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INTRODUCTION: Psoriasis is a chronic immune-mediated disorder affecting over 2-3% of the population worldwide, significantly impacting quality of life. Despite the availability of various therapeutic interventions, concerns persist regarding lesion recurrence and potential alterations in immune surveillance promoting cancer progression. Recent advancements in understanding cellular and molecular pathways have unveiled key factors in psoriasis etiology, including IL-17, 22, 23, TNF-α, PDE-4, JAK-STAT inhibitors, and AhR agonists. This work explores the potential of S-phase kinase-associated protein 2 (Skp2) as a therapeutic target in psoriasis. AREA COVERED: This review covers the current understanding of psoriasis pathophysiology, including immune dysregulation, and the role of keratinocytes and ubiquitin. It also delves into Skp2 role in cell cycle regulation, and its correlation with angiogenesis and ubiquitin in psoriasis. The evolving therapeutic approaches targeting Skp2, including small molecule inhibitors, are also discussed. EXPERT OPINION: Targeting Skp2 holds promise for developing novel therapeutic approaches for psoriasis. By modulating Skp2 activity or expression, it may be possible to intervene in inflammatory and proliferative processes underlying the disease. Further research into Skp2 inhibitors and their efficacy in preclinical and clinical settings is warranted to harness the full potential of Skp2 as a therapeutic target in psoriasis management.
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In recent years, significant advancements have been made in understanding Alzheimer's disease from both neurobiological and clinical perspectives. Exploring the complex systems underlying AD has unveiled insights that could potentially revolutionize therapeutic approaches. Recent investigations have highlighted intricate interactions among genetic, molecular, and environmental factors in AD. Optimism arises from neurobiological advancements and diverse treatment options, potentially slowing or halting disease progression. Amyloid-beta plaques and tau protein tangles crucially influence AD onset and progression. Emerging treatments involve diverse strategies, such as approaches targeting multiple pathways involved in AD pathogenesis, such as inflammation, oxidative stress, and synaptic dysfunction pathways. Clinical trials using humanized monoclonal antibodies, focusing on immunotherapies eliminating amyloid-beta, have shown promise. Nonpharmacological interventions such as light therapy, electrical stimulation, cognitive training, physical activity, and dietary changes have drawn attention for their potential to slow cognitive aging and enhance brain health. Precision medicine, which involves tailoring therapies to individual genetic and molecular profiles, has gained traction. Ongoing research and interdisciplinary collaboration are expected to yield more effective treatments.
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[This retracts the article DOI: 10.1007/s13205-021-02811-x.].
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Postbiotics, the next generation of probiotics, are extracts that are free of living and nonviable bacteria and show strong modulatory effects on the gut flora. Examples include vitamin B12, vitamin K, folate, lipopolysaccharides, enzymes, and short-chain fatty acids (SCFAs), representing a subset of essential nutrients commonly found in the human diet. Postbiotics have been observed to demonstrate antiobesity and antidiabetic effects through a variety of mechanisms. These pathways primarily involve an elevation in energy expenditure, a decrease in the formation and differentiation of adipocytes and food intake, modification of lipid and carbohydrate absorption and metabolism, and regulation of gut dysbiosis. Based on these above effects and mechanisms, the use of postbiotics can be considered as potential strategy for the treatment of metabolic disorders.
