells was observed, accompanied by downregulation of the anti-apoptotic Bcl2 gene and upregulation of the apoptotic p53 and mitochondrial ND3 genes. These findings highlight the selective toxicity of Y2O3-NPs towards cancerous PANC-1 cells, with minimal impact on normal cells. Y2O3-NPs appear to induce apoptosis in cancer cells by increasing ROS generation, damaging DNA, disrupting mitochondrial function, and triggering cell death. This study suggests that Y2O3-NPs may be a promising candidate for pancreatic cancer treatment. Further research is needed to fully explore their therapeutic potential.

Uterine leiomyosarcoma (Ut‑LMS) is a rare and aggressive malignant tumor with limited therapeutic options. Therefore, exploration of novel treatment strategies is necessary. MG132 is a potent proteasome inhibitor that has shown promising potential in cancer therapy by inducing apoptosis through disruption of protein homeostasis. Despite its promising applications in various cancers, its effects on Ut‑LMS remains largely unexplored. Therefore, the present study investigated the effects of MG132 on Ut‑LMS cell lines (SK‑LMS‑1, SK‑UT‑1 and SK‑UT‑1B) in terms of cytotoxicity, apoptosis induction, cell cycle progression, autophagy and reactive oxygen species (ROS) production. Treatment with MG132 (0‑2 µM for 24 h) induced a dose‑dependent reduction in cell viability across all three cell lines, and the lactate dehydrogenase release assays confirmed membrane damage. Moreover, apoptosis induction was assessed using annexin V and 7‑AAD staining, which revealed dose‑dependent apoptosis in all three cell lines. Western blot analysis revealed increased cleaved poly‑adenosine diphosphate ribose polymerase and caspase‑3 levels, thereby indicating activation of the apoptotic pathway in response to MG132 treatment. MG132 also induced G2/M phase arrest in SK‑LMS‑1 and SK‑UT‑1 cells and altered the expression of cell cycle regulatory proteins, such as p21, p27 and p53. Furthermore, MG132 promoted autophagy in all three cell lines by increasing light chain 3 II levels. ROS levels remained unchanged in SK‑LMS‑1 cells but increased in SK‑UT‑1B and SK‑UT‑1 cells. Furthermore, the ROS scavenger N‑acetylcysteine effectively reduced MG132‑induced apoptosis in SK‑UT‑1 cells. These findings highlight the cytotoxicity of MG132 in Ut‑LMS cells, emphasize its potential as a therapeutic agent for Ut‑LMS, provide insights into its mechanisms of action, and suggest possible strategies for improving treatment efficacy.

Alzheimer disease (AD) is a common neurologic disorder, impairing memory and spatial perception. Consistent with the extensive search for its treatment, we investigated the effect of Picein on inhibitory avoidance memory, lipid peroxidation, and the activity of hippocampal antioxidant enzymes in rats. Forty adult male Wistar rats were randomized into control group (no intervention), model group (intraperitoneal injection of 3-mg/kg scopolamine), and three interventional groups (1.5-, 2.5-, and 5-mg/kg intraventricular Picein, once a day for 7 days, 24 h after scopolamine injection). After behavioral test, the rats' hippocampus was isolated for measuring oxidative stress markers, including enzymes superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPX), catalase (CAT), and total antioxidant capacity (TAC). One-way ANOVA was used for comparing numeric variables among the groups using SPSS v.21. The results showed scopolamine decreased SOD, GPX, and CAT enzymes, and TAC level, and increased MDA level, compared with the control group (P < 0.001) that confirmed the scopolamine-induced AD model. The two doses of 2.5- and 5-mg/kg Picein increased latency for entering the dark room, compared to the scopolamine group (P < 0.05), making them similar to the control group. The number of entries into the dark room in the 2.5-mg/kg Picein reduced and approached the control group (P < 0.05). The 2.5-mg/kg Picein decreased MDA and increased SOD, GPX, and TAC, more than 5 mg/kg Picein, both different than scopolamine; only 2.5-mg/kg Picein had different CAT, compared to scopolamine group (P < 0.05). In conclusion, by lowering oxidative stress in the hippocampus, Picein was able to prevent the scopolamine-induced impaired learning and avoidance memory in rats.

Background: Mitochondria are essential for placental function as they regulate energy metabolism, oxidative balance, and apoptotic signaling. Increasing evidence suggests that placental mitochondrial dysfunction may play a role in the development of many poor perinatal outcomes, including preeclampsia, intrauterine growth restriction (IUGR), premature birth, and stillbirth. Nonetheless, no systematic review has thoroughly investigated this connection across human research. This study aims to consolidate evidence from human research concerning the link between placental mitochondrial dysfunction and negative birth outcomes. Methods: A systematic search of PubMed, Scopus, and Web of Science identified human research examining placental mitochondrial features (e.g., mtDNA copy number, ATP production, oxidative stress indicators) in connection with adverse pregnancy outcomes. Methodological variety resulted in narrative data extraction and synthesis. Results: Twenty-nine studies met the inclusion criteria. Mitochondrial dysfunction was consistently associated with PE, IUGR, FGR, and PTB. The most often observed outcomes included diminished mtDNA copy number, decreased ATP production, elevated reactive oxygen species (ROS), and disrupted mitochondrial dynamics, characterized by increased DRP1 and decreased MFN2. Early-onset preeclampsia and symmetric fetal growth restriction exhibited particularly severe mitochondrial abnormalities, indicating a primary placental origin of the condition. Conclusions: A significant factor contributing to adverse pregnancy outcomes is the dysfunction of placental mitochondria. The analogous molecular signatures across many disorders suggest promising avenues for developing targeted therapies aimed at improving maternal-fetal health and predictive biomarkers.

