Mil Med Res. 2023 Mar 6;10(1):10. doi: 10.1186/s40779-023-00446-y.

ABSTRACT

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

PMID:36872349 | DOI:10.1186/s40779-023-00446-y

Zhongguo Zhong Yao Za Zhi. 2023 Feb;48(3):841-846. doi: 10.19540/j.cnki.cjcmm.20220928.502.

ABSTRACT

The aging society has led to a substantial increase in the number of clinical comorbidities. To meet the needs of comorbidity treatment, polypharmacy is widely used in clinical practice. However, polypharmacy has drawbacks such as treatment conflict. Same treatment of different diseases refers to treating different diseases with same treatment. Therefore, the principle of same treatment of different diseases can alleviate the problems caused by polypharmacy. Under the research background of precision medicine, it becomes possible to explore the mechanism of same treatment of different diseases and achieve its clinical application. However, drugs successfully developed in the past have revealed shortcomings in clinical use. To better interpret the mechanism of precision medicine for same treatment of different diseases, under the multi-dimensional attributes including dynamic space and time, omics was performed, and a new strategy of tensor decomposition was proposed. With the characteristics of complete data, tensor decomposition is advantageous in data mining and can fully grasp the connotation of precision treatment of different diseases with same treatment under dynamic spatiotemporal changes. This method is used for drug repositioning in some biocomputations. By taking advantage of the dimensionality reduction of tensor decomposition and integrating the dual influences of time and space, this study achieved accurate target prediction of same treatment of different diseases at each stage, and discovered the mechanism of precision medicine of same treatment for different diseases, providing scientific support for precision prescription and treatment of different diseases with same treatment in clinical practice. This study thus conducted preliminary exploration of the pharmacological mechanism of precision Chinese medicine treatment.

PMID:36872249 | DOI:10.19540/j.cnki.cjcmm.20220928.502

J Infect Chemother. 2023 Mar 3:S1341-321X(23)00053-3. doi: 10.1016/j.jiac.2023.02.017. Online ahead of print.

ABSTRACT

Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC50]: 9.0-23.6 μM), whereas all the drugs inhibited SFTSV infection when infected cells were treated (IC50: 21.3-94.2 μM). Levodopa combined with carbidopa and/or entacapone inhibited SFTSV infection in both conditions: pretreatment of the virus (IC50: 2.9-5.8 μM) and treatment of infected cells (IC50: 10.7-15.4 μM). The IC50 of levodopa in the above-mentioned study for pretreatment of the virus and treatment of infected cells were 4.5 and 21.4 μM, respectively. This suggests that a synergistic effect was observed, especially for treatment of infected cells, although the effect is unclear for pretreatment of the virus. This study demonstrates the anti-SFTSV efficacy of levodopa-metabolizing enzyme inhibitors in vitro. These drugs may increase the time for which the levodopa concentration is maintained in vivo. The combination of levodopa and levodopa-metabolizing enzyme inhibitors might be a candidate for drug repurposing.

PMID:36871824 | DOI:10.1016/j.jiac.2023.02.017

Sci Rep. 2023 Mar 4;13(1):3643. doi: 10.1038/s41598-023-30095-z.

ABSTRACT

The search for an effective drug is still urgent for COVID-19 as no drug with proven clinical efficacy is available. Finding the new purpose of an approved or investigational drug, known as drug repurposing, has become increasingly popular in recent years. We propose here a new drug repurposing approach for COVID-19, based on knowledge graph (KG) embeddings. Our approach learns "ensemble embeddings" of entities and relations in a COVID-19 centric KG, in order to get a better latent representation of the graph elements. Ensemble KG-embeddings are subsequently used in a deep neural network trained for discovering potential drugs for COVID-19. Compared to related works, we retrieve more in-trial drugs among our top-ranked predictions, thus giving greater confidence in our prediction for out-of-trial drugs. For the first time to our knowledge, molecular docking is then used to evaluate the predictions obtained from drug repurposing using KG embedding. We show that Fosinopril is a potential ligand for the SARS-CoV-2 nsp13 target. We also provide explanations of our predictions thanks to rules extracted from the KG and instanciated by KG-derived explanatory paths. Molecular evaluation and explanatory paths bring reliability to our results and constitute new complementary and reusable methods for assessing KG-based drug repurposing.

