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This overview of the molecular pathology of lung cancer includes a review of the most salient molecular alterations of the genome, transcriptome, and the epigenome. The insights provided by the growing use of next-generation sequencing (NGS) in lung cancer will be discussed, and interrelated concepts such as intertumor heterogeneity, intratumor heterogeneity, tumor mutational burden, and the advent of liquid biopsy will be explored. Moreover, this work describes how the evolving field of molecular pathology refines the understanding of different histologic phenotypes of non-small-cell lung cancer (NSCLC) and the underlying biology of small-cell lung cancer. This review will provide an appreciation for how ongoing scientific findings and technologic advances in molecular pathology are crucial for development of biomarkers, therapeutic agents, clinical trials, and ultimately improved patient care.

• Genodermatoses are a broad spectrum of heritable disorders that affect the skin, and may or may not affect other organ systems. • Classification and nomenclature of these disorders is evolving as we learn more about the genetic basis and pathogenesis of these conditions. • Genodermatoses that present in the neonatal period are discussed in this chapter.

A new section on the approach to diagnostic histological interpretation, is the overture to this chapter on inherited and developmental disorders. This initial section is split chronologically into the early neonatal and infantile period and later childhood and adulthood; with the intention of reflecting clinical practice as closely and succinctly as possible. Disorders of the biliary tree, bile formation and secretion, and hepatocyte metabolism are the core of this chapter, a merger of chapters 3 and 4 of the previous edition. Considerations on the pathogenetic and/or clinical overlap between developmental, genetic and metabolic disorders were the rationale behind this change. The complexity of hepatocyte metabolism is reflected into the miriad of related pathological conditions. Recent technological advances, particularly in genomics in the last five years, have resulted in a plethora of new entities and changes in terminology, challenging the authors to balance detail and application to clinical practice. Tables and figures from previous editions have been largely kept due to their quality and contemporary relevance, whilst new ones have been added to accommodate new advances (e.g. classification of mitochondrial disorders), a compromise to bridge between the two editions for the accustomed reader. Liver involvement in immunodeficiency and miscellaneous disorders precede the final section on anatomical anomalies. Vascular anomalies are now included in the chapters on vascular disorders.

Studying the placenta can provide information about the mechanistic pathways of pregnancy disease. However, analyzing placental tissues and manipulating placental function in real-time during pregnancy is not feasible. The ex vivo placental perfusion model allows observing important aspects of the physiology and pathology of the placenta, while maintaining its viability and functional integrity, and without causing harm to mother or fetus. In this review, we describe and compare setups for this technically complex model and summarize outcomes from various published studies. We hope that our review will encourage wider use of ex vivo placental perfusion, which in turn would generate more knowledge to improve pregnancy outcomes.

Purpose: Intestinal fibrosis is a common complication of inflammatory bowel diseases. However, the possible involvement of epithelial-mesenchymal transition (EMT) has been scarcely investigated. This systematic review aims to search through research papers that are focusing on messenger RNA (mRNA) and protein expression profile in EMT in fistula or in intestinal fibrosis.Methods: Electronic exploration was performed until April 24, 2019 through PubMed, Ovid, Science Direct, and Scopus databases with the terms of “fistula” OR “intestinal fibrosis” AND “epithelial-mesenchymal transition”. Two independent reviewers scrutinized the suitability of the title and abstract before examining the full text that met the inclusion criteria. For each study, the sample types that were used, methods for analysis, and genes expressed were identified. The list of genes was further analyzed using DAVID (Database for Annotation, Visualization, and Integrated Discovery) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway.Results: There were 896 citations found; however, only 3 studies fulfilled the requirements. Among the EMT-related genes, 5 were upregulated genes at mRNA level while 6 were at protein level. However, only 2 downregulated genes were found at each mRNA and protein level. Of the 4 inflammation-related genes found, 3 genes were upregulated at mRNA level and 1 at protein level. These genes were confirmed to be involved in the development of inflammatory induced fibrosis and fistula through EMT. Results from quantitative real-time polymerase chain reaction analysis were consistent with the process of EMT, confirmed by the western blot protein analysis.Conclusion: Many significant genes which are involved in the process of EMT in fistula and intestinal fibrosis have been identified. With high-end technology many more genes could be identified. These genes will be good molecular targets in the development of biomarkers for precision drug targeting in the future treatment of intestinal fibrosis and fistula.

