Development Of New Drugs Research Articles

Review and Current Perspectives on DNA Topoisomerase I and II Enzymes of Fungi as Study Models for the Development of New Antifungal Drugs.

Fungal infections represent a growing public health problem, mainly stemming from two phenomena. Firstly, certain diseases (e.g., AIDS and COVID-19) have emerged that weaken the immune system, leaving patients susceptible to opportunistic pathogens. Secondly, an increasing number of pathogenic fungi are developing multi-drug resistance. Consequently, there is a need for new antifungal drugs with novel therapeutic targets, such as type I and II DNA topoisomerase enzymes of fungal organisms. This contribution summarizes the available information in the literature on the biology, topology, structural characteristics, and genes of topoisomerase (Topo) I and II enzymes in humans, two other mammals, and 29 fungi (including Basidiomycetes and Ascomycetes). The evidence of these enzymes as alternative targets for antifungal therapy is presented, as is a broad spectrum of Topo I and II inhibitors. Research has revealed the genes responsible for encoding the Topo I and II enzymes of fungal organisms and the amino acid residues and nucleotide residues at the active sites of the enzymes that are involved in the binding mode of topoisomerase inhibitors. Such residues are highly conserved. According to molecular docking studies, antifungal Topo I and II inhibitors have good affinity for the active site of the respective enzymes. The evidence presented in the current review supports the proposal of the suitability of Topo I and II enzymes as molecular targets for new antifungal drugs, which may be used in the future in combined therapies for the treatment of infections caused by fungal organisms.

Structural insight into synergistic activation of human 3-methylcrotonyl-CoA carboxylase.

The enzymes 3-methylcrotonyl-coenzyme A (CoA) carboxylase (MCC), pyruvate carboxylase and propionyl-CoA carboxylase belong to the biotin-dependent carboxylase family located in mitochondria. They participate in various metabolic pathways in human such as amino acid metabolism and tricarboxylic acid cycle. Many human diseases are caused by mutations in those enzymes but their structures have not been fully resolved so far. Here we report an optimized purification strategy to obtain high-resolution structures of intact human endogenous MCC, propionyl-CoA carboxylase and pyruvate carboxylase in different conformational states. We also determine the structures of MCC bound to different substrates. Analysis of MCC structures in different states reveals the mechanism of the substrate-induced, multi-element synergistic activation of MCC. These results provide important insights into the catalytic mechanism of the biotin-dependent carboxylase family and are of great value for the development of new drugs for the treatment of related diseases.

Hansch analysis by QSAR model of curcumin and eight of its transformed derivatives with antimicrobial activity against Staphylococcus aureus

Context: In the last decade, antimicrobial resistance cases have been widespread. The discovery and development of new drugs need to be done to overcome the case. Some research has found that some compounds, which are curcumin transformation derivatives, are able to inhibit the growth of Staphylococcus aureus. Aims: To evaluate the development of antimicrobial candidates of curcumin versus S. aureus. Methods: The in silico approach method, along with the QSAR technique, plays an important role in the process of discovery and development of new drugs. In this study, we focused on developing curcumin transformation derivatives that are much more potent by making the best QSAR equation of curcumin and eight curcumin transformation derivatives that have been tested in vitro for their antimicrobial activity against Staphylococcus aureus. Results: The best QSAR equation was obtained from curcumin transformation derivatives as antimicrobial activity against S. aureus, with pMIC = 0.812 (± 0.162)EHOMO +5.443 (± 1.659) (n = 9; Sig = 0.002; R = 0.884; R2 = 0.782; F = 25.153; Q2 = 0.57. Conclusions: In this study, an increase in the antimicrobial activity of curcumin transformation derivatives against S. aureus by increasing EHOMO was observed. The best QSAR equation can be a tool to obtain a more potential new chemical structure model and reduce trials and errors.