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Metabolic Diseases , Probiotics , Humans , Probiotics/therapeutic use , Fatty Acids, Volatile , Bacteria/metabolism , Metabolic Diseases/drug therapy , Energy MetabolismABSTRACT
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder. Approximately, around 2% to 3% percent of the general population experience symptoms of OCD over the course of their lifetime. OCD can lead to economic burden, poor quality of life, and disability. The characteristic features exhibited generally in OCD are continuous intrusive thoughts and periodic ritualized behaviours. Variations in genes, pathological function of Cortico-Striato-Thalamo-Cortical (CSTC) circuits and dysregulation in the synaptic conduction have been the major factors involved in the pathological progression of OCD. However, the basic mechanisms still largely unknown. Current therapies for OCD largely target monoaminergic neurotransmitters (NTs) in specific dopaminergic and serotonergic circuits. However, such therapies have limited efficacy and tolerability. Drug resistance has been one of the important reasons reported to critically influence the effectiveness of the available drugs. Inflammation has been a crucial factor which is believed to have a significant importance in OCD progression. A significant number of proinflammatory cytokines have been reportedly amplified in patients with OCD. Mechanisms of drug treatment involve attenuation of the symptoms via modulation of inflammatory signalling pathways, modification in brain structure, and synaptic plasticity. Hence, targeting inflammatory signaling may be considered as a suitable approach in the treatment of OCD. The present review focuses mainly on the significant findings from the animal and human studies conducted in this area, that targets inflammatory signaling in neurological conditions. In addition, it also focusses on the therapeutic approaches that target OCD via modification of the inflammatory signaling pathways.
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Obsessive-Compulsive Disorder , Quality of Life , Animals , Humans , Obsessive-Compulsive Disorder/diagnosis , Signal Transduction , Brain/metabolism , CognitionABSTRACT
Small-molecule oligonucleotides could be exploited therapeutically to silence the expression of viral infection-causing genes, and a few of them are now in clinical trials for the management of viral infections. The most challenging aspect of these oligonucleotides' therapeutic success involves their delivery. Thus medicinal chemistry strategies are inevitable to avoid degradation by serum nucleases, avoid kidney clearance and improve cellular uptake. Recently small-molecule oligonucleotide design has opened up new avenues to improve the treatment of drug-resistant viral infections, along with the development of COVID-19 medicines. This review is directed toward the recent advances in rational design, mechanism of action, structure-activity relationships and future perspective of the small-molecule oligonucleotides targeting viral infections, including COVID-19.
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COVID-19 , Oligonucleotides , Humans , Oligonucleotides/pharmacology , Oligonucleotides/chemistry , Oligonucleotides/therapeutic use , Chemistry, Pharmaceutical , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic useABSTRACT
Current treatments modalities for major depressive disorder (MDD) mainly target the monoaminergic neurotransmission. However, the therapeutic inadequacy and adverse effects confine the use of these conventional antidepressants to a limited subset of MDD patients. The classical antidepressants are increasingly proving unsatisfactory in tackling the treatment-resistant depression (TRD). Hence, the focus of treatment is shifting to alternative pathogenic pathways involved in depression. Preclinical and clinical evidences accumulated across the last decades have unequivocally affirmed the causative role of immuno-inflammatory pathways in the progression of depression. There is an upsurge in the clinical evaluations of the drugs having anti-inflammatory effects as antidepressants. This review highlights the molecular mechanisms connecting the inflammatory pathways to the MDD and current clinical status of inflammation modulating drugs in the treatment of MDD.
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Depressive Disorder, Major , Depressive Disorder, Treatment-Resistant , Humans , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Depressive Disorder, Treatment-Resistant/drug therapy , Inflammation/drug therapyABSTRACT
Alzheimer's disease (AD) is a complex neurological disorder that results in cognitive decline. The incidence rates of AD have been increasing, particularly among individuals 60 years of age or older. In June 2021, the US FDA approved aducanumab, the first humanized monoclonal antibody, as a potential therapeutic option for AD. Clinical trials have shown this drug to effectively target the accumulation of Aß (beta-amyloid) plaques in the brain, and its effectiveness is dependent on the dosage and duration of treatment. Additionally, aducanumab has been associated with improvements in cognitive function. Biogen, the pharmaceutical company responsible for developing and marketing aducanumab, has positioned it as a potential breakthrough for treating cerebral damage in AD. However, the drug has raised concerns due to its high cost, limitations, and potential side effects. AD is a progressive neurological condition that affects memory, cognitive function, and behaviour. It significantly impacts the quality of life of patients and caregivers and strains healthcare systems. Ongoing research focuses on developing disease-modifying therapies that can halt or slow down AD progression. The pathogenesis of AD involves various molecular cascades and signaling pathways. However, the formation of extracellular amyloid plaques is considered a critical mechanism driving the development and progression of the disease. Aducanumab, as a monoclonal antibody, has shown promising results in inhibiting amyloid plaque formation, which is the primary pathological feature of AD. This review explores the signaling pathways and molecular mechanisms through which aducanumab effectively prevents disease pathogenesis in AD.