Dietary nutrients are associated with the development of cardiovascular disease (CVD) both through traditional pathways (inducing hyperlipidemia and chronic inflammation) and through the emergence of a metaorganism-pathogenesis pathway (through the gut microbiota, its metabolites, and host). Several molecules from food play an important role as CVD risk-factor precursors either themselves or through the metabolism of the gut microbiome. Animal-based dietary proteins are the primary source of CVD risk-factor precursors; however, some plants also possess these precursors, though at relatively low levels compared with animal-source food products. Various medications have been developed to treat CVD through the gut-microbiota–circulation axis, and they exhibit potent effects in CVD treatment. Nevertheless, such medicines are still being improved, and there are many research gaps that need to be addressed. Furthermore, some medications have unpleasant or adverse effects. Numerous foods and herbs impart beneficial effects upon health and disease. In the past decade, many studies have focused on treating and preventing CVD by modulating the gut microbiota and their metabolites. This review provides an overview of the available information, summarizes current research related to the gut-microbiota–heart axis, enumerates the foods and herbs that are CVD-risk precursors, and illustrates how metabolites become CVD risk factors through the metabolism of gut microbiota. Moreover, we present perspectives on the application of foods and herbs—including prebiotics, probiotics, synbiotics, postbiotics, and antibiotic-like substances—as CVD prevention agents to modulate gut microbiota by inhibiting gut-derived CVD risk factors. Taxonomy (classification by EVISE) Cardiovascular disease, gut microbiota, herbal medicine, preventive medicine, dietary therapy, nutrition supplements.

Clozapine is an atypical antipsychotic used in refractory schizophrenia, also efficient in alleviating dyskinesia in Parkinson’s disease. Despite its potency, this drug is associated with severe metabolic side effects, including increased risk for diabetes. We report the case of a 45-year-old overweight woman with Parkinson’s disease who presented with rapid-onset hyperglycaemia within 2 months after starting clozapine for refractory dyskinaesia. She had a history of gestational diabetes. At presentation, her blood glucose level was 505 mg/dL and glycated haemoglobin 12.4%, with no catabolic symptoms. Clozapine was suspended and metformin was started, but adequate glycaemic control was achieved only with insulin therapy, along with exenatide and empagliflozin afterwards. We assume that clozapine acted as a trigger for rapid deterioration of glycaemic control through direct pathophysiological mechanisms, rather than an indirect slowly evolving weight gain-related metabolic syndrome pathway. Clinicians should be aware of this complication, enabling timely diagnosis and proper treatment.

Growing evidence from animal and human studies show that opioids have a major impact on the composition and function of gut microbiota. This leads to disruption in gut permeability and altered microbial metabolites, driving both systemic and neuroinflammation, which in turn impacts central nervous system (CNS) homeostasis. Tolerance and dependence are the major comorbidities associated with prolonged opioid use. Inflammatory mediators and signaling pathways have been implicated in both opioid tolerance and dependence. We provide evidence that targeting the gut microbiome during opioid use through prebiotics, probiotics, antibiotics, and fecal microbial transplantation holds the greatest promise for novel treatments for opioid abuse. Basic research and clinical trials are required to examine what is more efficacious to yield new insights into the role of the gut-brain axis in opioid abuse.

Glucagon-like peptide-1(GLP-1) is a multifunctional polypeptide throughout the lifespan via activating Glucagon-like peptide-1 receptor (GLP-1R).GLP-1 can affect food ingestion, enhance the secretion of insulin from pancreatic islets induced by glucose and be utilized to treat type 2 diabetes mellitus(T2DM).But, accumulating evidences from the decades suggest that activation GLP-1R can not only regulate the blood glucose, but also sustain the homeostasis of intracellular environment and protect neuron from various damaged responses such as oxidative stress, inflammation, excitotoxicity, ischemia and so on. And more and more pre-clinical and clinical studies identified that GLP-1 and its analogues may play a significant role in improving multiple central nervous system (CNS) diseases including neurodegenerative diseases, epilepsy, mental disorders, ischemic stroke, hemorrhagic stroke, traumatic brain injury, spinal cord injury, chronic pain, addictive disorders, other diseases neurological complications and so on. In order to better reveal the relationship between GLP-1/GLP-1R axis and the growth, development and survival of neurons, herein, this review is aimed to summarize the multi-function of GLP-1/GLP-1R axis in CNS diseases.