Hirshfeld surface, fukui function, molecular docking, molecular dynamics investigation on human immunodeficiency virus-1 (HIV) organism with 2,6-dibromo-4-chloroaniline

2,6-Dibromo-4-chloroaniline is a planar molecule. Functional analysis based on vibrational modes is made clearer by spectral analysis. Quantum chemical calculation are characterized, its electronegativity in addition to local characteristics such as electrophilicity and Fukui function. ELF study aims to understand the quantitative behavior of electrons within a system. Docking simulation has been used to assess the energy of binding and coupling between the enhanced protein and ligand combination molecules. The research and development of new drugs heavily relies on the chemical properties of toxicity, metabolism, excretion, distribution, and absorption. The Hirshfeld surface was a helpful tool for illustrating characteristics, such as the electrostatic potential of a molecule inside a crystal structure, that could be quickly and easily learned.

P01-67 Oxidative changes and cell death pathways induced by chlorpromazine photoproducts in breast normal versus cancer cells – contributions to development of new drugs for cancer therapy

P01-67 Oxidative changes and cell death pathways induced by chlorpromazine photoproducts in breast normal versus cancer cells – contributions to development of new drugs for cancer therapy

Cabazitaxel-Loaded Thermosensitive Hydrogel System for Suppressed Orthotopic Colorectal Cancer and Liver Metastasis.

The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.

In silico Investigation of Caged Xanthone Compounds Isolated from Cratoxylum sumatranum Stem Bark against Entamoeba histolytica Enzymes

Background: Amoebiasis is caused by Entamoeba histolytica, a pathogenic species living on human colon tissues. Metronidazole is currently used for the treatment of amoebiasis, but resistance of E. histolytica to the use of such treatment has been reported. Therefore, the development of new anti-amoebic drugs is still very much needed for clinical treatment. Preliminary research on extract and fractions from Cratoxylum sumatranum stem bark has shown their anti-amoebic activity. Two compounds from the cage xanthone groups, cochinchinoxanthone and cochinchinone D, have been isolated from the active fraction of C. sumatranum stem bark. Objective: This study aimed to investigate the anti-amoebic activity of the two known compounds against E. histolytica. Methods: The in silico method used was molecular docking with several receptors, including thioredoxin reductase, triose phosphate isomerase, pyruvate ferredoxin oxidoreductase, Giardia fructose-1,6-bisphosphate aldolase, serine acetyltransferase, and phosphoserine phosphatase. The prediction of ADMET properties was also carried out for both the compounds. Results: The results showed cochinchinone D to have a higher binding affinity to thioredoxin reductase, pyruvate ferredoxin oxidoreductase, and Giardia fructose-1,6-bisphosphate aldolase receptors than cochinchinoxanthone. In contrast, cochinchinoxanthone bound better to the triose phosphate isomerase and phosphoserine phosphatase receptors, while both exhibited the same affinity for serine acetyltransferase. In general, the two compounds were also found to have similar ADMET profiles. Conclusion: In conclusion, caged xanthone compounds from C. sumatranum have the potential to be developed as anti-amoebic agents against E. histolytica through the mechanism of inhibition of these enzymes.

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.

Tuberculosis (TB) remains a primary global health concern, necessitating the discovery and development of new anti-TB drugs, mainly to combat drug-resistant strains. In this context, thiourea derivatives have emerged as promising candidates in TB drug discovery due to their diverse chemical structures and pharmacological properties. This review aimed to explore this potential, identifying and exploring molecular targets for thiourea derivatives in Mycobacterium tuberculosis (Mtb) and the potential application of virtual screening techniques in drug discovery. We have compiled a comprehensive list of possible molecular targets of thiourea derivatives in Mtb. The enzymes are primarily involved in the biosynthesis of various cell wall components, including mycolic acids, peptidoglycans, and arabinans, or targets in the branched-chain amino acid biosynthesis (BCAA) pathway and detoxification mechanisms. We discuss the potential of these targets as critical constituents for the design of novel anti-TB drugs. Besides, we highlight the opportunities that virtual screening methodologies present in identifying potential thiourea derivatives that can interact with these molecular targets. The presented findings contribute to the ongoing efforts in TB drug discovery and lay the foundation for further research in designing and developing more effective treatments against this devastating disease.