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The immune system and inflammation are involved in the pathological progression of various psychiatric disorders such as depression or major depressive disorder (MDD), generalized anxiety disorder (GAD) or anxiety, schizophrenia, Alzheimer's disease (AD), and Huntington's disease. It is observed that levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and other markers are highly increased in the abovementioned disorders. The inflammation and immune component also lead to enhance the oxidative stress. The oxidative stress and increased production of reactive oxygen species (ROS) are considered as important factors that are involved in pathological progression of psychiatric disorders. Increase production of ROS is associated with excessive inflammation followed by cell necrosis and death. The psychotropic drugs are mainly work through modulations of neurotransmitter system. However, it is evident that inflammation and immune modulation are also having important role in the progression of psychiatric disorders. Rationale of the use of current psychotropic drugs is modulation of immune system by them. However, the effects of psychotropic drugs on the immune system and how these might contribute to their efficacy remain largely unclear. The drugs may act through modification of inflammation and related markers. The main purpose of this book chapter is to address the role of current psychotropic drugs on inflammation and immune system. Moreover, it will also address the role of inflammation in the progression of psychiatric disorders.
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Depressive Disorder, Major , Humans , Depressive Disorder, Major/drug therapy , Reactive Oxygen Species , Inflammation/drug therapy , Immune System , Tumor Necrosis Factor-alpha , Psychotropic Drugs/therapeutic useABSTRACT
The human gut microbiota plays a significant role in the pathophysiology of central nervous system-related diseases. Recent studies suggest correlations between the altered gut microbiota and major depressive disorder (MDD). It is proposed that normalization of the gut microbiota alleviates MDD. The imbalance of brain-gut-microbiota axis also results in dysregulation of the hypothalamicpituitary- adrenal (HPA) axis. This imbalance has a crucial role in the pathogenesis of depression. Treatment strategies with certain antibiotics lead to the depletion of useful microbes and thereby induce depression like effects in subjects. Microbiota is also involved in the synthesis of various neurotransmitters (NTs) like 5-hydroxy tryptamine (5-HT; serotonin), norepinephrine (NE) and dopamine (DA). In addition to NTs, the gut microbiota also has an influence on brain derived neurotrophic factor (BDNF) levels. Recent research findings have exhibited that transfer of stress prone microbiota in mice is also responsible for depression and anxiety-like behaviour in animals. The use of probiotics, prebiotics, synbiotics and proper diet have shown beneficial effects in the regulation of depression pathogenesis. Moreover, transplantation of fecal microbiota from depressed individuals to normal subjects also induces depression-like symptoms. With the precedence of limited therapeutic benefits from monoamine targeting drugs, the regulation of brain-gut microbiota is emerging as a new treatment modality for MDDs. In this review, we elaborate on the significance of brain-gut-microbiota axis in the progression of MDD, particularly focusing on the modulation of the gut microbiota as a mode of treating MDD.