Objective Patients with systemic lupus erythematosus (SLE) display symptoms that are not always related to disease activity and may distort clinical trial results. Recently, a clinical categorization based on the presence of type 1 (inflammatory manifestations) and/or type 2 (widespread pain, fatigue, depression) symptoms has been proposed in SLE. Our aim was to develop a type 2 score derived from the Short-Form health survey (SF-36) to categorize SLE patients and to compare immunological and transcriptomic profiles between groups. Methods Seventeen items from the SF-36 were selected to build a type 2 score for 50 SLE patients (100 visits; LUPUCE cohort) and the SLEDAI was used to define type 1 symptoms. Patients were categorized in four groups: minimal (no symptoms), type 1, type 2 and mixed (both type 1 and type 2 symptoms). Clinical, immunological and transcriptomic profiles were compared between the groups. Results Type 2 scores ranged from 0 to 31, with a cut-off value of 14 (75th percentile). The sample categorization was: minimal in 39%, type 1 in 37%, type 2 in 9% and mixed in 15%. Type 2 patients were older than minimal patients and had a longer disease duration than type 1 and mixed patients. Immunological data and modular interferon signatures did not differ between the groups. Conclusion Patients with SLE can be categorized into four clinical groups using the SLEDAI score and our SF-36-derived type 2 score. This categorization is non-redundant with immunological or transcriptomic profiles and could prove useful to stratify patients in clinical trials.

Danon disease (DD) is an X-linked multisystem disorder with clinical features characterized by the triad of hypertrophic cardiomyopathy, skeletal muscle weakness, and mental retardation. Cardiac involvement can be fatal in the absence of an effective treatment option such as heart transplantation. Molecular studies have proved that LAMP-2 protein deficiency, mainly LAMP-2B isoform, resulting from LAMP2 gene mutation, is the culprit for DD. Autophagy impairment due to LAMP-2 deficiency mediated the accumulation of abnormal autophagic vacuoles in cells. While it is not ideal for mimicking DD phenotypes in humans, the emergence of LAMP-2-deficient animal models and induced pluripotent stem cells from DD patients provided powerful tools for exploring DD mechanism. In both in vitro and in vivo studies, much evidence has demonstrated that mitochondria dysfunction and fragmentation can result in DD pathology. Fundamental research contributes to the therapeutic transformation. By targeting the molecular core, several potential therapies have demonstrated promising results in partial phenotypes improvement. Among them, gene therapies anticipate inaugurate a class of symptom control and prevention drugs as their in vivo effects are promising, and one clinical trial is currently underway.

Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience, such as tingling and burning sensation, hyperalgesia, numbness, etc. Globally, 50-60% of the diabetic population is suffering from such symptoms as microvascular complications. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in the homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions, causing neuropathy. Among these, pathways like Polyol and PARP are some of the most intensively studied ones whereas those like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in the management of DPN. This review, hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for the treatment of DPN.

Spinal muscular atrophy (SMA) is a rare neuromuscular condition, characterized by loss of motor neurons as a result of a mutation in the survival motor neuron gene. This results in muscle wasting and in the most common and severe type, death before 24 months. Over the recent years there has been a dynamic shift in the therapeutic options for these patients involving both clinical trials in genetic modifying therapies to indirectly improve the survival motor neuron protein level and hence strength, muscle promotor therapies, up/down regulation of modifier genes and more recently gene therapy to replace the mutated survival motor neuron gene. This review addresses the pathogenesis of SMA and the resultant therapeutic approaches as well as the current state in clinical trials and future development.

In this recent publication review the authors aimed to collect evidence of impact of nonsynonymous single nucleotide polymorphisms (nsSNP) in the renin–angiotensin–aldosterone system on patients’ phenotype not only regarding arterial hypertension and its complications, but also the impact on other diseases of interest outside the field of cardiovascular medicine. PubMed database records published between 2017–2020 were searched and all positive case-control studies or positive studies with human DNA were selected. The search identified 104 articles, of which 22 were included on the basis of the inclusion criteria. This paper presents the impact of 44 nsSNPs in panels for genes of renin, angiotensinogen, angiotensin-converting enzyme, angiotensin receptor and aldosterone on the clinical picture of investigated cohorts or on the peptide-protein interactions as consequence of nsSNPs. Genetic variability in nsSNPs of the RAAS is involved in the pathogenesis of arterial hypertension and its complications, and surprisingly also in the pathogenesis of conditions not associated with elevated blood pressure, like neoplasms or inflammatory diseases.

Introduction Adolescent idiopathic scoliosis (AIS) is a multifactorial condition with genetic predisposing factors, and several causes have been put forward for its aetiopathogenesis, including possible hormonal dysfunction. Melatonin seems to play significant role in AIS. Methods A systematic search in different database, to July 2021, was performed to define the role of melatonin in the pathophysiology of adolescent idiopathic scoliosis. Eight suitable studies were identified. Results The concentration and rhythm of melatonin secretion can play an important role by influencing the pathogenesis of adolescent idiopathic scoliosis. Conclusions Although there are many alterations of melatonin in subjects with adolescent idiopathic scoliosis, the many variables present do not allow to establish a direct cause–effect relationship. Level of evidence Level IV.