The objective of this study was to isolate and characterize a cytotoxic compound from the hydromethanolic extract of Dalbergia sissoo Roxb. ex DC. leaves using the cold percolation technique. Thin-layer chromatography was employed to isolate the cytotoxic component from the crude plant extract, and its cytotoxicity against lung adenocarcinoma (A549) cells was evaluated using the MTT assay. The structure of the isolated cytotoxic compound was determined through FTIR, NMR, UV analysis, and LC-MS/MS methods. Through comprehensive characterization, a cytotoxic compound called Biochanin A (BA) was identified, exhibiting significant anticancer activity with an IC50 value of 21.92 ± 2.19 μM against A549 cells, while demonstrating lower cytotoxicity towards normal lung cells (WI-38) with an IC50 value of 285.12 ± 2.19 μM. Notably, BA induced morphological changes in A549 cells, leading to apoptotic alterations and the generation of reactive oxygen species (ROS), as confirmed by multiple techniques (AO/EB, DAPI, Giemsa). In silico molecular docking, ADMET, MMGBSA, and molecular dynamics simulation investigations support the RT-PCR and cell biology findings. As a result, BA's molecular mechanism of action involves ROS-induced apoptosis mediated by caspases 9 and 3.

For more than a century, hypercholesterolemia has been linked to atherosclerotic cardiovascular disease. Notably, this metabolic condition has also been pointed out as a risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). Oxidative stress seems to be the connective factor between hypercholesterolemia and cardio and neurological disorders. By disturbing redox homeostasis, hypercholesterolemia impairs nitric oxide (NO) availability, an essential vasoprotective element, and jeopardizes endothelial function and selective permeability. The central nervous system (CNS) is partially protected from peripheral insults due to an arrangement between endothelial cells, astrocytes, microglia, and pericytes that form the blood-brain barrier (BBB). The endothelial dysfunction related to hypercholesterolemia increases the risk of developing cardiovascular diseases and also initiates BBB breakdown, which is a cause of brain damage characterized by neuroinflammation, oxidative stress, mitochondrial dysfunction, and, ultimately, neuronal and synaptic impairment. In this regard, we reviewed the mechanisms by which hypercholesterolemia-induced oxidative stress affects peripheral vessels, BBB, and leads to memory deficits. Finally, we suggest oxidative stress as the missing link between hypercholesterolemia and dementia.

The study synthesized Pluronic F-127 coated zinc oxide nanoparticles (PF-127ZnO NPs) using Gynura pseudochina leaf extract and evaluated their antibacterial, antioxidant, and anticancer properties using various characterization methods such as UV-Vis, Fourier Transform Infra-Red, Photoluminescence spectroscopy, FESEM, EDAX, TEM, SAED, XRD, and DLS. The disc diffusion technique was used to evaluate the antibacterial properties of synthesized Pluronic F-127 coated zinc oxide nanoparticles against various pathogens and significant anticancer activity was noticed. The study examined the cytotoxicity of PF127ZnO nanoparticles to Hep3B cells in vitro. The cytotoxicity was IC50 at 10 µM concentration. The study examined the biocompatibility of PF-127ZnO NPs, revealing membrane blebbing, chromatin condensation, and stimulation of the proapoptotic protein caspase cascade family. The study reveals that PF-127ZnO NPs, synthesized from G. pseudochina leaf extract, exhibit antibacterial and antihepatic properties, offering potential biomedical applications due to their high stability and biocompatibility.

Facioscapulohumeral Muscular Dystrophy (FSHD) is a genetically linked disorder characterized by the progressive deterioration of muscles controlling facial and scapular movement. The severity and distribution of affected muscle groups vary significantly across patient demographics, necessitating diverse assistive approaches.

This review aims to evaluate the effectiveness of assistive devices and therapeutic options, including medications and rehabilitative therapies, tailored to specific manifestations of FSHD.

An analysis of existing literature and clinical trials was conducted to explore current assistive technologies and pharmacological treatments, focusing on their application to FSHD patients with varying symptom severity.

Although several pharmacological treatments, such as steroids, supplements, protein inhibitors, and knockout strategies, are under investigation, none have yet fully counteracted the disease process driven by toxic DUX4 production. Consequently, the broad assortment of assistive devices currently on the market remain critical for improving quality of life.

Despite advances in pharmacological research, the variability in FSHD manifestations necessitates a personalized approach combining assistive technologies and tailored therapeutic interventions. Future research should continue exploring integrative strategies to address the unique needs of FSHD patients.

Constipation represents a common gastrointestinal disorder that has various adverse effects on the gastrointestinal tract. As a result, various civilizations have developed phytomedicines in order to treat and relieve its symptoms. In the current study, we evaluated the effect of Crataegus azarolus L. leaves decoction extract (CALDE) against loperamide (LOP)-induced constipation in rats. For 3 days, treated rats were administered LOP (3 mg/kg, b.w., p.o.) and CALDE (50, 100, and 200 mg/kg, b.w., p.o.) or yohimbine (2 mg/kg, b.w., p.o.). The gastric emptying test or intestinal transit time was calculated. The oxidative status was studied and evaluated using biochemical colorimetric methods. Results showed that CALDE administration improves gastric emptying and accelerates gastrointestinal transit. Pretreatment with LOP altered the defecation parameters and generated an oxidative status in healthy rats. In contrast, CALDE coadministration protected against the deregulation of intestinal motor function and frequency of defecation and significantly re-established oxidative marker levels. CALDE treatment demonstrated significant protection against experimental oxidative stress and constipation induced by LOP. Therefore, it can be considered a pharmacological drug to treat these gastrointestinal troubles.