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Depressive Disorder, Major , Humans , Mice , Animals , Depressive Disorder, Major/therapy , Anxiety , BrainABSTRACT
Major depressive disorder (MDD) or Depression is one of the serious neuropsychiatric disorders affecting over 280 million people worldwide. It is 4th important cause of disability, poor quality of life, and economic burden. Women are more affected with the depression as compared to men and severe depression can lead to suicide. Most of the antidepressants predominantly work through the modulation on the availability of monoaminergic neurotransmitter (NTs) levels in the synapse. Current antidepressants have limited efficacy and tolerability. Moreover, treatment resistant depression (TRD) is one of the main causes for failure of standard marketed antidepressants. Recently, inflammation has also emerged as a crucial factor in pathological progression of depression. Proinflammatory cytokine levels are increased in depressive patients. Antidepressant treatment may attenuate depression via modulation of pathways of inflammation, transformation in structure of brain, and synaptic plasticity. Hence, targeting inflammation may be emerged as an effective approach for the treatment of depression. The present review article will focus on the preclinical and clinical studies that targets inflammation. In addition, it also concentrates on the therapeutic approaches' that targets depression via influence on the inflammatory signaling pathways. Graphical abstract demonstrate the role of various factors in the progression and neuroinflammation, oxidative stress. It also exhibits the association of neuroinflammation, oxidative stress with depression.
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Depressive Disorder, Major , Male , Humans , Female , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/metabolism , Depression/drug therapy , Neuroinflammatory Diseases , Quality of Life , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Inflammation/drug therapy , Inflammation/metabolismABSTRACT
The human microbiota is fundamental to correct immune system development and balance. Dysbiosis, or microbial content alteration in the gut and respiratory tract, is associated with immune system dysfunction and lung disease development. The microbiota's influence on human health and disease is exerted through the abundance of metabolites produced by resident microorganisms, where short-chain fatty acids (SCFAs) represent the fundamental class. SCFAs are mainly produced by the gut microbiota through anaerobic fermentation of dietary fibers, and are known to influence the homeostasis, susceptibility to and outcome of many lung diseases. This article explores the microbial species found in healthy human gastrointestinal and respiratory tracts. We investigate factors contributing to dysbiosis in lung illness, and the gut-lung axis and its association with lung diseases, with a particular focus on the functions and mechanistic roles of SCFAs in these processes. The key focus of this review is a discussion of the main metabolites of the intestinal microbiota that contribute to host-pathogen interactions: SCFAs, which are formed by anaerobic fermentation. These metabolites include propionate, acetate, and butyrate, and are crucial for the preservation of immune homeostasis. Evidence suggests that SCFAs prevent infections by directly affecting host immune signaling. This review covers the various and intricate ways through which SCFAs affect the immune system's response to infections, with a focus on pulmonary diseases including chronic obstructive pulmonary diseases, asthma, lung cystic fibrosis, and tuberculosis. The findings reviewed suggest that the immunological state of the lung may be indirectly influenced by elements produced by the gut microbiota. SCFAs represent valuable potential therapeutic candidates in this context.
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Asthma , Gastrointestinal Microbiome , Humans , Dysbiosis/metabolism , Fatty Acids, Volatile/metabolism , Fatty Acids, Volatile/therapeutic use , Lung/metabolism , Asthma/drug therapyABSTRACT
Advances in biotechnology have led to improving human health with number of novel approaches to mitigate life-threatening diseases such as human immunodeficiency virus (HIV) infection, cancer, and neurodegenerative diseases. In the case of HIV, the damage caused by the retrovirus to the immune system leads to opportunistic infection as well as an elevated risk of autoimmune disease and cancer. Furthermore, clinical symptoms associated with the virus itself may arise. Antiretroviral drug therapy using reverse transcriptase inhibitors, protease inhibitors, fusion inhibitor, chemokine receptor 5 antagonist and integrase strand transfer inhibitors have shown promising results in treating HIV infection and available in market in the form of various dosage forms. However, they are unable to completely cure the disease because of complexity in pathogenesis of HIV. In addition, these drugs have some limitations of poor solubility, permeability or, poor receptor binding capacity. To overcome these drawbacks, many novel drug delivery systems for the drugs belonging to above mentioned categories have been developed. The possibility of treating HIV infection using CRISPR-Cas9 gene editing has been found in 2015. This provided a new area of research to the scientists who are working towards alternative treatment strategies for HIV infections. The present article describes about various treatment strategies used to treat HIV infections with special emphasis on the role of CRISPR/Cas9 gene-based technology. The potential benefits of specific epigenetic modification in the c-c chemokine receptor 5 gene (CCR5) via various delivery methods are also highlighted.