Inflammation is a natural process that occurs in the organism in response to harmful external agents. Despite being considered beneficial, exaggerated cases can cause severe problems for the body. The main inflammatory manifestations are pain, increased temperature, edema, decreased mobility, and quality of life for affected individuals. Diseases such as arthritis, cancer, allergies, infections, arteriosclerosis, neurodegenerative diseases, and metabolic problems are mainly characterized by an exaggerated inflammatory response. Inflammation is related to two categories of substances: pro- and anti-inflammatory mediators. Among the pro-inflammatory mediators is Tumor Necrosis Factor-α (TNF-α). It is associated with immune diseases, cancer, and psychiatric disorders which increase its excretion. Thus, it becomes a target widely used in discovering new antiinflammatory drugs. In this context, secondary metabolites biosynthesized by plants have been used for thousands of years and continue to be one of the primary sources of new drug scaffolds against inflammatory diseases. To decrease costs related to the drug discovery process, Computer-Aided Drug Design (CADD) techniques are broadly explored to increase the chances of success. In this review, the main natural compounds derived from alkaloids, flavonoids, terpene, and polyphenols as promising TNF-α inhibitors will be discussed. Finally, we applied a molecular modeling protocol involving all compounds described here, suggesting that their interactions with Tyr59, Tyr119, Tyr151, Leu57, and Gly121 residues are essential for the activity. Such findings can be useful for research groups worldwide to design new anti-inflammatory TNF-α inhibitors.

The interaction between gut microbes and gastrointestinal (GI) tract carcinogenesis has always attracted researchers' attention to identify therapeutic targets or potential prognostic biomarkers. Various studies have suggested that the microbiota do show inflammation and immune dysregulation, which led to carcinogenesis in GI tract. In this review, we have focused on the role of microbes present in the gut, intestine, or faeces in GI tract cancers, including esophageal cancer, gastric cancer, and colorectal cancer. Herein, we have discussed the importance of the microbes and their metabolites, which could serve as diagnostic biomarkers for cancer detection, especially in the early stage, and prognostic markers. To maximize the effect of the treatment strategies, an accurate evaluation of the prognosis is imperative for clinicians. There is a vast difference in the microbiota profiles within a population and across the populations depending upon age, diet, lifestyle, genetic makeup, use of antibiotics, and environmental factors. Therefore, the diagnostic efficiency of the microbial markers needs to be further validated. A deeper understanding of the GI cancer and the host microbiota is needed to acquire pivotal information about disease status.

Significance: Nonhealing wounds are a significant burden for the health care system all over the world. Existing treatment options are not enough to promote healing, highlighting the urgent need for improved therapies. In addition, the current advancements in tissue-engineered skin constructs and stem cell-based therapies are facing significant hurdles due to the absence of a renewable source of functional cells. Recent Advances: Induced pluripotent stem cell technology (iPSC) is emerging as a novel tool to develop the next generation of personalized medicine for the treatment of chronic wounds. The iPSC provides unlimited access to various skin cells to generate complex personalized three-dimensional skin constructs for disease modeling and autologous grafts. Furthermore, the iPSC-based therapies can target distinct wound healing phases and have shown accelerating wound closure by enhancing angiogenesis, cell migration, tissue regeneration, and modulating inflammation. Critical Issues: Since the last decade, iPSC has been revolutionizing the field of wound healing and skin tissue engineering. Despite the current progress, safety and heterogeneity among iPSC lines are still major hurdles in addition to the lack of large animal studies. These challenges need to be addressed before translating an iPSC-based therapy to the clinic. Future Directions: Future considerations should be given to performing large animal studies to check the safety and efficiency of iPSC-based therapy in a wound healing setup. Furthermore, strategies should be developed to overcome variation between hiPSC lines, develop an efficient manufacturing process for iPSC-derived products, and generate complex skin constructs with vasculature and skin appendages.

Pancreatic carcinoma is associated with one of the worst clinical outcomes throughout the globe because of its aggressive, metastatic, and drug-resistant nature. During the past decade, several studies have shown that oral, gut, and tumor microbiota play a critical role in the modulation of metabolism and immune responses. Growing pieces of evidence have proved beyond a doubt that the microbiota has a unique ability to influence the tumor microenvironment as well as the metabolism of chemotherapeutic agents or drugs. Given this, microbiota, known as the ecological community of microorganisms, stands to be an avenue of quality research. In this review, we provide detailed and critical information on the role of oral, gut, and pancreatic microbiota disruptions in the development of pancreatic carcinoma. Moreover, we comprehensively discuss the different types of microbiota, their potential role, and mechanism associated with pancreatic carcinoma. The microbiome provides the unique opportunity to enhance the effectiveness of chemotherapeutic agents and immunotherapies for pancreatic cancer by maintaining the right type of microbiota and holds a promising future to enhance the clinical outcomes of patients with pancreatic carcinoma.