Post-operative cognitive decline (POCD) is characterized by impairments in cognitive functions. Coronary artery bypass grafting (CABG) is associated with a high risk of POCD due to its impact on neuroinflammation and oxidative stress. In this study, we investigated the dynamics of neurotrophic, inflammatory, and oxidative stress markers in a cohort of post-CABG patients to identify potential biomarkers for POCD. Blood samples were collected at baseline (immediately post-surgery) and at 3-month follow-up. Expression levels of NRF2 and other regulators of oxidative stress (GST, GSS, HMOX1, CAT, HSP27, and LOX-1), inflammatory mediators (IL-6, IP-10, and NFκB), and neuroprotective factor (BDNF) were analyzed. Cognitive assessments were performed using RBANS, TMT, TIB and MMSE. POCD patients exhibited an initial upregulation of NRF2-related antioxidant genes, which failed to sustain at 3-months follow-up, leading to a decline in HMOX1, IP-10 and BDNF protein levels, along with increased LOX-1 protein level and NFκB expression, indicating persistent oxidative stress and inflammation. In contrast, non-POCD patients demonstrated a sustained increase in antioxidant and neuroprotective markers, suggesting a more effective compensatory response. ROC analysis identified HMOX1 and BDNF as significant predictors of POCD, with LOX-1 and IP-10 emerging as diagnostic markers at follow-up. In conclusion, our findings highlight the dynamic regulation of oxidative stress and inflammatory pathways in POCD, emphasizing the failure of sustained neuroprotection in affected patients. Further large-scale studies are necessary to validate these findings, and biomarker-based screening could facilitate early risk stratification and targeted interventions to improve cognitive outcomes after cardiac surgery.

Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that potentially render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, resulting in oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141).

Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.

This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.

TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.

TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.

Multiple sclerosis (MS) is a complex autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system (CNS). While the exact causes remain unclear, recent research highlights the significant role of epigenetic modifications and mitochondrial dysfunction in the disease's onset and progression. Epigenetic alterations, such as DNA methylation, histone modification, and microRNA regulation, influence gene expression without altering the DNA sequence, leading to immune dysregulation and inflammation. Similarly, mitochondrial dysfunction, marked by impaired oxidative phosphorylation, reduced adenosine triphosphate (ATP) production, and increased reactive oxygen species (ROS), contributes to neurodegeneration and impaired remyelination in MS. The growing interest in targeting these two interconnected mechanisms has opened new avenues for MS treatment. Herbal drugs, known for their multi-targeted effects, have shown potential in modulating epigenetic markers and enhancing mitochondrial function. Compounds such as resveratrol, curcumin, epigallocatechin-3-gallate (EGCG), quercetin, and omega-3 fatty acids demonstrate potential in regulating DNA methylation, histone deacetylation, and mitochondrial biogenesis. These natural agents offer dual-action therapies by reducing oxidative stress and inflammation while promoting neuronal survival and remyelination. This review explores the therapeutic potential of herbal drugs targeting epigenetic and mitochondrial pathways in MS, evaluating their mechanisms of action and highlighting their promise as novel therapeutic agents. While initial findings are encouraging, further research and clinical trials are required to validate the efficacy of these herbal treatments and fully understand their potential in slowing disease progression and improving patient outcomes in MS. Such exploration could pave the way for safer, multi-targeted therapies, offering new hope in the management of MS and other neurodegenerative diseases.

Disruptions in brain development can impact behavioral traits and increase the risk of neurodevelopmental conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder, often in sex-specific ways. Dysregulation of the kynurenine pathway (KP) of tryptophan metabolism has been implicated in cognitive and neurodevelopmental disorders. Increased brain kynurenic acid (KYNA), a neuroactive metabolite implicated in cognition and sleep homeostasis, and variations in the Kmo gene, which encodes kynurenine 3-monooxygenase (KMO), have been identified in these patients. We hypothesize that parental Kmo genetics influence KP biochemistry, sleep behavior and brain energy demands, contributing to impairments in cognition and sleep in offspring through the influence of parental genotype and genetic nurture mechanisms.

A mouse model of partial Kmo deficiency, Kmo heterozygous (HET-Kmo+/-), was used to examine brain KMO activity, KYNA levels, and sleep behavior in HET-Kmo+/- compared to wild-type control (WT-Control) mice. Brain mitochondrial respiration was assessed, and KP metabolites and corticosterone levels were measured in breast milk. Behavioral assessments were conducted on wild-type offspring from two parental groups: (i) WT-Control from WT-Control parents, (ii) wild-type Kmo (WT-Kmo+/+) from Kmo heterozygous parents (HET-Kmo+/-). All mice were C57Bl/6J background strain. Adult female and male offspring underwent behavioral testing for learning, memory, anxiety-like behavior and sleep-wake patterns.

HET-Kmo+/- mice exhibited reduced brain KMO activity, increased KYNA levels, and disrupted sleep architecture and electroencephalogram (EEG) power spectra. Mitochondrial respiration (Complex I and Complex II activity) and electron transport chain protein levels were impaired in the hippocampus of HET-Kmo+/- females. Breast milk from HET-Kmo+/- mothers increased kynurenine exposure during lactation but corticosterone levels were unchanged. Compared to WT-Control offspring, WT-Kmo+/+ females showed impaired spatial learning, heightened anxiety, reduced sleep and abnormal EEG spectral power. WT-Kmo+/+ males had deficits in reversal learning but no sleep disturbances or anxiety-like behaviors.

These findings suggest that Kmo deficiency impacts KP biochemistry, sleep behavior, and brain mitochondrial function. Even though WT-Kmo+/+ inherit identical genetic material as WT-Control, their development might be shaped by the parent's physiology, behavior, or metabolic state influenced by their Kmo genotype, leading to phenotypic sex-specific differences in offspring.

Thioredoxin-interacting protein (TXNIP) plays a pivotal role in glucose metabolism and redox signaling. Its emerging function as a potent suppressor of cell proliferation in various cancer contexts underscores its importance in cancer development. In a previous study, we found TXNIP activation by UNC0642, an inhibitor of histone methyltransferase G9A, significantly inhibited MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. Here, we demonstrated that TXNIP knockdown increased MDA-MB-231 tumor growth and metastasis in a mouse model. Reintroducing TXNIP into TXNIP-deficient HCC-1954 breast cancer cells decreased cell proliferation and migration while boosting the generation of reactive oxygen species, alongside reductions in mitochondrial respiration, mitochondrial membrane potential, and glycolysis. To elucidate the mechanisms underlying TXNIP's antitumor effects in breast cancer cells, we conducted co-immunoprecipitation and proteomic analyses that revealed calpastatin (CAST) as a novel TXNIP-interacting protein in MDA-MB-231 and HCC-1954 cells. Overexpression of CAST, an endogenous inhibitor of calpains, significantly increased xenograft tumor growth for both MDA-MB-231 and HCC-1954 cells, underscoring its novel role as a tumor promoter. In addition, we identified a positive correlation between the expression of TXNIP and interleukin-24 (IL-24), a molecule that induces cancer-specific apoptosis in several breast cancer cell lines. Our findings also show TXNIP's ability to decrease activation of STAT3, a key driver of oncogenesis. Finally, cells with high levels of TXNIP expression displayed increased susceptibility to IL-24 and WP1066, a specific STAT3 inhibitor, suggesting possible predictive value for TXNIP. Collectively, these findings unveil novel TXNIP-dependent pathways that may contribute to breast cancer pathogenesis, enriching our understanding of this molecule's intricate role in cancer and potentially paving the way for clinical translation.

