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Directly administering medication to inflamed intestinal sites for treating ulcerative colitis (UC), poses significant challenges like retention time, absorption variability, side effects, drug stability, and non-specific delivery. Recent advancements in therapy to treat colitis aim to improve local drug availability that is enema therapy at the site of inflammation, thereby reducing systemic adverse effects. Nevertheless, a key limitation lies in enemas' inability to sustain medication in the colon due to rapid peristaltic movement, diarrhea, and poor local adherence. Therefore, in this work, we have developed site-specific thiolated mucoadhesive anionic nanoliposomes to overcome the limitations of conventional enema therapy. The thiolated delivery system allows prolonged residence of the delivery system at the inflamed site in the colon, confirmed by the adhesion potential of thiolated nanoliposomes using in-vitro and in-vivo models. To further provide therapeutic efficacy thiolated nanoliposomes were loaded with gallic acid (GA), a natural compound known for its antibacterial, antioxidant, and potent anti-inflammatory properties. Consequently, Gallic Acid-loaded Thiolated 2,6 DALP DMPG (GATh@APDL) demonstrates the potential for targeted adhesion to the inflamed colon, facilitated by their small size 100 nm and anionic nature. Therapeutic studies indicate that this formulation offers protective effects by mitigating colonic inflammation, downregulating the expression of NF-κB, HIF-1α, and MMP-9, and demonstrating superior efficacy compared to the free GA enema. The encapsulated GA inhibits the NF-κB expression, leading to enhanced expression of MUC2 protein, thereby promoting mucosal healing in the colon. Furthermore, GATh@APDL effectively reduces neutrophil infiltration and regulates immune cell quantification in colonic lamina propria. Our findings suggest that GATh@APDL holds promise for alleviating UC and addressing the limitations of conventional enema therapy.
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Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints. RA is one of the major causes of disability and morbidity worldwide. Administration of conventional drugs through the systemic route restricts the bioavailability of drugs, systemic toxicity, and reduced efficacy. We have introduced Rebamipide (Reb)-loaded Sinapic acid (SA)-Pullulan (PL) nanomicelles (Reb@SA-PL NMs), a nanotechnology based drug delivery system for the treatment of inflammatory arthritis. PL is a polysaccharide obtained from the fungus Aureobasidium pullulans, and SA is a bioactive polyphenol found in various plants. Both are classified by US-FDA Generally Recognised as Safe (GRAS) materials. Reb@SA-PL NMs found to be cytocompatible. Subsequently, intra-articular administration of Reb@SA-PL NMs enhances the anti-arthritic potential compared to free Reb drug in collagen-induced experimental inflammatory arthritis rat model. Reb@SA-PL NMs reduced the expression of RANKL receptor and Nf-κB. Reb@SA-PL NMs reverses the breakdown of type II collagen, MMP-13, and inhibits the pro-inflammatory markers. Reb@SA-PL NMs prevented bone erosion, cartilage degradation, joint oedema, and synovial inflammation. The results of the study demonstrated that Reb@SA-PL NMs, an enzyme-responsive drug delivery system, has excellent potential for alleviating inflammatory arthritis by blocking MMP-13 and RANKL.
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Visnagin is a furanochromone and one of the most important compound in the Ammi visnaga (L.) Lam (a synonym of Visnaga daucoides Gaertn.) plant, which is used to cure various ailments. Many investigations into the bioactive properties of visnagin have been studied to date. The literature on visnagin demonstrates its biological properties, including anti-inflammatory, anti-diabetic, and beneficial effects in cardiovascular and renal diseases. Moreover, visnagin improves sperm quality parameters, stimulates steroidogenesis, and increases serum gonadotropins and testosterone levels, while decreasing pro-inflammatory cytokines, oxidative damage, genomic instability, and it modulates apoptosis. Thus, visnagin has emerged as an exciting lead for further research, owing to its potential in various unmet clinical needs. The current review summarized its basic structure, pharmacokinetics, and pharmacological effects, focusing on its mechanisms of action. The review will help to understand the potential of visnagin as an alternative treatment strategy for several diseases and provide insight into research topics that need further exploration for visnagin's safe clinical use. Please cite this article as: Yadav P, Singh SK, Datta S, Verma S, Verma A, Rakshit A, Bali A, Bhatti JS, Khurana A, Navik U. Therapeutic potential and pharmacological mechanism of visnagin. J Integr Med. 2024; 22(4): 399-412.