The active role of bacteria in oncogenesis has long been a topic of debate. Although, it was speculated to be a transmissible cause of cancer as early as the 16th-century, yet the idea about the direct involvement of bacteria in cancer development has only been explored in recent decades. More recently, several studies have uncovered the mechanisms behind the carcinogenic potential of bacteria which are inflammation, immune evasion, pro-carcinogenic metabolite production, DNA damage and genomic instability. On the other side, the recent development on the understanding of tumor microenvironment and technological advancements has turned this enemy into an ally. Studies using bacteria for cancer treatment and detection have shown noticeable effects. Therapeutic abilities of bioengineered live bacteria such as high specificity, selective cytotoxicity to cancer cells, responsiveness to external signals and control after ingestion have helped to overcome the challenges faced by conventional cancer therapies and highlighted the bacterial based therapy as an ideal approach for cancer treatment. In this review, we have made an effort to compile substantial evidence to support the multidimensional role of bacteria in cancer. We have discussed the multifaceted role of bacteria in cancer by highlighting the wide impact of bacteria on different cancer types, their mechanisms of actions in inducing carcinogenicity, followed by the diagnostic and therapeutic potential of bacteria in cancers. Moreover, we have also highlighted the existing gaps in the knowledge of the association between bacteria and cancer as well as the limitation and advantage of bacteria-based therapies in cancer. A better understanding of these multidimensional roles of bacteria in cancer can open up the new doorways to develop early detection strategies, prevent cancer, and develop therapeutic tactics to cure this devastating disease.

Cancer is one of the leading global causes of death in both men and women. Colorectal cancer (CRC) alone accounts for ∼10 % of total new global cases and poses an over 4% lifetime risk of developing cancer. Recent advancements in the field of biotechnology and microbiology concocted novel microbe-based therapies to treat various cancers, including CRC. Microbes have been explored for human use since centuries, especially for the treatment of various ailments. The utility of microbes in cancer therapeutics is widely explored, and various bacteria, fungi, and viruses are currently in use for the development of cancer therapeutics. The human gut hosts about 100 trillion microbes that release their metabolites in active, inactive, or dead conditions. Microbial secondary metabolites, proteins, immunotoxins, and enzymes are used to target cancer cells to induce cell cycle arrest, apoptosis, and death. Various approaches, such as dietary interventions, the use of prebiotics and probiotics, and fecal microbiota transplantation have been used to modulate the gut microbiota in order to prevent or treat CRC pathogenesis. The present review highlights the role of the gut microbiota in CRC precipitation, the potential mechanisms and use of microorganisms as CRC biomarkers, and strategies to modulate microbiota for the prevention and treatment of CRC.

The intentional use of viruses for cancer therapy dates back over a century. As viruses are inherently immunogenic and naturally optimized delivery vehicles, repurposing viruses for drug delivery, tumor antigen presentation, or selective replication in cancer cells represents a simple and elegant approach to cancer treatment. While early virotherapy was fraught with harsh side effects and low response rates, virus-based therapies have recently seen a resurgence due to newfound abilities to engineer and tune oncolytic viruses, virus-like particles, and virus-mimicking nanoparticles for improved safety and efficacy. However, despite their great potential, very few virus-based therapies have made it through clinical trials. In this review, we present an overview of virus-inspired approaches for cancer therapy, discuss engineering strategies to enhance their mechanisms of action, and highlight their application for overcoming the challenges of traditional cancer therapies.

There is an increase in the incidence of cardiovascular diseases with aging and it is one of the leading causes of death worldwide. The main cardiovascular pathologies include atherosclerosis, myocardial infarction, hypertension and stroke. Chronic inflammation is one of the significant contributors to the age-related vascular diseases. Therefore, it is important to understand the molecular mechanisms of the persistent inflammatory conditions occurring in the blood vessels as well as the signaling pathways involved. Herein, we performed an extant search of literature involving PubMed, ISI, WoS and Scopus databases for retrieving all relevant articles with the most recent findings illustrating the potential role of various inflammatory mediators along with their proposed activated pathways in the pathogenesis and progression of vascular aging. We also highlight the major pathways contributing to age-related vascular disorders. The outlined molecular mechanisms, pathways and mediators of vascular aging represent potential drug targets that can be utilized to inhibit and/or slow the pathogenesis and progression of vascular aging.

