Homeostasis is the regulatory mechanism for the expression of all genes, the function of all metabolic pathways, the utilization of any essential trace element (TEs), while its disruptions lead to many pathological states. The pathologies include cardiovascular disease, anaemia, diabetes, neurological disorders, and cell death. For this, copper and zinc are two of the major TEs involved in controlling the physiological and pathological processes in both humans and animals. Zinc deficiency, for instance, is linked with decreased body weight, decreased ability to metabolize glucose, and impaired immune function. By contrast, deficiency of copper can lead to several neurological disorders, oxidative stress, mitochondrial dysfunction, and changes in lipid metabolism. On the other hand, there excessive exposure can have adverse effects on health, including the development of epilepsy, neuronal excitability, genotoxic effects, and cellular toxicity. Moreover, dual biological functions of zinc further complicate the understanding of their roles in both health and disease. Such as, zinc has a neuromodulatory function and helps to control excitably in neurons, but sometimes zinc in the synapse, inhibit the functioning of inhibitory neurotransmitter and cause damage to the neurons. Likewise, in metabolic diseases, particularly diabetes mellitus, there is often dysregulation of the levels of zinc and copper, resulting in steel-like interactions; elevated levels of copper and reduced levels of zinc contribute towards the pathogenesis of both the disease and the progression of dementia. Despite this antagonistic relationship, both trace metals act synergistically as necessary derivatives of superoxide dismutase; therefore, both play a vital role in maintaining cellular antioxidant defense systems. Therefore, this review covers published articles from 1992-2025 with regard to zinc and copper in their dietary and nanoparticle forms in animal and human models to demonstrate their differing roles and how they complement one another, or conflict with one another.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), developed for the treatment of diabetes mellitus, exert remarkable cardiovascular benefits beyond glycaemic control. The underlying mechanism of this pluripotent protection is heterogeneous and involves interactions with a number of haemodynamic, metabolic and cellular signalling pathways. Emerging findings demonstrate that a natural gaseous product of arterial wall, H2S, participates in a number of physiological reactions, and its deficiency is associated with cardiovascular pathologies, such as arterial hypertension, heart failure and chronic kidney disease. Recent experimental observations have suggested the possibility of a functional link between SGLT2i and H2S signalling in the context of cardiovascular protection. Emerging data suggest that SGLT2i- and H2S-dependent pathways may overlap or complement each other in protective mechanisms. Several plausible areas of interaction between SGLT2i and H2S have recently emerged. Both agents stimulate PI3K/Akt/eNOS signalling, thereby increasing the bioavailability of NO with beneficial vasodilatory and antiproliferative effects. SGLT2i and H2S also favourably regulate the redox state through inhibition of NADPH oxidase, thus protecting subcellular structures. Moreover, both SGLT2i and H2S appear to affect autophagy and improve mitochondrial function through AMPK and sirtuin signalling, thus contributing to the restoration of physiological substrate processing pathways and cellular energy balance. In addition, both SGLT2i and H2S supposedly downregulate the Na+/H+ exchanger, normalize the Fe2+ cytosolic level in cardiomyocytes and promote erythropoietin release, actions that could improve the metabolism and function of cardiovascular organs. Elucidating the nature of possible crosstalk between H2S, delivered by endogenous stimulation or exogenous supplementation, and SGLT2i may desirably modify the approach to the treatment of cardiovascular diseases and represents a challenging research topic.

BackgroundWith the aging population, the number of Alzheimer's disease (AD) patients has been increasing annually, creating an urgent need for AD therapeutic drugs. Donepezil combined with nimodipine (DN) has demonstrated therapeutic potential in the treatment of AD, but its mechanism of action remains unclear.ObjectiveTo reveal the mechanism of DN in the treatment of AD rats.MethodsThe AD rat model was established and evaluated by behavioral experiments and pathology. The therapeutic mechanism of DN in AD treatment was investigated through lipidomics and hippocampal metabolomics analyses based on ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF/MS).ResultsThe learning and memory ability of AD rats can be improved after DN treatment. Significant changes were observed in 40 serum lipid metabolites and 19 hippocampal metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, sphingolipid metabolism, amino acid metabolism, unsaturated fatty acid metabolism and other processes in AD rats.ConclusionsDN could improve cognitive function and nerve damage in AD rats. It may plays a therapeutic role in AD rats by regulating cholinergic damage, Ca2+ overload, oxidative stress, neuroinflammation, and energy deficiency caused by metabolic disorders, which has practical significance for further research and clinical application of DN.

Metabolic disorders such as insulin resistance and hypertension are potential risk factors for aging and neurodegenerative diseases. These conditions are reversed in Chromogranin A (CgA) knockout (CgA-KO) mice. CgA is known to be associated with protein aggregates in the brains of neurodegenerative diseases including Alzheimer's disease (AD). Here, we investigated the role of CgA in Tau pathogenesis in AD and corticobasal degeneration (CBD). CgA ablation in Tauopathy mice (PS19) (CgA-KO/PS19) reduced pathological Tau aggregation and spreading, extended lifespan, and improved cognitive function. Transcriptomic and metabolite analysis of mouse cortices revealed elevated alpha-1-adrenergic receptors (Adra1) expression and high Epinephrine (EPI) levels in PS19 mice compared to WT mice, mirroring observations in AD and CBD patients. CgA depletion in PS19 mice lowered cortical EPI levels and the expression of Adra1 back to normal. Treatment of WT hippocampal organotypic slice cultures with EPI or Adra1 agonist promoted, while an Adra1 antagonist inhibited Tau hyperphosphorylation and formation of neurofibrillary tangles, which is unaltered upon CgA depletion. These findings demonstrate the involvement of CgA in Tau pathogenesis and highlight the interplay between the EPI-Adra1 signaling pathway and CgA in Tauopathy.

Hyperhomocysteinemia (HHcy) influences the development and progression of neurodegenerative disorders in different ways. Homocysteine (Hcy) metabolism is related to that of asymmetric dimethylarginine (ADMA) and group B vitamins. The breakdown of the pathway involving nitric oxide (NO) and ADMA can be considered one of the causes of endothelial alteration that represents a crucial step in the development of several neurodegenerative disorders. Deficiencies of vitamins other than group B ones, such as D and A, have also been associated with central nervous system disorders. The aim of this narrative review is to describe the link between HHcy, ADMA, and vitamins in Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS) in terms of dysfunctional pathways and neuropathological processes, performing a literature search from 2015 to 2025 on PubMed. This review also provides an overview of the effects of vitamin supplementation on neurodegenerative diseases. The alteration of pathways involving NO production can lead to HHcy and elevated ADMA concentrations, causing neurodegeneration through various mechanisms, while vitamin supplementation has been shown to reduce Hcy levels, although with conflicting results about the improvement in clinical symptoms. Further studies are needed to develop optimal combined therapeutic strategies.