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HIV Infections , CRISPR-Cas Systems/genetics , Gene Editing/methods , Genetic Therapy/methods , HIV Infections/drug therapy , HIV Infections/genetics , Humans , Receptors, Chemokine/geneticsABSTRACT
Extrachromosomal DNA (ecDNA) is often found in cancerous cells, and numerous scientific investigations have already shown that ecDNA-mediated oncogene amplification which contributes to cancer therapy resistance. This ecDNA is found to be essential for enhancing gene transcription and resistance to chemotherapeutic drugs, as well as promoting tumor heterogeneity and reversing tumor phenotypes, suggesting that it plays a key role in carcinogenesis. The ecDNA induces tumors to become hostile which results in a lower survival rate and chemotherapy tolerance. It also holds the potential as a target for treatment or diagnostic procedure of tumors. The review describes the properties and origins of ecDNA, as well as how it affects carcinogenesis, its function in cancer etiology and progression, and its therapeutic value. Propagation of oncogenes and resistance genes situated in extra-chromosomal DNA has been discovered to become one of the primary causes of intra-tumor genetic heterogeneity and may result in a threshold of probable evolutionary adaptation in many investigations.
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Neoplasms , Oncogenes , Carcinogenesis/genetics , Cell Transformation, Neoplastic/genetics , DNA , Drug Resistance, Neoplasm/genetics , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathologyABSTRACT
The human coronavirus disease (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Natural products, secondary metabolites show positive leads with antiviral and immunotherapy treatments using genomic studies in silico docking. In addition, it includes the action of a mechanism targeting the SARS-CoV-2. In this literature, we aimed to evaluate the antiviral movement of the NT-VRL-1 unique terpene definition to Human coronavirus (HCoV-229E). The effects of 19 hydrolysable tannins on the SARS-CoV-2 were therefore theoretically reviewed and analyzed utilising the molecular operating surroundings for their C-Like protease 3CLpro catalytic dyad residues Angiotensin converting enzyme-2 (MOE 09). Pedunculagin, tercatan, and castalin were detected as interacting strongly with SARS-receptor Cov-2's binding site and catalytic dyad (Cys145 and His41). SARS-CoV-2 methods of subunit S1 (ACE2) inhibit the interaction of the receiver with the s-protein once a drug molecule is coupled to the s-protein and prevent it from infecting the target cells in alkaloids. Our review strongly demonstrates the evidence that natural compounds and their derivatives can be used against the human coronavirus and serves as an area of research for future perspective.
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Biological Products , COVID-19 , Antiviral Agents/pharmacology , Biological Products/pharmacology , Humans , Pandemics , SARS-CoV-2ABSTRACT
Diseases related to the lungs are among the most prevalent medical problems threatening human life. The treatment options and therapeutics available for these diseases are hindered by inadequate drug concentrations at pathological sites, a dearth of cell-specific targeting and different biological barriers in the alveoli or conducting airways. Nanostructured delivery systems for lung drug delivery have been significant in addressing these issues. The strategies used include surface engineering by altering the material structure or incorporation of specific ligands to reach prespecified targets. The unique characteristics of nanoparticles, such as controlled size and distribution, surface functional groups and therapeutic release triggering capabilities, are tailored to specific requirements to overcome the major therapeutic barriers in pulmonary diseases. In the present review, the authors intend to deliver significant up-to-date research in nanostructured therapies in inflammatory lung diseases with an emphasis on biocomposite-based nanoparticles.