Chronic, non-healing, dermal wounds form a worldwide medical problem with limited and inadequate treatment options and high societal burden and costs. With the advent of regenerative therapies exploiting extracellular matrix (ECM) components, its efficacy to augment wound healing is to be explored. This systematic review was performed to assess and compare the current therapeutic efficacy of ECM hydrogels on dermal wound healing. The electronic databases of Embase, Medline Ovid, and Cochrane Central were searched for in vivo and clinical studies on the therapeutic effect of ECM-composed hydrogels on dermal wound healing (April 13, 2021). Two reviewers selected studies independently. Studies were assessed based on ECM content, ECM hydrogel composition, additives, and wound healing outcomes, such as wound size, angiogenesis, and complications. Of the 2102 publications, 9 rodent-based studies were included while clinical studies were not published at the time of the search. Procedures to decellularize tissue or cultured cells and subsequently generate hydrogels were highly variable and in demand of standardization. ECM hydrogels with or without additives reduced wound size and also seem to enhance angiogenesis. Serious complications were not reported. To date, preclinical studies preclude to draw firm conclusions on the efficacy and working mechanism of ECM-derived hydrogels on dermal wound healing. The use of ECM hydrogels can be considered safe. Standardization of decellularization protocols and implementation of quality and cytotoxicity controls will enable obtaining a generic and comparable ECM product. Impact statementExtracellular matrix (ECM)-based hydrogels are biocompatible and harbor growth factors that can instruct tissue healing. Their application is a novelty in (pre)clinical wound healing treatment. This systematic review provides an overview of the current evidence for ECM hydrogels in enhancing wound healing and an extensive overview of the decellularization procedures used. Lastly, challenges and future directions to standardize decellularization procedures and implement quality controls are proposed.

Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed.Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed.All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high.Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness.

Acute Lung Injury (ALI) and its severe form Acute Respiratory Distress Syndrome (ARDS) are the major cause of ICU death worldwide. ALI/ARDS is characterized by severe hypoxemia and inflammation that leads to poor lung compliance. Despite many advances in understanding and management, ALI/ARDS is still causing significant morbidity and mortality. Long non-coding RNA (lncRNA) is a fast-growing topic in lung inflammation and injury. lncRNA is a class of non-coding RNA having a length of more than 200 nucleotides. It has been a center of research for understanding the pathophysiology of various diseases in the past few years. Multiple studies have shown that lncRNAs are abundant in acute lung injury/injuries in mouse models and cell lines. By targeting these long non-coding RNAs, many investigators have demonstrated the alleviation of ALI in various mouse models. Therefore, lncRNAs show great promise as a therapeutic target in ALI. This review provides the current state of knowledge about the relationship between lncRNAs in various biological processes in acute lung injury and its use as a potential therapeutic target.

Significance: Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with...

We report the case of a 21-year-old female patient with unilateral acute macular neuroretinopathy (AMN) two days after the administration of the Oxford-AstraZeneca COVID-19 vaccination.

There is increasing evidence that dsyregulated epigenetic mechanisms of gene expression are involved in the pathogenesis of attention deficit hyperactivity disorder (ADHD). This review presents a comprehensive summary of the current state of research on the role of epigenetics in the pathogenesis of ADHD. The potential role of epigenetic drugs in the treatment of ADHD is also reviewed. Several studies suggest there are epigenetic abnormalities in preclinical models of ADHD and in ADHD patients. Regarding DNA methylation many studies have reported DNA hypermethylation. There is evidence that there is increased histone deacetylation in ADHD patients. Abnormalities in the expression of microRNAs (miRNAs) in ADHD patients have also been found. Some currently used drugs for treating ADHD, in addition to their more well established mechanisms of action, have been shown to alter epigenetic mechanisms of gene expression. Clinical trials of epigenetic drugs in patients with ADHD are reporting favorable results. These data suggest that abnormal epigenetic mechanisms of gene expression may be involved in the pathogenesis of ADHD. Drugs acting on epigenetic mechanisms may be a potential new class of drugs for treating ADHD.

Aging promotes a range of degenerative pathologies characterized by progressive losses of tissue and/or cellular function. Fibrosis is the hardening, overgrowth and scarring of various tissues characterized by the accumulation of extracellular matrix components. Aging is an important predisposing factor common for fibrotic heart and respiratory disease. Age-related processes such as senescence, inflammaging, autophagy and mitochondrial dysfunction are interconnected biological processes that diminish the regenerative capacity of the aged heart and lung and have been shown to play a crucial role in cardiac fibrosis and idiopathic pulmonary fibrosis. This review focuses on these four processes of aging in relation to their role in fibrosis. It has long been established that the heart and lung are linked both functionally and anatomically when it comes to health and disease, with an ever-expanding aging population, the incidence of fibrotic disease and therefore the number of fibrosis-related deaths will continue to rise. There are currently no feasible therapies to treat the effects of chronic fibrosis therefore highlighting the importance of exploring the processes of aging and its role in inducing and exacerbating fibrosis of each organ. The focus of this review may help to highlight potential avenues of therapeutic exploration.