Arsenic-mediated neurodegenerative disorders affect millions of individuals globally, but the specific impact of environmental arsenic on adult cerebellar degeneration and neurogenesis is incompletely understood. Of particular concern is arsenic-induced apoptosis-driven neurodegeneration. Our major objective was to investigate the molecular signaling intricacies associated with arsenic-induced death of cerebellar neurons and to propose folic acid as a possible intervention. Swiss albino mice were treated with sodium arsenite (orally: 0.05 mg/L) and folic acid (orally:10 mg/kg) for 28 days. We observed that arsenic caused noticeable cell loss with morphological alterations in cerebellum, which was remarkably restored by folic acid. Arsenic-induced morphological alterations consequently perturbed transcriptional activities of neural stem cell factors-SOX2 and KLF9, which resulted in the suppression of pro-neurogenic mediators NeuroD1, Neurogenin2, calbindin and NeuN. Interestingly, folic acid reversed the expression of these critical pro-neurogenic mediators to mitigate these degenerative changes to promote neurogenesis. Delving deep, we found that folic acid rescued arsenic-exposed cerebellum from severe oxidative and pro-inflammatory insults by increasing antioxidants like SOD, Catalase, GSH, upregulating Nrf2 and downregulating M1 macrophages, JNK, NF-κB, and STAT3 activities. For the first time, we are reporting that arsenic induced a G1/S cell cycle arrest and triggered apoptosis in mouse cerebellum by activating the p53-p21 axis, downregulating CDKs and instigated p21-mediated suppression of SOX2 transcriptional activity. Folic acid abated such alterations by modulating the p53/p21/SOX2 axis. Collectively, the anti-apoptotic and pro-neurogenic effects of folic acid present it as a promising therapeutic candidate, warranting further research into its efficacy against metal-induced neurodegenerative disorders.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.

Oxidation and reduction are vital for keeping life through several prime mechanisms, including respiration, metabolism, and other energy supplies. Mitochondria are considered the cell's powerhouse and use nutrients to produce redox potential and generate ATP and H2O through the process of oxidative phosphorylation by operating electron transfer and proton pumping. Simultaneously, mitochondria also produce oxygen free radicals, called superoxide (O2 -), non-enzymatically, which interacts with other moieties and generate reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hydroxyl radical (OH-). These reactive oxygen species modify nucleic acids, proteins, and carbohydrates and ultimately cause damage to organs. The nutrient-sensing kinases, such as AMPK and mTOR, function as a key regulator of cellular ROS levels, as loss of AMPK or aberrant activation of mTOR signaling causes ROS production and compromises the cell's oxidant status, resulting in various cellular injuries. The increased ROS not only directly damages DNA, proteins, and lipids but also alters cellular signaling pathways, such as the activation of MAPK or PI3K, the accumulation of HIF-1α in the nucleus, and NFkB-mediated transcription of pro-inflammatory cytokines. These factors cause mesenchymal activation in renal endothelial cells. Here, we discuss the biology of redox signaling that underlies the pathophysiology of diabetic renal endothelial cells.

Oxidative stress (OS) is an established hallmark of cancer and neurodegenerative disorders (NDDs), which contributes to genomic instability and neuronal loss. This review explores the contrasting role of OS in cancer stem cells (CSCs) and NDDs. Elevated levels of reactive oxygen species (ROS) contribute to genomic instability and promote tumor initiation and progression in CSCs, while in NDDs such as Alzheimer's and Parkinson's disease, OS accelerates neuronal death and impairs cellular repair mechanisms. Both scenarios involve disruption of the delicate balance between pro-oxidant and antioxidant systems, which leads to chronic oxidative stress. Notably, CSCs and neurons display alterations in redox-sensitive signaling pathways, including Nrf2 and NF-κB, which influence cell survival, proliferation, and differentiation. Mitochondrial dynamics further illustrate these differences: enhanced function in CSCs supports adaptability and survival, whereas impairments in neurons heighten vulnerability. Understanding these common mechanisms of OS-induced redox imbalance may provide insights for developing interventions, addressing aging hallmarks, and potentially mitigating or preventing both cancer and NDDs.

Background/Objectives: Amyloid-β (Aβ) plaque accumulation, oxidative stress, and cholinergic dysfunction are hallmarks of Alzheimer's disease (AD), a neurodegenerative disability that progresses over time, ultimately resulting in the loss of neurons. The side effects and limitations of current synthetic drugs have shifted attention toward natural alternatives. This study investigates the ethanolic extract of Aegle marmelos (L.) Corrêa fruits for their antioxidant, AChE-inhibitory, and anti-amyloidogenic properties, as well as their neuroprotective effects against amyloid beta-peptide (Aβ1-42). Methods: Phytochemical constituents were identified through HR-LCMS analysis and their antioxidant (DPPH, FRAP) and neuroprotective activities (AChE inhibition, ThT binding, MTT assay, ROS reduction, MMP restoration, and AD-related gene expression via qRT-PCR) were assessed using SHSY-5Y neuroblastoma cells. Results: The extract revealed the existence of flavonoids, phenols, and other bioactive substances. In vitro assays demonstrated strong antioxidant and AChE-inhibitory activities, while the ThT binding assay showed protection against amyloid-β aggregation. The extract exhibited no cytotoxicity in SHSY-5Y cells, even at a concentration of 500 μg/mL, whereas Aβ1-42 at 20 μM induced significant cytotoxicity. Co-treatment with Aβ1-42 (10 μM and 20 μM) and the extract improved cell viability (˃50%) and reduced ROS levels. Additionally, the extract restored mitochondrial membrane potential in Aβ1-42 treated cells, highlighting its role in preserving mitochondrial function. Conclusions: These findings suggest that A. marmelos fruits serve as a powerful source of natural antioxidants, AChE inhibitors, and anti-amyloidogenic agents, positioning them as a compelling option for AD treatment.