PMID:36871056 | DOI:10.1038/s41598-023-30095-z

Br J Cancer. 2023 Mar 4. doi: 10.1038/s41416-023-02210-4. Online ahead of print.

ABSTRACT

BACKGROUND: Autophagy plays an important role in tumour cell growth and survival and also promotes resistance to chemotherapy. Hence, autophagy has been targeted for cancer therapy. We previously reported that macrolide antibiotics including azithromycin (AZM) inhibit autophagy in various types of cancer cells in vitro. However, the underlying molecular mechanism for autophagy inhibition remains unclear. Here, we aimed to identify the molecular target of AZM for inhibiting autophagy.

METHODS: We identified the AZM-binding proteins using AZM-conjugated magnetic nanobeads for high-throughput affinity purification. Autophagy inhibitory mechanism of AZM was analysed by confocal microscopic and transmission electron microscopic observation. The anti-tumour effect with autophagy inhibition by oral AZM administration was assessed in the xenografted mice model.

RESULTS: We elucidated that keratin-18 (KRT18) and α/β-tubulin specifically bind to AZM. Treatment of the cells with AZM disrupts intracellular KRT18 dynamics, and KRT18 knockdown resulted in autophagy inhibition. Additionally, AZM treatment suppresses intracellular lysosomal trafficking along the microtubules for blocking autophagic flux. Oral AZM administration suppressed tumour growth while inhibiting autophagy in tumour tissue.

CONCLUSIONS: As drug-repurposing, our results indicate that AZM is a potent autophagy inhibitor for cancer treatment, which acts by directly interacting with cytoskeletal proteins and perturbing their dynamics.

PMID:36871041 | DOI:10.1038/s41416-023-02210-4

Hereditas. 2023 Mar 4;160(1):9. doi: 10.1186/s41065-023-00270-3.

ABSTRACT

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder which could lead to inflammation and fibrosis in various organs. Pulmonary fibrosis is a severe complication in patients with SLE. Nonetheless, SLE-derived pulmonary fibrosis has unknown pathogenesis. Of pulmonary fibrosis, Idiopathic pulmonary fibrosis (IPF) is a typicality and deadly form. Aiming to investigate the gene signatures and possible immune mechanisms in SLE-derived pulmonary fibrosis, we explored common characters between SLE and IPF from Gene Expression Omnibus (GEO) database.

RESULTS: We employed the weighted gene co-expression network analysis (WGCNA) to identify the shared genes. Two modules were significantly identified in both SLE and IPF, respectively. The overlapped 40 genes were selected out for further analysis. The GO enrichment analysis of shared genes between SLE and IPF was performed with ClueGO and indicated that p38MAPK cascade, a key inflammation response pathway, may be a common feature in both SLE and IPF. The validation datasets also illustrated this point. The enrichment analysis of common miRNAs was obtained from the Human microRNA Disease Database (HMDD) and the enrichment analysis with the DIANA tools also indicated that MAPK pathways' role in the pathogenesis of SLE and IPF. The target genes of these common miRNAs were identified by the TargetScan7.2 and a common miRNAs-mRNAs network was constructed with the overlapped genes in target and shared genes to show the regulated target of SLE-derived pulmonary fibrosis. The result of CIBERSORT showed decreased regulatory T cells (Tregs), naïve CD4+ T cells and rest mast cells but increased activated NK cells and activated mast cells in both SLE and IPF. The target genes of cyclophosphamide were also obtained from the Drug Repurposing Hub and had an interaction with the common gene PTGS2 predicted with protein-protein interaction (PPI) and molecular docking, indicating its potential treatment effect.