Changes in bioenergetic characteristics of the murine lymphoma cells under the action of a thiazole derivative in complex with polymeric nanoparticles

Background. Mitochondria can influence cancer cells both indirectly via reactive oxygen species mediation and directly through mitochondrial biogenesis. Energy production in mitochondria is crucial as it facilitates the synthesis of essential molecules needed for cellular biosynthesis, growth, and proliferation. The development of new anticancer drugs that target the energy metabolism of tumor cells shows promise in cancer treatment. Our study aimed to investigate how the thiazole derivative N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide (BF1), the polymeric nanoparticles based on the polyethylene glycol (PEG-PN, Th5), and their complex with BF1 (Th6) affect respiration and mitochondrial membrane potential in murine NK/Ly tumor cells. Materials and Methods. The study was performed on white wild-type male mice with grafted NK/Ly lymphoma. The test substances were added to the cell suspension at a final concentration of 10 μM and incubated for 15 min at 37 °C. Oxygen uptake rates in NK/Ly cells were measured using a polarographic method with Clark electrode. Changes in mitochondrial membrane potential were assessed using the tetramethylrhodamine methyl ester fluorescence dye. The fluorescence intensity was evaluated using the ImageJ computer program. Results. After incubating NK/Ly cells with BF1 (10 µM), Th5, or the BF1 + PEG-PN complex (Th6) for 15 min, no changes were observed in glucose-fueled basal respiration. However, the Th6 complex significantly activated FCCP-stimulated respiratory processes in NK/Ly lymphoma cells. Fluorescent microscopy data indicated that BF1 or Th5 alone did not affect mitochondrial membrane potential values. However, the Th6 complex significantly decreased mitochondrial membrane potential, suggesting a reduction in NK/Ly cell viability. Conclusions The investigated complex of thiazole derivative BF1 with PEG-based polymeric nanoparticles may realize its cytotoxic effect by depolarization of mitochondrial membrane in NK/Ly lymphoma cells.

On the pathogenesis and treatment of infectious-toxic (endotoxic) shock

The article is devoted to the issues of etiology, pathogenesis, classification, basic approaches to the diagnosis and treatment of infectious-toxic shock. Despite progress in studying the pathophysiology of sepsis and the development of new antibacterial drugs, mortality from endotoxic shock remains high. In recent years, antishock vaccines have been actively developed, but they have not yet received widespread use in clinical practice. The introduction of these drugs in the future may contribute to the survival of patients with various pathologies, as well as those in the “shock” risk group (military, emergency services personnel, etc.).

A Review on Synthesis and Biological Activities of 2‐Aminophenol‐Based Schiff Bases and Their Transition Metal Complexes

ABSTRACT2‐Aminophenol‐based Schiff bases and their metal complexes have drawn a lot of interest because of their wide range of biological activity and their uses in several fields. These Schiff bases are synthesized through the condensation of 2‐aminophenol and various carbonyl compounds, and metal complexes formed easily by coordinating Schiff bases with transition metal ions possess a wide range of intriguing properties that have rendered them promising candidates in biomedical research. These compounds have a diverse array of captivating biological properties including antibacterial, antifungal, anticancer, and antioxidant actions. Their versatile nature and potential for tailored modifications hold the promise for innovative biomedical applications. Compared to standard antibiotics and other studied compounds, C2, C8–C11, and C116 complexes, along with L16 and L17 ligands, exhibit the highest antibacterial activity, while C3 and C115 complexes demonstrate the highest antifungal activity. The metal chelate formation of the ligands enhanced the antimicrobial activity by increasing their lipophilic nature. C66, C76, and C112 complexes and L39 ligand showed higher anticancer activity than standard anticancer drugs. The metal complexes have higher anticancer activity than the ligand due to improved permeability and cellular uptake. The anticancer activity of the complexes is related to the substituents of the Schiff base ligands. In compounds containing an electron‐withdrawing group (e.g., Cl or Br or NO2), the activity is obviously better than others. Ligands L1–L3 and L5, L6, and L32 demonstrated the most potent antioxidant activity, surpassing both metal complexes and standard conventional antioxidants. The ligands showed greater antioxidant activity than the metal complexes due to their capability of donating free protons to scavenge free radicals. More study is needed to fully explore the potential of 2‐aminophenol‐based Schiff bases and their transition metal complexes for the development of new drugs. This review summarizes different synthetic methods, biological activities, and the structure–activity relationship. This study aims to conduct further research on 2‐aminophenol‐based Schiff bases and their metal complexes.