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Quelina , Humanos , Quelina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêuticoRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disorder affecting nearly 1% of the global population. In RA, synovial joints are infiltrated by inflammatory mediators and enzymes, leading to articular cartilage deterioration, joint damage, and bone erosion. Herein, the 9-aminoacridine-6-O-stearoyl-L-ascorbic acid hydrogel (9AA-SAA hydrogel) was formulated by the heat-cool method and further characterized for surface charge, surface morphology, rheology, and cytocompatibility. Furthermore, we evaluated the therapeutic efficacy of the 9AA-SAA hydrogel, an enzyme-responsive drug delivery system with on-and-off switching capabilities based on disease severity against collagen-induced experimental arthritis in Wistar rats. The anti-inflammatory action of the US FDA-approved drug 9-aminoacridine (9AA) was revealed which acted through nuclear receptor subfamily 4 group A member 1 (NR4A1), an anti-inflammatory orphan nuclear receptor that inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, we have explored the role of ascorbic acid, an active moiety of 6-O-stearoyl-L-ascorbic acid (SAA), in promoting the production of collagen production through ten-eleven translocation-2 (TET2) upregulation. Targeting through NR4A1 and TET2 could be the probable mechanism for the treatment of experimental arthritis. The combination of 9AA and ascorbic acid demonstrated enhanced therapeutic efficacy in the 9AA-SAA hydrogel, significantly reducing the severity of experimental arthritis. This approach, in contrast to existing treatments with limited effectiveness, presents a promising and more effective strategy for RA treatment by mitigating inflammation in experimental arthritis.
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Artrite Experimental , Ácido Ascórbico , Hidrogéis , Ratos Wistar , Animais , Ácido Ascórbico/farmacologia , Ácido Ascórbico/química , Ácido Ascórbico/administração & dosagem , Hidrogéis/química , Hidrogéis/administração & dosagem , Hidrogéis/farmacologia , Ratos , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/administração & dosagem , Camundongos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/administração & dosagem , InjeçõesRESUMO
Mitochondria are central to cellular energy production and metabolic regulation, particularly in cardiomyocytes. These organelles constantly undergo cycles of fusion and fission, orchestrated by key proteins like Dynamin-related Protein 1 (Drp-1). This review focuses on the intricate roles of Drp-1 in regulating mitochondrial dynamics, its implications in cardiovascular health, and particularly in myocardial infarction. Drp-1 is not merely a mediator of mitochondrial fission; it also plays pivotal roles in autophagy, mitophagy, apoptosis, and necrosis in cardiac cells. This multifaceted functionality is often modulated through various post-translational alterations, and Drp-1's interaction with intracellular calcium (Ca2 + ) adds another layer of complexity. We also explore the pathological consequences of Drp-1 dysregulation, including increased reactive oxygen species (ROS) production and endothelial dysfunction. Furthermore, this review delves into the potential therapeutic interventions targeting Drp-1 to modulate mitochondrial dynamics and improve cardiovascular outcomes. We highlight recent findings on the interaction between Drp-1 and sirtuin-3 and suggest that understanding this interaction may open new avenues for therapeutically modulating endothelial cells, fibroblasts, and cardiomyocytes. As the cardiovascular system increasingly becomes the focal point of aging and chronic disease research, understanding the nuances of Drp-1's functionality can lead to innovative therapeutic approaches.