Parkinson's disease (PD) is a multi-system disorder characterized histopathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta. While the etiology of PD remains multifactorial and complex, growing evidence suggests that cellular metabolic dysfunction is a critical driver of neuronal death. Defects in cellular metabolism related to energy production, oxidative stress, metabolic organelle health, and protein homeostasis have been reported in both neurons and immune cells in PD. We propose that these factors act synergistically in immune cells to drive aberrant inflammation in both the CNS and the periphery in PD, contributing to a hostile inflammatory environment which renders certain subsets of neurons vulnerable to degeneration. This review highlights the overlap between established neuronal metabolic deficits in PD with emerging findings in central and peripheral immune cells. By discussing the rapidly expanding literature on immunometabolic dysfunction in PD, we aim to draw attention to potential biomarkers and facilitate future development of immunomodulatory strategies to prevent or delay the progression of PD.

Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's are on the rise and pose significant challenges due to the lack of effective treatments. This review critically examines the neuroprotective effects of various natural products derived from plants, marine organisms, and fungi. Natural products have long been used in traditional medicine and are gaining attention in modern drug discovery for their unique properties. The review explains how these natural products can protect neurons by influencing the key biological pathways involved in neurodegeneration. It discusses mechanisms including antioxidant effects, anti-inflammatory actions, modulation of cellular signalling, and support for mitochondrial function. A systematic literature search was conducted to minimize bias and ensure rigorous study selection. Preclinical studies using animal models and cell cultures show that secondary metabolites like polyphenols, alkaloids, and terpenoids can significantly reduce neuronal damage. Some clinical trials have shown promising results. However, challenges such as bioavailability, standardization, and dosage must be addressed to translate these findings into clinical practice. The review also evaluates the potential synergy of combining natural products with conventional treatments, offering a complementary therapeutic approach. Natural products represent a promising avenue for developing innovative treatments for neurodegenerative diseases. The review highlights key research gaps and proposes future directions. Future studies should focus on overcoming existing challenges and refining these natural products to improve their efficacy and safety in clinical settings. The application of existing knowledge has the potential to significantly enhance the quality of life for individuals affected by neurodegenerative diseases.

Neurodegenerative diseases are often linked to oxidative stress (OS), which worsen neuroinflammation and cause neuronal damage. Managing OS with gasotransmitters such as hydrogen sulphide (H2S) is a promising therapeutic approach to protecting brain cells from oxidative damage. AP39, a mitochondria-targeted H2S donor, has shown neuroprotective potential by reducing OS and improving mitochondrial function. However, its clinical application is limited due to poor stability and rapid release, necessitating a drug delivery system to enhance therapeutic efficacy.

This study aimed to develop a novel AP39-loaded liposomal formulation to provide controlled H2S release, facilitate AP39 permeation across the blood-brain barrier (BBB), and assess functional effects in mitigating oxidative stress and preserving mitochondrial function.

AP39-loaded unilamellar liposomes were prepared via ethanol injection and characterised for size, polydispersity, and zeta potential. Entrapment efficiency was determined using HPLC, while cytotoxicity was assessed in human vein endothelial (HUVEC) and neuroblastoma (SHSY5Y) cells. Liposomal permeability, AP39 release kinetics, and cellular uptake were evaluated using a microvasculature BBB model. Mitochondrial function under oxidative stress was assessed using a Seahorse XFe24 Analyzer.

AP39-loaded liposomes had an average size of 135.92 ± 10.05 nm, a zeta potential of 17.35 ± 3.40 mV, and an entrapment efficiency of 84.48% ± 4.7. Cytotoxicity studies showed no adverse effects after 4 h. Cellular uptake of encapsulated AP39 was significantly higher (7.13 ± 0.28 µg) than the free form (5.8 ± 0.31 µg). The BBB model demonstrated sustained AP39 release (7.28 µg/mL vs 6.44 µg/mL for free AP39). Mitochondrial assays confirmed liposomal AP39 preserved H2S antioxidant properties and enhanced oxygen consumption.

Our novel liposomal formulation encapsulating AP39 improves stability, promotes sustained release, and enhances BBB permeability while preserving antioxidant effects. These findings indicate that liposomal AP39 is a suitable therapeutic approach to further investigate in the treatment of neurodegenerative diseases.

Migraine, as a widespread neurological condition, substantially impacts quality of life, particularly among women. Therefore, this study aimed to explore the potential effects of alpha-linolenic acid (ALA) and L-carnitine co-supplementation on migraine symptoms, mental health, and life quality in women with migraine.

In this randomized, triple-blind, placebo-controlled trial, 80 women with migraine were randomly assigned to receive either ALA (1000 mg) plus L-carnitine (500 mg) or matching placebos daily for 12 weeks. Migraine characteristics, mental health parameters, and quality of life measures were assessed at baseline and study end.