MFF-DTA: Multi-scale feature fusion for drug-target affinity prediction

Accurately predicting drug-target affinity is crucial in expediting the discovery and development of new drugs, which is a complex and risky process. Identifying these interactions not only aids in screening potential compounds but also guides further optimization. To address this, we propose a multi-perspective feature fusion model, MFF-DTA, which integrates chemical structure, biological sequence, and other data to comprehensively capture drug-target affinity features. The MFF-DTA model incorporates multiple feature learning components, each of which is capable of extracting drug molecular features and protein target information, respectively. These components are able to obtain key information from both global and local perspectives. Then, these features from different perspectives are efficiently combined using specific splicing strategies to create a comprehensive representation. Finally, the model uses the fused features to predict drug-target affinity. Comparative experiments show that MFF-DTA performs optimally on the Davis and KIBA data sets. Ablation experiments demonstrate that removing specific components results in the loss of unique information, thus confirming the effectiveness of the MFF-DTA design. Improvements in DTA prediction methods will decrease costs and time in drug development, enhancing industry efficiency and ultimately benefiting patients.

Secondary Metabolites of Fomitopsis betulina: Chemical Structures, Biological Activity and Application Prospects.

Fomitopsis betulina, as a macrofungus with both medicinal and dietary applications, is renowned for its rich content of bioactive substances. The recent advancements in research have significantly enhanced our understanding of its polysaccharides, cellulose-degrading enzymes, and wide range of secondary metabolites. This paper provides a comprehensive review of the artificial cultivation techniques and the chemical profiling of over 100 secondary metabolites identified in F. betulina, including terpenoids, phenols, and various other classes. These compounds exhibit notable pharmacological activities, such as anti-cancer, anti-inflammatory, antimicrobial, antiviral, and anti-malarial effects. Moreover, this review delves into the genomic analysis of F. betulina, focusing on the prediction and classification of terpene synthases, which play a crucial role in the biosynthesis of these bioactive compounds. This insight is instrumental for potentially facilitating future biochemical studies and pharmaceutical applications. Through this review, we aim to solidify the foundation for future in-depth studies and the development of new drugs derived from this promising natural resource.

NSC-38270 Exhibits Anti-invasive and Pro-apoptotic Effects on Hepatocellular Carcinoma Huh7 Cells.

Hepatocellular carcinoma (HCC) is a main type of liver cancer with high metastatic potential, and its incidence is steadily increasing worldwide. However, the development of new drugs for the treatment of HCC is still insufficient. This study aimed to determine the anticancer effect of NSC-38270, a natural product, on HCC. After treating HCC Huh7 cells with NSC-38270, cell growth, wound healing, migration, and invasion assays were conducted. We investigated the effects of NSC-38270 on Twist1, a crucial epithelial-mesenchymal transition (EMT)-related transcription factor. In addition, apoptosis, histone H2A.X activation, and cell morphology assays were performed in Huh7 and immortalized normal liver cells following treatment with NSC-38270. NSC-38270 reduced the migration and invasion ability of Huh7 cells, accompanied by a decrease in Twist1. Furthermore, NSC-38270 induced apoptosis in Huh7 cells, whereas apoptosis was not observed in immortalized normal liver cells (THLE-2 cells and Chang liver cells). NSC-38270 exhibited significant inhibitory effects on the migration and invasion of Huh7 cells by repressing Twist1. Importantly, it induced cancer cell-specific apoptotic effects. These findings suggest that NSC-38270 holds promising potential as a therapeutic candidate for cancer treatment.