Congenital cataract can be caused by several systemic diseases and differential diagnosis should be done between infections, genetic or metabolic diseases. We present a case of a 12-month-old girl with bilateral nuclear cataracts that was referred for investigation. Since she did not present a family history of congenital cataracts or metabolic diseases, and her physical examination was normal, a systemic evaluation was performed. Biochemical studies disclosed abnormal galactose metabolism signs. The diagnosis of galactokinase (GALK1) deficiency was considered and the study of the GALK1 gene allowed identifying a pathogenic genetic variant and a predictably pathogenic missense mutation, previously not described. Dietary measures were imposed with a good evolution.

Abstract: Ketogenic diet and ketone bodies gained significant attention in recent years due to their ability to influence the specific energy metabolism and restoration of mitochondrial homeostasis that can help in hindering the progression of many metabolic diseases, including diabetes and neurodegenerative diseases. A ketogenic diet consists of high fat and low carbohydrate contents, which makes the body glucose deprived and rely on alternative sources (ketone bodies) for energy. It has been initially designed and supplemented for the treatment of epilepsy, and, later, its influence on many energyderiving biochemical pathways made it a highly sorted food supplement for many metabolic diseases and even for bodybuilding and calorie restriction in healthy individuals. Among the reported therapeutic action over a range of diseases, neurodegenerative disorders, especially Alzheimer’s disease, gained the attention of many researchers and clinicians because of the higher benefits of the ketogenic diet on this disease. Complex pathology and multiple influencing factors of Alzheimer’s disease make exploration of its therapeutic strategies a demanding task. It was a common phenomenon that energy deprivation in neurological disorders, including Alzheimer’s disease, progress rapidly. The ability of ketone bodies to stabilize the mitochondrial energy metabolism makes it a suitable intervening agent. In this review, we will discuss various research progress made with regards to ketone bodies/ketogenic diet for the management of Alzheimer’s disease and elaborate in detail about the mechanisms that are influenced during their therapeutic action.

Alzheimer’s Disease (AD) is one of the most common neurodegenerative diseases, which affects millions of people worldwide. Accumulation of amyloid-β plaques and hyperphosphorylated neurofibrillary tangles are the key mechanisms involved in the etiopathogenesis of AD, characterized by memory loss and behavioural changes. Effective therapies targeting AD pathogenesis are limited, making it the largest unmet clinical need. Unfortunately, the available drugs provide symptomatic relief and primary care, with no substantial impact on the disease pathology. However, in recent years researchers are working hard on several potential therapeutic targets to combat disease pathogenesis, and few drugs have also reached clinical trials. In addition, drugs are being repurposed both in the preclinical and clinical studies for the treatment of AD. For instance, montelukast is the most commonly used leukotriene receptor antagonist for treating asthma and seasonal allergy. Its leukotriene antagonistic action can also be beneficial for the reduction of detrimental effects of leukotriene against neuro-inflammation, a hallmark feature of AD. The available marketed formulations of montelukast present challenges such as poor bioavailability and reduced uptake, reflecting the lack of effectiveness of its desired action in the CNS. While on the other side, targeted drug delivery is a satisfactory approach to surpass the challenges associated with the therapeutic agents. This review will discuss the enhancement of montelukast treatment efficacy and its access to CNS by using new approaches like nano-formulation, nasal gel, solid lipid formulation, nano-structure lipid carrier (NSLC), highlighting lessons learned to target AD pathologies and hurdles that persist.