The intervention group demonstrated a significant reduction in migraine frequency (-2.96; 95% CI (-3.48, -2.45) vs -0.07; 95% CI (-0.68, 0.53), P < 0.001), severity (-1.6; 95% CI (-2.05, -1.15) vs - 0.44; 95% CI (-0.91, 0.02), P = 0.001), and duration (-4.9; 95% CI (-6.34, -3.45) vs -0.5; 95% CI (-1.06, 0.66) hours, P < 0.001) compared to the placebo group. Mental health improvements were observed in depression (-7.4; 95% CI (-9.24, -5.55) vs 0.05; 95% CI (-1.16, 1.26), P < 0.001), and anxiety scores (-5.7; 95% CI (-7.26, -4.14) vs - 0.65; 95% CI (-2.33, 1.03), P < 0.001). Quality of life measures showed significant enhancement, with increased migraine-specific quality of life (9.75; 95% CI (8.01, 11.49) vs 1.22; 95% CI (-0.66, 3.11), P < 0.001) and decreased headache impact test-6 scores (-8.57; 95% CI (-11.79, -5.36) vs -1.35; 95% CI (-3.41, 0.71), P = 0.005) in the intervention group compared to the controls.

Co-supplementation with ALA and L-carnitine may offer a promising adjuvant therapy for managing migraine in women, addressing both physical symptoms and psychological burdens.

IRCT20121216011763N57.

Mechanistic studies have been suggested that adverse effect of bleomycin is attributed to formation of free radicals, mitochondria damages, oxidative stress and inflammation in lung tissue. Mitochondria act as central regulators in the oxidative stress and inflammatory responses in lung tissue, then it can be a promising approach for management bleomycin-induced pneumotoxicity. In the current study, we aim to investigated the injection of exogenous mitochondria into blood as one of the most promising pharmacological approaches to reduce bleomycin-induced lung toxicity in rats. Rats were divided into 4 groups as control, bleomycin (5 mg/kg), bleomycin + mitochondria (250 µg/kg), and mitochondria (250 µg/kg) alone. After 2 weeks, the survival rate, weight changes of animals, wet/dry ratio of lung tissue, alterations of histopathology, hydroxyproline content, oxidative stress and mitochondrial biomarkers were determined. Except the survival rate, weight changes of animals and wet/dry ratio of lung tissue, administration of bleomycin resulted in significant alteration in GSH content, MDA level, hydroxyproline amount, collapse of mitochondrial membrane potential (MMP), reduction of succinate dehydrogenases (SDH) activity and histopathological abnormality in comparison with control group. While exogenous mitochondria could inhibit GSH depletion, reduce production of MDA, improve the activity of SDH, prevent loss of MMP and histopathological abnormality. To the best of our knowledge, our data provides the first direct experimental evidence that injection of exogenous mitochondria into blood is capable of ameliorating bleomycin-induced lung toxicity in rats. These findings support that mitochondrial transplantation can be a promising therapeutic strategy for bleomycin-associated mitochondrial dysfunction and lung damage.

Many factors negatively affect a generalization of the findings in discovery proteomics. They include differentiation between patient cohorts, a variety of experimental conditions, etc. We presented a machine-learning-based workflow for proteomics data analysis, aiming at improving generalizability across multiple data sets. In particular, we customized the decision tree model by introducing a new parameter, min_groups_leaf, which regulates the presence of the samples from each data set inside the model's leaves. Further, we analyzed a trend for the feature importance's curve as a function of the novel parameter for feature selection to a list of proteins with significantly improved generalization. The developed workflow was tested using five proteomic data sets obtained for post-mortem human brain samples of Alzheimer's disease. The data sets consisted of 535 LC-MS/MS acquisition files. The results were obtained for two different pipelines of data processing: (1) MS1-only processing based on DirectMS1 search engine and (2) a standard MS/MS-based one. Using the developed workflow, we found seven proteins with expression patterns that were unique for asymptomatic Alzheimer patients. Two of them, Serotransferrin TRFE and DNA repair nuclease APEX1, may be potentially important for explaining the lack of dementia in patients with the presence of neuritic plaques and neurofibrillary tangles.

As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence. These factors can lead to higher morbidity, extended hospital stays, reduced quality of life, and even mortality. The decrease in homeostatic capacity varies among individuals, contributing to the greater variability observed in geriatric populations. Significant pharmacokinetic and pharmacodynamic alterations accompany ageing. Pharmacokinetic changes include decreased renal and hepatic clearance and an increased volume of distribution for lipid-soluble drugs, which prolong their elimination half-life. Pharmacodynamic changes typically involve increased sensitivity to various drug classes, such as anticoagulants, antidiabetic and psychotropic medications. This review examines the primary age-related physiological changes in geriatrics and their impact on the pharmacokinetics and pharmacodynamics of medications.

Studies in the existing literature propose that allocryptopine possesses both antioxidant and anti-inflammatory properties, showcasing its neuroprotective effects by potentially mitigating oxidative stress and inflammation. This study aims to investigate the antioxidant and anti-inflammatory effects of allocryptopine on various targets and potential mechanisms that have not been previously explored in the literature. Initially, we used MTT and LDH methods to evaluate the effects of allocryptopine on cell viability in BV-2 cells exposed to LPS-induced damage. Subsequently, we evaluated the impact of allocryptopine on pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), other inflammatory mediators (Cox-2 and iNOS), and p38 MAPK genes and proteins through qRT-PCR and Western blot analyses. Also, we evaluated the impact of allocryptopine on NF-κB proteins (TLR4, MyD88, IκBα, p-p50, and p-p65) through ELISA assay. Molecular docking analyses were performed to investigate the potential binding of allocryptopine to target proteins (TLR4, MyD88, IκBα, p50, p65, MKK3, MKK4, MKK6, p38, AP-1 (c-Jun and ATF2), IL-1β, IL-6, TNF-α, Cox-2, and iNOS) associated with the TLR4, NF-κB, and p38 MAPK pathways. Our results indicate that allocryptopine exerts a comprehensive influence on pro-inflammatory cytokines and other inflammatory mediators by inhibiting TLR4 signaling and modulating the NF-κB and p38 MAPK pathways. The outcomes of our study suggest that the antioxidant and anti-inflammatory efficacy of allocryptopine is intricately linked to the modulation of key molecular pathways associated with oxidative stress and inflammation. These findings highlight the potential of allocryptopine as a therapeutic agent for addressing neurodegenerative diseases by safeguarding neuronal health.