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Doxorubicin (DOX) is a broad-spectrum antibiotic with potent anti-cancer activity. Nevertheless, despite having effective anti-neoplasm activity, its use has been clinically restricted due to its life-threatening side effects, such as cardiotoxicity. It is evident that betaine has anti-oxidant, and anti-inflammatory activity and has several beneficial effects, such as decreasing the amyloid-ß generation, reducing obesity, improving steatosis and fibrosis, and activating AMP-activated protein kinase (AMPK). However, whether betaine could mitigate DOX-induced cardiomyopathy is still unexplored. Cardiomyopathy was induced in male Sprague Dawley rats using DOX (4 mg/kg dose with a cumulative dose of 20 mg/kg, i.p.). Further, betaine (200 and 400 mg/kg) was co-treated with DOX through oral gavage for 28 days. After the completion of the study, several biochemical, oxidative stress parameters, histopathology, western blotting, and qRT-PCR were performed. Betaine treatment significantly reduced CK-MB, LDH, SGOT, and triglyceride levels, which are associated with cardiotoxicity. DOX-induced increased oxidative stress was also mitigated by betaine intervention as the SOD, catalase, MDA, and nitrite levels were restored. The histopathological investigation also confirmed the cardioprotective effect of betaine against DOX-induced cardiomyopathy as the tissue injury was reversed. Further, molecular analysis revealed that betaine suppressed the DOX-induced increased expression of phospho-p53, phospho-p38 MAPK, NF-kB p65, and PINK 1 with an upregulation of AMPK and downregulation of Nrf2 expression. Interestingly, qRT-PCR experiments show that betaine treatment alleviates the DOX-induced increase in inflammatory (TNF-α, NLRP3, and IL-6) and fibrosis (TGF-ß and Acta2) related gene expression, halting the cardiac injury. Interestingly, betaine also improves the mRNA expression of Nrf2, thus modulating the expression of antioxidant proteins and preventing oxidative damage. Here, we provide the first evidence that betaine treatment prevents DOX-induced cardiomyopathy by inhibiting oxidative stress, inflammation, and fibrosis by regulating AMPK/Nrf2/TGF-ß expression. We believe that betaine can be utilized as a potential novel therapeutic strategy for preventing DOX-induced cardiotoxicity.
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Proteínas Quinases Ativadas por AMP , Betaína , Cardiomiopatias , Doxorrubicina , Fibrose , Inflamação , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta , Animais , Betaína/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Doxorrubicina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/prevenção & controle , Cardiomiopatias/patologia , Cardiomiopatias/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Ratos , Fator de Crescimento Transformador beta/metabolismo , Antibióticos Antineoplásicos/toxicidadeRESUMO
Aging is a multifaceted process involving genetic and environmental interactions often resulting in epigenetic changes, potentially leading to aging-related diseases. Various strategies, like dietary interventions and calorie restrictions, have been employed to modify these epigenetic landscapes. A burgeoning field of interest focuses on the role of microbiota in human health, emphasizing system biology and computational approaches. These methods help decipher the intricate interplay between diet and gut microbiota, facilitating the creation of personalized nutrition strategies. In this review, we analysed the mechanisms related to nutritional interventions while highlighting the influence of dietary strategies, like calorie restriction and intermittent fasting, on microbial composition and function. We explore how gut microbiota affects the efficacy of interventions using tools like multi-omics data integration, network analysis, and machine learning. These tools enable us to pinpoint critical regulatory elements and generate individualized models for dietary responses. Lastly, we emphasize the need for a deeper comprehension of nutrient-epigenome interactions and the potential of personalized nutrition informed by individual genetic and epigenetic profiles. As knowledge and technology advance, dietary epigenetics stands on the cusp of reshaping our strategy against aging and related diseases.
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Epigenoma , Estado Nutricional , Humanos , Dieta , Nutrientes , Envelhecimento/genéticaRESUMO
The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-ß, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ERK, Notch, and Wnt/ß-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-α and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and anti-inflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis.