CONCLUSIONS: This study originally uncovered the MAPK pathway, and the infiltration of some immune-cell subsets might be pivotal factors for pulmonary fibrosis complication in SLE, which could be used as potentially therapeutic targets. The cyclophosphamide may treat SLE-derived pulmonary fibrosis through interaction with PTGS2, which could be activated by p38MAPK.

PMID:36871016 | DOI:10.1186/s41065-023-00270-3

Eur J Pharm Sci. 2023 Mar 2:106418. doi: 10.1016/j.ejps.2023.106418. Online ahead of print.

ABSTRACT

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations.

AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters.

METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Ctrough) and average AUC (AUCave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders.

RESULTS: AUCave and Ctrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Ctrough, not AUCave, associated significantly with P/F (β=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Ctrough, but not AUCave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Ctrough and AUCave, and PD outcomes.

CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Total Ctrough and AUCave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

PMID:36870577 | DOI:10.1016/j.ejps.2023.106418

Kidney Int. 2023 Mar 2:S0085-2538(23)00133-3. doi: 10.1016/j.kint.2023.02.010. Online ahead of print.

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor (V2R) antagonist, is the only drug approved to treat ADPKD patients with rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of ADPKD is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition due to its cost- and time-efficiencies and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat ADPKD and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.

PMID:36870435 | DOI:10.1016/j.kint.2023.02.010

Rheumatology (Oxford). 2023 Mar 3:kead096. doi: 10.1093/rheumatology/kead096. Online ahead of print.

ABSTRACT

OBJECTIVES: To date, no immunomodulatory drug has demonstrated its efficacy in primary Sjögren's syndrome (pSS). We sought to analyze potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes.

METHODS: Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in 2 cohorts and 3 public databases. In each of the 5 datasets, we analyzed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on 9 cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database.

RESULTS: We analyzed 1008 peripheral blood transcriptomes from 5 independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated.

CONCLUSION: This first drug repositioning transcriptomic approach in Sjögren's syndrome confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.

PMID:36869684 | DOI:10.1093/rheumatology/kead096

Eur J Med Chem. 2023 Feb 27;250:115238. doi: 10.1016/j.ejmech.2023.115238. Online ahead of print.

ABSTRACT

Conjunctival melanoma (CM), a rare and fatal malignant ocular tumor, lacks proper diagnostic biomarkers and therapy. Herein, we revealed the novel application of propafenone, an FDA-approved antiarrhythmic medication, which was identified effective in inhibiting CM cells viability and homologous recombination pathway. Detailed structure-activity relationships generated D34 as one of the most promising derivatives, which strongly suppressed the proliferation, viability, and migration of CM cells at submicromolar concentrations. Mechanically, D34 had the potential to increase γ-H2AX nuclear foci and aggravated DNA damage by suppressing homologous recombination pathway and its factors, particularly the complex of MRE11-RAD50-NBS1. D34 bound to human recombinant MRE11 protein and inhibited its endonuclease activity. Moreover, D34 dihydrochloride significantly suppressed tumor growth in the CRMM1 NCG xenograft model without obvious toxicity. Our finding shows that propafenone derivatives modulating the MRE11-RAD50-NBS1 complex will most likely provide an approach for CM targeted therapy, especially for improving chemo- and radio-sensitivity for CM patients.

PMID:36868105 | DOI:10.1016/j.ejmech.2023.115238

Ther Adv Hematol. 2023 Feb 27;14:20406207231152746. doi: 10.1177/20406207231152746. eCollection 2023.

ABSTRACT

Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression. Thrombopoiesis is a dynamic process regulated by various signaling pathways in which thrombopoietin (THPO)-MPL is dominant. Thrombopoiesis-stimulating agents could promote platelet production, showing therapeutic effects in different kinds of thrombocytopenia. Some thrombopoiesis-stimulating agents are currently used in clinical practices to treat thrombocytopenia. The others are not in clinical investigations to deal with thrombocytopenia but have potential in thrombopoiesis. Their potential values in thrombocytopenia treatment should be highly regarded. Novel drug screening models and drug repurposing research have found many new agents and yielded promising outcomes in preclinical or clinical studies. This review will briefly introduce thrombopoiesis-stimulating agents currently or potentially valuable in thrombocytopenia treatment and summarize the possible mechanisms and therapeutic effects, which may enrich the pharmacological armamentarium for the medical treatment of thrombocytopenia.