Novel Targets and Strategies Addressing Residual Cardiovascular Risk in Post-acute Coronary Syndromes Patients.

Despite the advancement in secondary cardiovascular prevention strategies for post-acute coronary syndrome (ACS) patients, the development of new drugs addressing dyslipidemia and the personalization of dual antiplatelet therapies (DAPT), these patients continue to suffer a significant incidence of recurrent ischemic events. Therefore, novel targets that can be tackled to reduce cardiovascular risk are needed to improve the outcome of this very high-risk population. The role of chronic inflammation and inflammasome in the development and progression of atherosclerosis has been broadly investigated in patients with established coronary artery disease (CAD) and recent randomized trials have highlighted the possibility to manage these targets with specific drugs such as colchicine and monocolonal antibodies with a significant improvement of cardiovascular outcomes in post-ACS patients. Lipoprotein(a) [Lp(a)] is the most promising non-traditional risk factor and has shown to predict worse outcome in post-ACS patients. Lowering Lp(a) through PCSK9 inhibitors and specific targeted therapies has shown positive results in reducing adverse cardiovascular events in patients with established CAD. The effect of microbiome and its alteration in gut dysbiosis seems to actively participate in residual cardiovascular risk of CAD patients; however, the risk-modifying effect of targeted-microbiome therapies hasn't been yet investigated in large population-based studies. Long-term outcome of post-ACS patients is a complex puzzle of multiple factors. In this minireview, we summarize the emerging risk factors that may interplay in the residual risk of post-ACS patients and their possible prognostic and therapeutic implications.

Psychedelic and dissociative agents in psychiatry: challenges in the treatment

With the discovery of the antidepressive effects of ketamine and the increasing withdrawal of the pharmaceutical industry from the development of new psychotropic drugs, the psychiatric research into the clinical application of hallucinogens in psychiatry has literally blossomed in the last two decades. Promising results for various treatment approaches with psychedelic agents, such lysergic acid diethylamide (LSD) and psilocybin, and dissociative agents, such as ketamine and esketamine, have raised great hopes among researchers, clinicians and patients in recent years, so that there was already talk of a new era in psychiatry. As one of the first of these substances, in December 2019 intranasal esketamine was approved in the USA and the EU for the treatment of treatment-resistant depression and Switzerland followed in 2020. Recently, psilocybin was approved in Australia, Canada and Switzerland for compassionate use in exceptional cases for the treatment of depression, while large approval studies with various psychedelic agents are currently ongoing worldwide. The medical application of psychedelic agents and ketamine/esketamine is considered to be safe; however, as with all new forms of treatment it is of crucial importance that, in addition to the hopes, the specific challenges of these new treatment approaches must also be carefully considered and assessed. Excessive expectations and an insufficient risk-benefit estimation are detrimental to the patients and the reputation of the treating physician. Although a possible paradigm shift in the care of mental health is already being discussed, this review article consciously concentrates on the possible risks of treatment and the methodological weaknesses of the studies carried out so far.

Comparative in vitro and in silico analysis of the ability of basic Asp49 phospholipase A2 and Lys49-phospholipase A2-like myotoxins from Bothrops diporus venom to inhibit the metastatic potential of murine mammary tumor cells and endothelial cell tubulogenesis: Asp49 vs Lys49 phospholipases A2: Inhibition of metastasis and angiogenesis