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Hepatopatias , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Humanos , Linfócitos T CD8-Positivos/patologia , Fígado , Hepatopatias/terapia , Cirrose Hepática/patologia , Anti-InflamatóriosRESUMO
Doxorubicin (Dox) is an anthracycline antibiotic used to treat various cancers and shows severe toxicity in multiple organ systems, including kidneys. Evidence shows that betaine's antioxidant and anti-inflammatory properties could prevent the onset of several disorders. Hence, the present study aims to investigate the therapeutic potential of betaine on Dox-induced nephrotoxicity (DIN). Nephrotoxicity was induced in male Sprague Dawley rats using Dox at a dose of 4 mg/kg (cumulative dose: 20 mg/kg) by the intraperitoneal route and cotreated with betaine through oral gavage (200 and 400 mg/kg) for 28 days. At the end of the experiment, biochemical, oxidative stress parameters, histopathology, and qRT-PCR were performed. DIN was indicated by elevated serum creatinine, urea, and decreased albumin levels representing kidney damage; the histopathological lesions (increased capsular space, renal tubule damage, and fibrosis) in renal tissues supported these biochemical findings. Interestingly, betaine treatment improves these alterations in Dox-treated rats. Further, betaine treatment decreases the lipid peroxidation and nitrite concentration and increases the superoxide dismutases and catalase enzyme concentration in Dox-treated rats. Fascinatingly, at the molecular level, DIN in rats shows upregulation of the Nrf2/HO-1 gene, while betaine treatment attenuated its expression along with the downregulation of inflammatory genes (NLRP3, TLR-4, TNF-α, and IL-6) and fibrosis-related genes (TGF-ß and Acta2) expression in Dox-treated rats. These results showed that betaine has reno-protective properties by reducing inflammatory and fibrotic mediators and enhancing antioxidant capacity in the renal tissue of rats treated with Dox. We believe betaine can be exploited as a dietary supplement to attenuate DIN.
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Antioxidantes , Betaína , Ratos , Masculino , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Betaína/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Doxorrubicina/toxicidade , Rim/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse OxidativoRESUMO
Deficiency of selenium (Se) has been described in a significant number of COVID-19 patients having a higher incidence of mortality, which makes it a pertinent issue to be addressed clinically for effective management of the COVID-19 pandemic. Se nanoparticles (SeNPs) provide a unique option for managing the havoc caused by the COVID-19 pandemic. SeNPs possess promising anti-inflammatory and anti-fibrotic effects by virtue of their nuclear factor kappa-light-chain-stimulator of activated B cells (NFκB), mitogen-activated protein kinase (MAPKs), and transforming growth factor-beta (TGF-ß) modulatory activity. In addition, SeNPs possess remarkable immunomodulatory effects, making them a suitable option for supplementation with a much lower risk of toxicity compared to their elemental counterpart. Further, SeNPs have been shown to curtail viral and microbial infections, thus, making it a novel means to halt viral growth. In addition, it can be administered in the form of aerosol spray, direct injection, or infused thin-film transdermal patches to reduce the spread of this highly contagious viral infection. Moreover, a considerable decrease in the expression of selenoprotein along with enhanced expression of IL-6 in COVID-19 suggests a potential association among selenoprotein expression and COVID-19. In this review, we highlight the unique antimicrobial and antiviral properties of SeNPs and the immunomodulatory potential of selenoproteins. We provide the rationale behind their potentially interesting properties and further exploration in the context of microbial and viral infections. Further, the importance of selenoproteins and their role in maintaining a successful immune response along with their association to Se status is summarized.
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Huntington's disease (HD) is a complex progressive neurodegenerative disorder affected by genetic, environmental, and metabolic factors contributing to its pathogenesis. Gut dysbiosis is termed as the alterations of intestinal microbial profile. Emerging research has highlighted the pivotal role of gut dysbiosis in HD, focusing on the gut-brain axis as a novel research parameter in science. This review article provides a comprehensive overview of gut microbiota dysbiosis and its relationship with HD and its pathogenesis along with the future challenges and opportunities. The focuses on the essential mechanisms which link gut dysbiosis to HD pathophysiology including neuroinflammation, immune system dysregulation, altered metabolites composition, and neurotransmitter imbalances. We also explored the impacts of gut dysbiosis on HD onset, severity, and symptoms such as cognitive decline, motor dysfunction, and psychiatric symptoms. Furthermore, we highlight recent advances in therapeutics including microbiota-based therapeutic approaches, including dietary interventions, prebiotics, probiotics, fecal microbiota transplantation, and combination therapies with conventional HD treatments and their applications in managing HD. The future challenges are also highlighted as the heterogeneity of gut microbiota, interindividual variability, establishing causality between gut dysbiosis and HD, identifying optimal therapeutic targets and strategies, and ensuring the long-term safety and efficacy of microbiota-based interventions. This review provides a better understanding of the potential role of gut microbiota in HD pathogenesis and guides the development of novel therapeutic approaches.