PMID:36865986 | PMC:PMC9972067 | DOI:10.1177/20406207231152746

Clin Infect Dis. 2023 Mar 2:ciad086. doi: 10.1093/cid/ciad086. Online ahead of print.

NO ABSTRACT

PMID:36861337 | DOI:10.1093/cid/ciad086

Front Pharmacol. 2023 Feb 13;14:1093038. doi: 10.3389/fphar.2023.1093038. eCollection 2023.

ABSTRACT

Mitochondria are the primary source of energy production in cells, supporting the metabolic demand of tissue. The dysfunctional mitochondria are implicated in various diseases ranging from neurodegeneration to cancer. Therefore, regulating dysfunctional mitochondria offers a new therapeutic opportunity for diseases with mitochondrial dysfunction. Natural products are pleiotropic and readily obtainable sources of therapeutic agents, which have broad prospects in new drug discovery. Recently, many mitochondria-targeting natural products have been extensively studied and have shown promising pharmacological activity in regulating mitochondrial dysfunction. Hence, we summarize recent advances in natural products in targeting mitochondria and regulating mitochondrial dysfunction in this review. We discuss natural products in terms of their mechanisms on mitochondrial dysfunction, including modulating mitochondrial quality control system and regulating mitochondrial functions. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products, emphasizing the potential value of natural products in mitochondrial dysfunction.

PMID:36860298 | PMC:PMC9968749 | DOI:10.3389/fphar.2023.1093038

Clin Transl Med. 2023 Mar;13(3):e1143. doi: 10.1002/ctm2.1143.

NO ABSTRACT

PMID:36855775 | DOI:10.1002/ctm2.1143

Heliyon. 2023 Feb 24:e14059. doi: 10.1016/j.heliyon.2023.e14059. Online ahead of print.

ABSTRACT

In the severe acute respiratory coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need to develop effective treatments. Through a network-based drug repurposing approach, several effective drug candidates are identified for treating COVID-19 patients in different clinical stages. The proposed approach takes advantage of computational prediction methods by integrating publicly available clinical transcriptome and experimental data. We identify 51 drugs that regulate proteins interacted with SARS-CoV-2 protein through biological pathways against COVID-19, some of which have been experimented in clinical trials. Among the repurposed drug candidates, lovastatin leads to differential gene expression in clinical transcriptome for mild COVID-19 patients, and estradiol cypionate mainly regulates hormone-related biological functions to treat severe COVID-19 patients. Multi-target mechanisms of drug candidates are also explored. Erlotinib targets the viral protein interacted with cytokine and cytokine receptors to affect SARS-CoV-2 attachment and invasion. Lovastatin and testosterone block the angiotensin system to suppress the SARS-CoV-2 infection. In summary, our study has identified effective drug candidates against COVID-19 for patients in different clinical stages and provides comprehensive understanding of potential drug mechanisms.

PMID:36855680 | PMC:PMC9951095 | DOI:10.1016/j.heliyon.2023.e14059

Clin Case Rep. 2023 Feb 26;11(2):e6980. doi: 10.1002/ccr3.6980. eCollection 2023 Feb.

ABSTRACT

In an open pilot trial, six patients with various hereditary forms of spinocerebellar ataxia (SCA) were assigned to topiramate (50 mg/day) for 24 weeks. Four patients completed the protocol without adverse events. Of these four patients, topiramate was effective for three patients. Some patients with SCA could respond to treatment with topiramate.

PMID:36855409 | PMC:PMC9968455 | DOI:10.1002/ccr3.6980

OMICS. 2023 Feb 28. doi: 10.1089/omi.2022.0157. Online ahead of print.