Silymarin is an extract obtained from the seeds of milk thistle (Sylibum marianum L., Asteraceae) and contains several structurally related flavonolignans and a small family of flavonoids. Mouse spleen cells represent highly sensitive primary cells suitable for studying the pharmacological potential and biofunctional properties of natural substances. Cultivation of splenocytes for 24 h under standard culture conditions (humidity, 37 °C, 5% CO2, atmospheric oxygen) resulted in decreased viability of splenocytes compared to intact cells. A cytoprotective effect of silybin (SB), silychristin (SCH) and 2,3-dehydrosilybin (DHSB) was observed at concentrations as low as 5 µmol/ml. At 50 µmol/ml, these substances restored and/or stimulated viability and mitochondrial membrane potential and had anti-apoptotic effect in the order SB > DHSB > SCH. The substances demonstrated a concentration-dependent activity in restoring the redox balance based on the changes in the concentration of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and nitric oxide. This was in the order DHSB > SCH > SB, which correlated with the suppressed expression of nuclear factor erythroid 2-related factor 2 (Nrf2), catalase and glutathione peroxidase. The strong stimulation of the superoxide dismutase 1 gene converting ROS to H2O2 points to its dominant role in the maintaining redox homeostasis in splenocytes, which was disrupted by oxidative stress due to non-physiological culture conditions. Our study showed significant differences in the cytoprotective, antioxidant and anti-apoptotic activities of SB, SCH, and DHSB on splenocytes exposed to mild and AAPH-induced oxidative stress.

Various assaults on mitochondria occur during the human aging process, contributing to mitochondrial dysfunction. This mitochondrial dysfunction is intricately connected with aging and diseases associated with it. In vivo, the accumulation of defective mitochondria can precipitate inflammatory and oxidative stress, thereby accelerating aging. Mitophagy, an essential selective autophagy process, plays a crucial role in managing mitochondrial quality control and homeostasis. It is a highly specialized mechanism that systematically removes damaged or impaired mitochondria from cells, ensuring their optimal functioning and survival. By engaging in mitophagy, cells are able to maintain a balanced and stable environment, free from the potentially harmful effects of dysfunctional mitochondria. An ever-growing body of research highlights the significance of mitophagy in both aging and age-related diseases. Nonetheless, the association between mitophagy and inflammation or oxidative stress induced by mitochondrial dysfunction remains ambiguous. We review the fundamental mechanisms of mitophagy in this paper, delve into its relationship with age-related stress, and propose suggestions for future research directions.

The modulation of the brain's electrical activity for therapeutic purposes has recently gained attention, supported by the promising results obtained through the non-invasive application of transcranial direct current stimulation (tDCS) in the treatment of neurodegenerative and neurological diseases. To optimize therapeutic efficacy, it is crucial to investigate the cellular and molecular effects of tDCS. This will help to identify important biomarkers, predict patient's response and develop personalized treatments. In this study, we applied direct current stimulation (DCS) to a neural cell line, using mild currents over short periods of time (0.5 mA, 20 min), with 24-h intervals. We observed that DCS induced changes in the cellular lipidome, with transient effects observed after a single stimulation (lasting 24 h) and more significant, long-lasting effects (up to 72 h) after repeated stimulation cycles. In neural cells, multiple DCS treatment modulated structural membrane lipids (PE, PS, PI), downregulated glycerol lipids with ether-linked fatty acids and pro-inflammatory lipids (ceramides and lyso-glycerophospholipids) (p ≤ 0.005). Multiple DCS sessions altered transcriptional activity by decreasing the expression of inflammatory cytokines (TNF-α, p ≤ 0.05; IL-1β, p ≤ 0.01), while increasing the expression of neuroprotective factors such as heme oxygenase-1 (p ≤ 0.0001) and brain-derived neurotrophic factor (p ≤ 0.05), as well as proteins involved in vesicular transport (SNARE, sorting nexins and seipin and α-synuclein; p ≤ 0.05). In addition, DCS enhanced the release of extracellular vesicles, with repeated stimulations significantly increasing the release of exosomes threefold. In conclusion, while a single electrical stimulation induces transient metabolic changes with limited phenotypic effects, repeated applications induce a broader and deeper modulation of lipid species. This may lead to a neuroprotective and neuroplasticity-focussed transcriptional profile, potentially supporting the therapeutic effects of tDCS at the cellular and molecular level in patients..

Normal brain functioning relies on high aerobic energy production provided by mitochondria. Failure to supply a sufficient amount of energy, seen in different brain disorders, including autism spectrum disorder (ASD), may have a significant negative impact on brain development and support of different brain functions. Mitochondrial dysfunction, manifested in the abnormal activities of the electron transport chain and impaired energy metabolism, greatly contributes to ASD. The aberrant functioning of this organelle is of such high importance that ASD has been proposed as a mitochondrial disease. It should be noted that aerobic energy production is not the only function of the mitochondria. In particular, these organelles are involved in the regulation of Ca2+ homeostasis, different mechanisms of programmed cell death, autophagy, and reactive oxygen and nitrogen species (ROS and RNS) production. Several syndromes originated from mitochondria-related mutations display ASD phenotype. Abnormalities in Ca2+ handling and ATP production in the brain mitochondria affect synaptic transmission, plasticity, and synaptic development, contributing to ASD. ROS and Ca2+ regulate the activity of the mitochondrial permeability transition pore (mPTP). The prolonged opening of this pore affects the redox state of the mitochondria, impairs oxidative phosphorylation, and activates apoptosis, ultimately leading to cell death. A dysregulation between the enhanced mitochondria-related processes of apoptosis and the inhibited autophagy leads to the accumulation of toxic products in the brains of individuals with ASD. Although many mitochondria-related mechanisms still have to be investigated, and whether they are the cause or consequence of this disorder is still unknown, the accumulating data show that the breakdown of any of the mitochondrial functions may contribute to abnormal brain development leading to ASD. In this review, we discuss the multifaceted role of mitochondria in ASD from the various aspects of neuroscience.