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Microbioma Gastrointestinal , Doença de Huntington , Microbiota , Probióticos , Humanos , Microbioma Gastrointestinal/fisiologia , Eixo Encéfalo-Intestino , Disbiose/terapia , Doença de Huntington/terapia , Probióticos/uso terapêuticoRESUMO
Nanotechnology is one of the most appealing area for developing new applications in biotechnology and medicine. For decades, nanoparticles have been extensively studied for a variety of biomedical applications. Silver has evolved into a potent antibacterial agent that can be used in a variety of nanostructured materials of various shapes and sizes. Silver nanoparticles (AgNP) based antimicrobial compounds are employed in a wide range of applications, including medicinal uses, surface treatment and coatings, the chemical and food industries, and agricultural productivity. When designing formulations for specific applications, the size, shape, and surface area of AgNPs are all crucial structural aspects to consider. Different methods for producing AgNPs with varying sizes and forms that are less harmful have been devised. The anticancer, anti-inflammatory, antibacterial, antiviral, and anti-angiogenic properties of AgNPs have been addressed in this review, as well as their generation and processes. Herein, we have reviewed the advances in therapeutic applications of AgNPs, as well as their limitations and barriers for future applications.
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Nanopartículas Metálicas , Prata , Prata/efeitos adversos , Prata/uso terapêutico , Nanopartículas Metálicas/efeitos adversos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Animais , Humanos , Antineoplásicos/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Técnicas Biossensoriais , Hipoglicemiantes/uso terapêuticoRESUMO
BACKGROUND: According to the WHO report of 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer. OBJECTIVE: To find the potential targets of vincamine using a network pharmacology approach and docking studies and to evaluate the anti-cancer effect of vincamine on A549 cell line. METHODS: Hence, in the present study, we explored the anti-cancer potential of vincamine by using network pharmacology, molecular docking, and in vitro approaches. Network pharmacology demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer. RESULTS: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dosedependent (0-500 µM) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 µΜ. The wound-healing assay showed that vincamine treatment (150 and 300 µM) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells. CONCLUSION: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Vincamina , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Vincamina/farmacologia , Vincamina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Proliferação de Células , Apoptose , Receptores Proteína Tirosina Quinases , Receptor ErbB-2RESUMO
Aging bears many hard knocks, but heart disorders earn a particular allusion, being the most widespread. Cardiovascular diseases (CVDs) are becoming the biggest concern to mankind due to sundry health conditions directly or indirectly related to heart-linked abnormalities. Scientists know that mitochondria play a critical role in the pathophysiology of cardiac diseases. Both environment and genetics play an essential role in modulating and controlling mitochondrial functions. Even a minor abnormality may prove detrimental to heart function. Advanced age combined with an unhealthy lifestyle can cause most cardiomyocytes to be replaced by fibrotic tissue which upsets the conducting system and leads to arrhythmias. An aging heart encounters far more heart-associated comorbidities than a young heart. Many state-of-the-art technologies and procedures are already being used to prevent and treat heart attacks worldwide. However, it remains a mystery when this heart bomb would explode because it lacks an alarm. This calls for a novel and effective strategy for timely diagnosis and a sure-fire treatment. This review article provides a comprehensive overture of prospective potentials of mitochondrial miRNAs that predict complicated and interconnected pathways concerning heart ailments and signature compilations of relevant miRNAs as biomarkers to plot the role of miRNAs in epigenomics. This article suggests that analysis of DNA methylation patterns in age-associated heart diseases may determine age-impelled biomarkers of heart disease.