ABSTRACT

As COVID-19 continues to evolve around the world, there are unmet needs for rapid discovery, repurposing, and development of antiviral drugs. COVID-19 drug development is relevant for acute/pandemic context as well as the endemic disease with SARS-CoV-2 going forward. In the present study, the transcriptome data of the SARS-CoV-2-infected human lung cell lines were used to identify the signature genes for COVID-19 infection. A set of 14 genes was considered as gene signatures from the SARS-CoV-2-infected human bronchial epithelial cells and human alveolar epithelial cell lines. With a translational bioinformatics approach based on reversal of differentially expressed gene signatures, we found that four Food and Drug Administration-approved drugs offer potential for repurposing in a context of COVID-19: Mitomycin, 4-Guanidino-Benzoic Acid, Etretinate, and Staurosporine. We suggest that these drugs warrant further consideration for possible repurposing for the treatment of COVID-19. In summary, the present study underlines the ways in which an omics approach can be harnessed toward translational bioinformatics and rapid COVID-19 drug repurposing.

PMID:36854133 | DOI:10.1089/omi.2022.0157

Russ J Bioorg Chem. 2023 Feb 21:1-10. doi: 10.1134/S1068162023020139. Online ahead of print.

ABSTRACT

Drug repurposing is using an existing drug for a new treatment that was not indicated before. It has received immense attention during the COVID-19 pandemic emergency. Drug repurposing has become the need of time to fasten the drug discovery process and find quicker solutions to the over-exerted healthcare scenario and drug needs. Drug repurposing involves identifying the drug, evaluating its efficiency using preclinical models, and proceeding to phase II clinical trials. Identification of the drug candidate can be made through computational and experimental approaches. This approach usually utilizes public databases for drugs. Data from primary and translational research, clinical trials, anecdotal reports regarding off-label uses, and other published human data information available are included. Using artificial intelligence algorithms and other bioinformatics tools, investigators systematically try to identify the interaction between drugs and protein targets. It can be combined with genetic data, clinical analysis, structure (molecular docking), pathways, signatures, targets, phenotypes, binding assays, and artificial intelligence to get an optimum outcome in repurposing. This article describes the strategies involved in drug repurposing and enlists a series of repurposed drugs and their indications.

PMID:36852389 | PMC:PMC9945820 | DOI:10.1134/S1068162023020139

Viruses. 2023 Feb 19;15(2):568. doi: 10.3390/v15020568.

ABSTRACT

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

PMID:36851782 | DOI:10.3390/v15020568

Toxics. 2023 Jan 30;11(2):135. doi: 10.3390/toxics11020135.

ABSTRACT

Autophagy is an evolutionarily conserved cellular system crucial for cellular homeostasis that protects cells from a broad range of internal and extracellular stresses. Autophagy decreases metabolic load and toxicity by removing damaged cellular components. Environmental contaminants, particularly industrial substances, can influence autophagic flux by enhancing it as a protective response, preventing it, or converting its protective function into a pro-cell death mechanism. Environmental toxic materials are also notorious for their tendency to bioaccumulate and induce pathophysiological vulnerability. Many environmental pollutants have been found to influence stress which increases autophagy. Increasing autophagy was recently shown to improve stress resistance and reduce genetic damage. Moreover, suppressing autophagy or depleting its resources either increases or decreases toxicity, depending on the circumstances. The essential process of selective autophagy is utilized by mammalian cells in order to eliminate particulate matter, nanoparticles, toxic metals, and smoke exposure without inflicting damage on cytosolic components. Moreover, cigarette smoke and aging are the chief causes of chronic obstructive pulmonary disease (COPD)-emphysema; however, the disease's molecular mechanism is poorly known. Therefore, understanding the impacts of environmental exposure via autophagy offers new approaches for risk assessment, protection, and preventative actions which will counter the harmful effects of environmental contaminants on human and animal health.

PMID:36851010 | DOI:10.3390/toxics11020135