Withaferin A (WA), a manifold studied, C28-steroidal lactone withanolide found in Withania somnifera. Given its unique beneficial effects, it has gathered attention in the era of modern science. Cancer, being considered a “hopeless case and the leading cause of death worldwide, and the available conventional therapies have many lacunae in the form of side effects. The poly pharmaceutical natural compound, WA treatment, displayed attenuation of various cancer hallmarks by altering oxidative stress, promoting apoptosis, and autophagy, inhibiting cell proliferation, reducing angiogenesis, and metastasis progression. The cellular proteins associated with antitumor pathways were also discussed. WA structural modifications attack multiple signal transduction pathways and enhance the therapeutic outcomes in various diseases. Moreover, it has shown validated pharmacological effects against multiple neurodegenerative diseases by inhibiting acetylcholesterinases and butyrylcholinesterases enzyme activity, antidiabetic activity by upregulating adiponectin and preventing the phosphorylation of peroxisome proliferator-activated receptors (PPARγ), cardioprotective activity by AMP-activated protein kinase (AMPK) activation and suppressing mitochondrial apoptosis. The current review is an extensive survey of various WA associated disease targets, its pharmacokinetics, synergistic combination, modifications, and biological activities.

Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels. Such phytonutrients may also be beneficial to prevent and treat BC. In this review, we will focus on the nutrigenomic effects of various phytochemicals including polyphenols, phytosterols, terpenoids, alkaloids, and other compounds from different sources. Overall, these phytonutrients are found to inhibit BC cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways. They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. Such phytochemicals may be used for the effective management of BC patients in the clinical setting in the future. The present article aims to summarize the specific molecular pathways involved in the genetic effects of phytochemicals in BC.

One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million by 2030. The disease results in neural atrophy and disrupted inter-neuronal connections. Amongst multiple AD pathogenesis hypotheses, the amyloid beta (Aβ) cascade is the most relevant and accepted form of the hypothesis, which suggests that Aβ monomers are formed as a result of the cleavage of amyloid precursor protein (APP), followed by the conversion of these monomers to toxic oligomers, which in turn develop β-sheets, fibrils and plaques. The review targets the events in the amyloid hypothesis and elaborates suitable therapeutic agents that function by hindering the steps of plaque formation and lowering Aβ levels in the brain. The authors discuss treatment possibilities, including the inhibition of β- and γ-secretase-mediated enzymatic cleavage of APP, the immune response generating active immunotherapy and passive immunotherapeutic approaches targeting monoclonal antibodies towards Aβ aggregates, the removal of amyloid aggregates by the activation of enzymatic pathways or the regulation of Aβ circulation, glucagon-like peptide-1 (GLP-1)-mediated curbed accumulation and the neurotoxic potential of Aβ aggregates, bapineuzumab-mediated vascular permeability alterations, statin-mediated Aβ peptide degradation, the potential role of ibuprofen and the significance of natural drugs and dyes in hindering the amyloid cascade events. Thus, the authors aim to highlight the treatment perspective, targeting the amyloid hypothesis, while simultaneously emphasizing the need to conduct further investigations, in order to provide an opportunity to neurologists to develop novel and reliable treatment therapies for the retardation of AD progression.

Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.

Background: Glycated hemoglobin (HbA1c) is widely used for the diagnosis and monitoring of diabetes mellitus. However, its potential role as a marker of metabolic stratification and early complication risk beyond diagnostic thresholds remains insufficiently explored. Prediabetes is often considered a transitional state, although growing evidence suggests the presence of early metabolic and microvascular alterations. Methods: In this cross-sectional observational study, adult subjects were stratified into three groups based on HbA1c levels: normoglycemic (HbA1c < 5.7%), prediabetic (HbA1c 5.7–6.4%), and diabetic (HbA1c ≥ 6.5%). Demographic data, metabolic parameters, cardiometabolic comorbidities, and diabetes-related complications were analyzed. Group differences were assessed using appropriate statistical tests. Cumulative complication burden was evaluated, and risk estimation was performed using univariate logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 839 subjects were included in the analysis. HbA1c and fasting glucose levels increased progressively across groups (p < 0.001). Prediabetic individuals already exhibited a higher prevalence of peripheral neuropathy and retinopathy compared to normoglycemic subjects, while diabetic patients showed the highest overall complication burden. The cumulative number of complications increased significantly across HbA1c-based groups (p = 0.033). Risk estimation analyses revealed increased odds for presenting at least one complication and for peripheral neuropathy in diabetic subjects, with intermediate risk levels observed in the prediabetic group. Conclusions: HbA1c-based stratification captures meaningful differences in metabolic status, complication burden, and estimated risk across normoglycemic, prediabetic, and diabetic individuals. Prediabetes is associated with detectable microvascular involvement and higher complication risk. Given the cross-sectional design, these findings reflect associations rather than causal relationships. These findings highlight the potential clinical value of HbA1c for early risk assessment and targeted preventive strategies.

Background: Glycated hemoglobin (HbA1c) is widely used for the diagnosis and monitoring of diabetes mellitus; however, its interpretation is largely based on fixed diagnostic thresholds. This study moves beyond describing a glycemic continuum by translating the non-linear HbA1c–microvascular relationship into an individualized risk estimation framework. Methods: In this cross-sectional observational study, adult subjects from a real-world clinical cohort were analyzed using HbA1c as a continuous variable. Associations between HbA1c and metabolic parameters were assessed using correlation analysis. Linear regression was applied to evaluate the relationship between HbA1c and cumulative diabetes-related complication burden. Non-linear associations between HbA1c and the risk of presenting at least one complication were explored using restricted cubic spline logistic regression models. Additional risk estimation analyses focused on the HbA1c gray zone (5.5–6.4%). Results: HbA1c showed a strong continuous association with fasting plasma glucose (ρ = 0.73, p < 0.001) and was positively associated with cumulative complication burden (β = 0.016 per 1% increase in HbA1c, p = 0.009). Non-linear modeling revealed a progressive increase in complication risk beginning below the diagnostic threshold for diabetes, with an inflection of the risk curve within the HbA1c gray zone. Individuals within this interval exhibited a higher prevalence and increased odds of presenting at least one complication compared with lower HbA1c values, although some estimates did not reach statistical significance. Conclusions: HbA1c acts as a continuous and non-linear marker of metabolic stress, with potentially biologically meaningful increases in complication risk emerging below traditional diagnostic thresholds. We demonstrate a non-linear acceleration of microvascular risk within the 5.5–6.4% interval, rather than a simple linear gradient. These findings support the concept of a glycemic risk continuum and highlight the clinical relevance of the HbA1c sub-diagnostic interval for early risk stratification and preventive strategies.