Lung-related disorders such as asthma, chronic obstructive pulmonary diseases and pulmonary fibrosis are the result of inflammatory processes in the human body. The causes of these lung diseases can vary from unknown to specific. Chronic obstructive pulmonary disease is most commonly caused by smoking, whereas asthma may be caused by allergens, infections, cold air or smoke. Targeting these lung-related diseases with biologically degradable polymeric nanoparticles has recently been proposed as an effective treatment. These nanoparticles can be made by combining different materials to form biocomposite nanoparticles. Different drugs can be loaded into nanoparticles, and the surface of nanoparticles can be modified to change their properties; for example, to make them target diseased parts of the lung. In this article, the authors discuss current trends in nanoparticle treatment of inflammatory lung diseases, including the significance of biologically degradable materials.
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Lung Diseases , Nanoparticles , Drug Delivery Systems , Humans , Lung/metabolism , Lung Diseases/drug therapy , Nanoparticles/chemistryABSTRACT
Coronavirus disease (COVID-19), a coronavirus-induced illness attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, is thought to have first emerged on November 17, 2019. According to World Health Organization (WHO). COVID-19 has been linked to 379,223,560 documented occurrences and 5,693,245 fatalities globally as of 1st Feb 2022. Influenza A virus that has also been discovered diarrhea and gastrointestinal discomfort was found in the infected person, highlighting the need of monitoring them for gastro intestinal tract (GIT) symptoms regardless of whether the sickness is respiration related. The majority of the microbiome in the intestines is Firmicutes and Bacteroidetes, while Bacteroidetes, Proteobacteria, and Firmicutes are found in the lungs. Although most people overcome SARS-CoV-2 infections, many people continue to have symptoms months after the original sickness, called Long-COVID or Post COVID. The term "post-COVID-19 symptoms" refers to those that occur with or after COVID-19 and last for more than 12 weeks (long-COVID-19). The possible understanding of biological components such as inflammatory, immunological, metabolic activity biomarkers in peripheral blood is needed to evaluate the study. Therefore, this article aims to review the informative data that supports the idea underlying the disruption mechanisms of the microbiome of the gastrointestinal tract in the acute COVID-19 or post-COVID-mediated elevation of severity biomarkers.
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COVID-19 , Gastrointestinal Diseases , Gastrointestinal Microbiome , Biomarkers , COVID-19/complications , Humans , SARS-CoV-2 , Post-Acute COVID-19 SyndromeABSTRACT
Objectives: The study aimed to explore the in vivo protective potential of rosuvastatin (ROSS), an oral antihyperlipidemic drug against doxorubicin (DOXO) induced cardio toxicity in rats. Materials and Methods: Cardiac toxicity was induced by DOXO injection (10 mg/kg, i.p.), once on the 20th day of the experiment. Except for the control rats, all were received DOXO and the study was continued for up to 21 days. The influence of ROSS on acute treatment was analyzed by quantification of cardiac marker enzymes such as creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and liver marker enzymes like aspartate aminotransferase (AST), alanine aminotransferase (ALT) along with the measurement of in vivo antioxidants like superoxide dismutase and catalase. To observe histological changes of myocardial tissue hematoxylin and eosin staining were used. Results: Acute administration of DOXO resulted in a marked rise of cardiac marker enzymes that confirms the myocardial damage compared to control animals whereas administration of ROSS (10 mg/kg, p.o.) resulted in the significant reduction of CK-MB, LDH levels (p<0.05) and AST, ALT levels to a remarkable extent. Moreover, ROSS administration significantly increased the activities of various in vivo antioxidant levels. Conclusion: From the results, the acute administration of ROSS showed significant cardioprotective property, which was evidenced by a significant reduction of cardiac and liver marker enzymes along with significant improvement of in vivo antioxidant activities. Furthermore the results were supported with histopathological observations. Hence, it can be concluded that cardioprotective potential of ROSS may be through attenuation of oxidative stress by modulating oxidative damage in rats.