Parkinson's disease (PD) is a progressive age-related neurodegenerative disease whose annual incidence is increasing as populations continue to age. Although its pathogenesis has not been fully elucidated, oxidative stress has been shown to play an important role in promoting the occurrence and development of the disease. Long noncoding RNAs (lncRNAs), which are more than 200 nucleotides in length, are also involved in the pathogenesis of PD at the transcriptional level via epigenetic regulation, or at the post-transcriptional level by participating in physiological processes, including aggregation of the α-synuclein, mitochondrial dysfunction, oxidative stress, calcium stabilization, and neuroinflammation. LncRNAs and oxidative stress are correlated during neurodegenerative processes: oxidative stress affects the expression of multiple lncRNAs, while lncRNAs regulate many genes involved in oxidative stress responses. Oxidative stress and lncRNAs also affect other processes associated with neurodegeneration, including mitochondrial dysfunction and increased neuroinflammation that lead to neuronal death. Therefore, modulating the levels of specific lncRNAs may alleviate pathological oxidative damage and have neuroprotective effects. This review discusses the general mechanisms of oxidative stress, pathological mechanism underlying the role of oxidative stress in the pathogenesis of PD, and teases out the mechanisms through which lncRNAs regulate oxidative stress during PD pathogenesis, as well as identifies the possible neuroprotective mechanisms of lncRNAs. Reviewing published studies will help us further understand the mechanisms underlying the role of lncRNAs in the oxidative stress process in PD and to identify potential therapeutic strategies for PD.

Free radicals, characterized by the presence of unpaired electrons, are highly reactive species that play a significant role in human health. These molecules can be generated through various endogenous processes, such as mitochondrial respiration and immune cell activation, as well as exogenous sources, including radiation, pollution, and smoking. While free radicals are essential for certain physiological processes, such as cell signaling and immune defense, their overproduction can disrupt the delicate balance between oxidants and antioxidants, leading to oxidative stress. Oxidative stress results in the damage of critical biomolecules like DNA, proteins, and lipids, contributing to the pathogenesis of various diseases. Chronic conditions such as cancer, cardiovascular diseases, neurodegenerative disorders, and inflammatory diseases have been strongly associated with the harmful effects of free radicals. This review provides a comprehensive overview of the characteristics and types of free radicals, their mechanisms of formation, and biological impacts. Additionally, we explore natural compounds and extracts studied for their antioxidant properties, offering potential therapeutic avenues for managing free radical-induced damage. Future research directions are also discussed to advance our understanding and treatment of free radical-associated diseases.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility among women of reproductive age, yet the range of effective treatment options remains limited. Our previous study revealed that reduced levels of nicotinamide adenine dinucleotide (NAD+) in ovarian granulosa cells (GCs) of women with PCOS resulted in the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction. However, it is still uncertain whether increasing NAD+ levels in the ovaries could improve ovarian function in PCOS. In this study, we demonstrated that supplementation with the NAD+ precursor nicotinamide riboside (NR) prevented the decrease in ovarian NAD+ levels, normalized estrous cycle irregularities, and enhanced ovulation potential in dehydroepiandrosterone (DHEA)-induced PCOS mice. Moreover, NR supplementation alleviated ovarian fibrosis and enhanced mitochondrial function in ovarian stromal cells of PCOS mice. Furthermore, NR supplementation improved oocyte quality in PCOS mice, as evidenced by reduced abnormal mitochondrial clustering, enhanced mitochondrial membrane potential, decreased ROS levels, reduced spindle abnormality rates, and increased early embryonic development potential in fertilized oocytes. These findings suggest that supplementing with NAD+ precursors could be a promising therapeutic strategy for addressing ovarian infertility associated with PCOS.

Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.

Yttrium oxide nanoparticles (Y2O3NPs) have emerged as a promising avenue for cancer therapy, primarily due to their distinctive properties that facilitate selective targeting of cancer cells. Despite their potential, the therapeutic effects of Y2O3NPs on human epidermoid skin cancer remain largely unexplored. This study was thus conducted to investigate the impact of Y2O3NPs on both human skin normal and cancer cells, with an emphasis on assessing their cytotoxicity, genotoxicity, and the mechanisms underlying these effects. Cell viability and apoptosis induction were assessed using the Sulforhodamine B and chromatin diffusion assay, respectively. Reactive oxygen species (ROS) level, mitochondrial membrane potential integrity, oxidative stress markers and expression level of apoptotic and mitochondrial genes were also estimated. Our findings highlight the selective and significant cytotoxicity of Y2O3NPs against human epidermoid A-431 cancer cells. Notably, exposure to five Y2O3NPs concentrations (0.1, 1, 10, 100 and 1000 µg/ml) resulted in a high concentration-dependent reduction in cell viability and a corresponding increase in cell death observed 72 h post-treatment specifically in A-431 cancer cells, while normal skin fibroblast (HSF) cells exhibited minimal toxicity. When A-431 cancer cells were treated with the half-maximal inhibitory concentration (IC50) of Y2O3NPs for 72 h, a significant increase in ROS generation was noted. This led to oxidative stress, along with severe damage to genomic DNA and mitochondrial membrane potential, triggering substantial apoptosis. Furthermore, a concurrent significant upregulation of apoptotic p53 and mitochondrial ND3 genes was observed, coupled with a notable decrease in the anti-apoptotic Bcl2 gene expression.Overall, Y2O3NPs demonstrate considerable promise as a therapeutic agent for skin epidermoid cancer due to their ability to selectively target and induce cytotoxic effects in A-431 cancer cells, all while causing minimal harm to normal HSF cells. This selective cytotoxicity appears to be associated with Y2O3NPs' ability to induce excessive ROS production and subsequent oxidative stress, leading to significant genomic DNA fragmentation, loss of mitochondrial permeability, and alterations in apoptotic and mitochondrial genes' expression, ultimately promoting apoptosis in A-431 cancer cells. These findings establish a foundation for further research into the utilization of Y2O3NPs in targeted cancer therapies and underscore the necessity for ongoing investigation into their safety and efficacy in clinical applications.