Snake venoms are a complex mixture of proteins and polypeptides that represent a valuable source of potential molecular tools for understanding physiological processes for the development of new drugs. In this study two major PLA2s, named PLA2-I (Asp49) and PLA2-II (Lys49), isolated from the venom of Bothrops diporus from Northeastern Argentina, have shown cytotoxic effects on LM3 murine mammary tumor cells, with PLA2-II-like exhibiting a stronger effect compared to PLA2-I. At sub-cytotoxic levels, both PLA2s inhibited adhesion, migration, and invasion of these adenocarcinoma cells. Moreover, these toxins hindered tubulogenesis in endothelial cells, implicating a potential role in inhibiting tumor angiogenesis. All these inhibitory effects were more pronounced for the catalytically-inactive toxin. Additionally, in silico studies strongly suggest that this PLA2-II-like myotoxin could effectively block fibronectin binding to the integrin receptor, offering a dual advantage over PLA2-I in interacting with the αVβ3 integrin. In conclusion, this study reports for the first time, integrating both in vitro and in silico approaches, a comparative analysis of the antimetastatic and antiangiogenic potential effects of two isoforms, an Asp49 PLA2-I and a Lys49 PLA2-II-like, both isolated from Bothrops diporus venom.

Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells.

Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay,5‑Ethynyl‑2'‑deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.

Computational exploration of bioactive compounds from Albizia procera: Molecular docking, dynamics, and pharmacokinetics for AchE and BchE inhibition in Alzheimer's disease treatment

Current treatments for Alzheimer's disease (AD) are inadequate and primarily target inhibition of butyrylcholinesterase (BchE) and acetylcholinesterase (AChE) enzymes. This study focused on identifying potential anti-AD compounds from the leaf extract of Albizia procera using gas chromatography-tandem mass spectrometry (GC-MS) analysis and computational approaches. Ethanol seed extract analysis revealed 10 phytoconstituents, which were evaluated for their binding affinities using Autodock Vina and Desmond software against AD-related targets (PDB IDs: 4PQE, 2WJO, and 2POA). Five compounds, along with the control drug, showed significant docking energies. Subsequent in silico ADMET analysis assessed parameters such as intestinal absorption, blood-brain barrier permeability, gastrointestinal absorption, carcinogenicity, and acute oral toxicity. The results extract showed notable affinity for BchE and acetylcholinesterase targets. Molecular dynamics (MD) simulations supported the involvement of hydrogen bonding with ASP207 and GLY75 residues in binding these ligands, demonstrating that disrupting these forces causes destabilization. A ligand plot study also presented a two-dimensional plot of these interactions. The docking results indicate that 7-Oxabicyclo [4.1.0] heptan-2-one could be a promising agent for the treatment of AD because of its higher stability with respect to the two best ligands among all compounds tested. Therefore, from this study, it can be concluded that the compounds present in the leaf extract of A. procera have potential as targets linked to AD and may be helpful for the development of new drugs. Therefore, these data draw a focus on non-synthetic compounds during drug discovery and could possibly provide approaches for exploring existing therapies for AD.

The mechanisms of Ca2+ regulating autophagy and its research progress in neurodegenerative diseases: A review.

Neurodegenerative diseases are complex disorders that significantly challenge human health, with their incidence increasing with age. A key pathological feature of these diseases is the accumulation of misfolded proteins. The underlying mechanisms involve an imbalance in calcium homeostasis and disturbances in autophagy, indicating a likely correlation between them. As the most important second messenger, Ca2+ plays a vital role in regulating various cell activities, including autophagy. Different organelles within cells serve as Ca2+ storage chambers and regulate Ca2+ levels under different conditions. Ca2+ in these compartments can affect autophagy via Ca2+ channels or other related signaling proteins. Researchers propose that Ca2+ regulates autophagy through distinct signal transduction mechanisms, under normal or stressful conditions, and thereby contributing to the occurrence and development of neurodegenerative diseases. This review provides a systematic examination of the regulatory mechanisms of Ca2+ in cell membranes and different organelles, as well as its downstream pathways that influence autophagy and its implications for neurodegenerative diseases. This comprehensive analysis may facilitate the development of new drugs and provide more precise treatments for neurodegenerative diseases.