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Doenças Cardiovasculares , Cardiopatias , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Epigenômica , Mitocôndrias/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Biomarcadores/metabolismoRESUMO
Autophagy is essential in regulating the turnover of macromolecules via removing damaged organelles, misfolded proteins in various tissues, including liver, skeletal muscles, and adipose tissue to maintain the cellular homeostasis. In these tissues, a specific type of autophagy maintains the accumulation of lipid droplets which is directly related to obesity and the development of insulin resistance. It appears to play a protective role in a normal physiological environment by eliminating the invading pathogens, protein aggregates, and damaged organelles and generating energy and new building blocks by recycling the cellular components. Ageing is also a crucial modulator of autophagy process. During stress conditions involving nutrient deficiency, lipids excess, hypoxia etc., autophagy serves as a pro-survival mechanism by recycling the free amino acids to maintain the synthesis of proteins. The dysregulated autophagy has been found in several ageing associated diseases including type 2 diabetes (T2DM), cancer, and neurodegenerative disorders. So, targeting autophagy can be a promising therapeutic strategy against the progression to diabetes related complications. Our article provides a comprehensive outline of understanding of the autophagy process, including its types, mechanisms, regulation, and role in the pathophysiology of T2DM and related complications. We also explored the significance of autophagy in the homeostasis of ß-cells, insulin resistance (IR), clearance of protein aggregates such as islet amyloid polypeptide, and various insulin-sensitive tissues. This will further pave the way for developing novel therapeutic strategies for diabetes-related complications.
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Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Agregados Proteicos , Autofagia/fisiologia , Polipeptídeo Amiloide das Ilhotas PancreáticasRESUMO
Sepsis-induced myocardial injury is a consequence of septicemia and is one of the major causes of death in intensive care units. A serum glycoprotein called fetuin-A is secreted largely by the liver, tongue, placenta, and adipose tissue. Fetuin-A has a variety of biological and pharmacological properties. The anti-inflammatory and antioxidant glycoprotein fetuin-A has shown its efficacy in a number of inflammatory disorders including sepsis. However, its protective role against sepsis-induced myocardial injury remains elusive. The purpose of this work is to explore the role of fetuin-A in mouse models of myocardial injury brought on by cecal ligation and puncture (CLP). CLP significantly induced the myocardial injury assessed in terms of elevated myocardial markers (serum CK-MB, cTnI levels), inflammatory markers (IL-6, TNF-α) in the serum, and oxidative stress markers (increased MDA levels and decreased reduced glutathione) in heart tissue homogenate following 24 h of ligation and puncture. Further, hematoxylin and eosin (H&E) staining showed considerable histological alterations in the myocardial tissue of sepsis-developed mice. Interestingly, fetuin-A pretreatment (50 and 100 mg/kg) for 4 days before the CLP procedure significantly improved the myocardial injury and was evaluated in perspective of a reduction in the CK-MB, cTnI levels, IL-6, and TNF-α in sepsis-developed animals. Fetuin-A pretreatment significantly attenuated the oxidative stress and improved the myocardial morphology in a dose-dependent manner. The present study provides preliminary evidence that fetuin-A exerts protection against sepsis-induced cardiac dysfunction in vivo via suppression of inflammation and oxidative damage.
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Sepse , alfa-2-Glicoproteína-HS , Animais , Camundongos , alfa-2-Glicoproteína-HS/uso terapêutico , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Interleucina-6 , Estresse Oxidativo , Sepse/complicações , Sepse/tratamento farmacológico , Fator de Necrose Tumoral alfaRESUMO
Artemisinin and its derivatives, since their discovery by professor Tu Youyou in the early 1970s, have been the bedrock for the management of malaria globally. Recent works have implied that they could be used to manage other diseases including neurodegenerative disorders. Neurodegenerative disorders mainly occur in the adult population resulting from a progressive deterioration of neuronal structures. These include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and Multiple sclerosis (MS), among others. The PI3K/Akt signaling pathway plays a significant role in the central nervous system. It has been investigated extensively for its role in central nervous system physiological processes such as cell survival, autophagy, neuronal proliferation, and synaptic plasticity. Therefore, the modulation of this pathway will be crucial in the management of neurodegenerative disorders. This review seeks to compile most of the research findings on the possible neuroprotective role of artemisinins with special emphasis on their modulatory role on the PI3k/Akt pathway. A literature survey was conducted on PubMed, EBSCO, Web of Science, and EMBASE using the keyword artemisinins, and a total of 10,281 articles were retrieved from 1956 to 2022. Among these, 120 articles were examined using Mesh words like PI3k/Akt, neurodegeneration, and neuroinflammation coupled with boolean operators. Most research revealed that artemisinins could help neurodegenerative disorders by modulating the PI3k/Akt with subsequent inhibition of oxidative stress, neuroinflammation, and apoptosis. This paper illustrates that artemisinins could be repurposed as a neuroprotective agent.
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Artemisininas , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Doenças Neuroinflamatórias , Transdução de Sinais , Doenças Neurodegenerativas/tratamento farmacológico , Artemisininas/farmacologia , Artemisininas/uso terapêuticoRESUMO
Chemical composition of the essential oil (EO) of Eucalyptus tereticornis leaves was studied by gas chromatography-mass spectrometry. Forty-five constituents were identified in the oil hydrodistilled from the sample collected from Ghudda Village, Bathinda (Pb), India of which eucalyptol (34.39%) and ledol (9.92%) were the major constituents. In vitro antioxidant and anticancer potential of EO was analysed by DPPH 2,2-diphenylpicrylhydrazyl (DPPH) and MTT assay. The percentage free radical scavenging activity was found to be 63.77%. The antiproliferative activity was analysed using MTT assay in adenocarcinomic human alveolar basal epithelial A549 cancer cell line and showed IC50 value of 47.14 µg/ml. In silico study of EO, constituents were performed using Maestro 12.9 against EGFR (PDB ID-2RGP). Five constituents from EO showed high dockscore as compared to standard Mobicertinib which indicated the effectiveness of oil constituents against lung cancer.
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Eucalyptus , Neoplasias Pulmonares , Óleos Voláteis , Humanos , Óleos Voláteis/química , Eucalyptus/química , Antioxidantes/química , Eucaliptol/análise , Folhas de Planta/química , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Monkeypox is a zoonotic illness caused by the monkeypox virus (MPXV) that has a similar etiology to smallpox. The first case of monkeypox was reported in Western and Central Africa in 1971, and in 2003, there was an outbreak of monkeypox viruses outside Africa. According to the World Health Organization (WHO) and Center for Disease Control and Prevention (CDC), monkeypox is transmitted through direct contact with infected animals or persons exposed to infectious sores, scabs, or body fluids. Also, intimate contact between people during sex, kissing, cuddling, or touching parts of the body can result in the spreading of this disease. The use of the smallpox vaccine against monkeypox has several challenges and hence anti-virals such as cidofovir, brincidofovir, and tecovirimat have been used for the symptomatic relief of patients and reversing the lesion formation on the skin. Despite the recent outbreak of monkeypox most especially in hitherto non-endemic countries, there is still a lack of definitive treatment for monkeypox. In the present review, emphasis was focused on etiopathology, transmission, currently available therapeutic agents, and future targets that could be explored to halt the progression of monkeypox. From our review we can postulate that owing to the lack of a definitive cure to this reemerging disorder, there is a need for general awareness about the transmission as well as to develop appropriate diagnostic procedures, immunizations, and antiviral medication.
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Mpox , Vacina Antivariólica , Animais , Mpox/diagnóstico , Mpox/epidemiologia , Mpox/tratamento farmacológico , Monkeypox virus , Cidofovir/uso terapêutico , Antivirais/uso terapêuticoRESUMO
INTRODUCTION: Over the past two decades, understanding of hepatic macrophage biology has provided astounding details of their role in the progression and regression of liver diseases. The hepatic macrophages constitute resident macrophages, Kupffer cells, and circulating bone marrow monocyte-derived macrophages, which play a diverse role in liver injury and repair. Imbalance in the macrophage population leads to pathological consequences and is responsible for the initiation and progression of acute and chronic liver injuries. Further, distinct populations of hepatic macrophages and their high heterogeneity make their complex role enigmatic. The unique features of distinct phenotypes of macrophages have provided novel biomarkers for defining the stages of liver diseases. The distinct mechanisms of hepatic macrophages polarization and recruitment have been at the fore front of research. In addition, the secretome of hepatic macrophages and their immune regulation has provided clinically relevant therapeutic targets. AREAS COVERED: Herein, we have highlighted the current understanding in the area of hepatic macrophages, and their role in the progression of liver injury. EXPERT OPINION: It is essential to ascertain the physiological and pathological role of evolutionarily conserved distinct macrophage phenotypes in different liver diseases before viable approaches may see a clinical translation.