Introduction: Traumatic brain injury (TBI) has become the signature wound of recent military operations and training over the past two decades. A treatment that would protect against secondary brain injury in TBI and improve the long-term functional outcomes of traumatic brain injury on service personnel is therefore of great interest. One agent that has shown promise in modifying the post-traumatic neuroinflammatory response in murine closed-head injury models of TBI is a novel, small 5 amino acid apolipoprotein E (ApoE) mimetic peptide, CN-105. The goal of this study was to determine whether CN-105 would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model.Materials and Methods: CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) to > 99% purity. We examined the efficacy of prophylactic administration of CN-105 in a well-established closed head injury model associated with reproducible vestibulomotor deficits. CN-105 was dissolved in sterile 0.9% saline and administered to male 12 week old C57-BL/6 mice intravenously (IV) through a tail vein and/or by intraperitoneal (IP) injection in a volume of 100 microliters at various time points prior to injury. Vehicle treated animals received IV and/or IP injection of 100 microliters of normal saline at the same time points. Animals were randomly assigned to treatment groups immediately following injury and all behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy). An in vivo assessment of the pharmacokinetics of CN-105 following IV or IP administration in healthy fed adult male CD-1 mice was conducted by Charles River (Worcester, MA). Mouse brains were harvested and sectioned 7 days post TBI with 25 ml phosphate buffered saline (PBS) and fixed overnight in 4% paraformaldehyde in PBS. Brains were left in sucrose 30% prior to being sectioned in 40 µm sections by microtome. Microglial activation in rat hippocampi was assessed in 5 vehicle and 5 CN-105 treated rats who had been received CN-105 three hours prior to injury using F4/80 immunohistochemical staining.Results: Intravenous (IV) administration of CN-105 up to thirty minutes prior to closed head injury significantly improved durable vestibulomotor function compared to vehicle control-treated animals. In pharmacokinetic studies in uninjured CD-1 mice, IP administration of CN-105 resulted in an ~ 3-fold increase in the time to reach maximal plasma concentration (Tmax) and an ~1.5-fold increase in mean plasma residence time (MRT) compared to IV administration although the terminal elimination half-lives (T1/2) were similar. When CN-105 was co-administered by IP and IV dosing 6 hours prior to injury, a durable improvement in vestibulomotor function was observed up to 28 days following injury. Microglial counted in CN-105 treated specimens were significantly less (p = 0.0327) than those counted in vehicle specimens. Conclusion: CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury. This may be adaptable in the future as a means of preventing or reducing TBI-related secondary brain injury and improving clinical outcomes in service members who are identified as high-risk for TBI, are pre-treated, and subsequently suffer a TBI in the line of duty.

Vitamin D as a prohormone is converted into the active form in vivo and binds to vitamin D receptors, exercising a wide range of biological functions. Recent studies strongly support that vitamin D supplementation is associated with reduced cancer risk and a good prognosis. Gastrointestinal cancer is the leading cause of cancer-related deaths worldwide. The key role of vitamin D in the development of gastrointestinal cancer has been observed. Moreover, Vitamin D can also affect innate immunity and perform anti-inflammation and anti-infection actions. Given the intimate relationship between cancer and inflammation, we herein summarize epidemiological and preclinical studies of vitamin D and the underlying mechanism of its action in inflammation, gastric and colorectal cancer by our group and other researchers. A beneficial effect of vitamin D in cancer and inflammatory disease has been supported by different studies. More controlled and larger clinical trials are needed before a reliable conclusion and realization of vitamin D supplementation in the adjunct treatment of gastrointestinal inflammation and cancer.

Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets and summarize the promising therapeutic strategies targeting mitochondria for SAH.

Abstract: The prevalence of obesity continues to increase to the extent that it became a worldwide pandemic. An accumulating body of evidence has associated obesity with the development of different types of cancer, including colorectal cancer, which is a notorious disease with a high mortality rate. At the molecular level, colorectal cancer is a heterogenous disease characterized by a myriad of genetic and epigenetic alterations associated with various forms of genomic instability (detailed in Supplementary Materials). Recently, the microenvironment has emerged as a major factor in carcinogenesis. Our aim is to define the different molecular alterations leading to the development of colorectal cancer in obese patients with a focus on the role of the microenvironment in carcinogenesis. We also highlight all existent molecules in clinical trials that target the activated pathways in obesity-associated colorectal cancer, whether used as single treatments or in combination. Obesity predisposes to colorectal cancer via creating a state of chronic inflammation with dysregulated adipokines, inflammatory mediators, and other factors such as immune cell infiltration. A unifying theme in obesity-mediated colorectal cancer is the activation of the PI3K/AKT, mTOR/MAPK, and STAT3 signaling pathways. Different inhibitory molecules towards these pathways exist, increasing the therapeutic choice of obesity-associated colon cancer. However, obese patients are more likely to suffer from chemotherapy overdosing. Preventing obesity through maintaining a healthy and active lifestyle remains to be the best remedy.

Protein kinases, a class of enzymes that govern various biological phenomena at a cellular level, are responsible for signal transduction in cells that regulate cellular proliferation, differentiation, and growth. Protein kinase enzyme mutation results in abnormal cell division leading to a pathological condition like cancer. Tyrosine kinase (TK) inhibitors, which helps as a potential drug candidate for the treatment of cancer, are continuously being developed. Majority of these drug candidates are being administered as conventional oral dosage form, which provides limited safety and efficacy due to non-specific delivery and uncontrolled biodistribution resulting into the adverse effects. A controlled drug delivery approach for the delivery of TK inhibitors may be a potential strategy with significant safety and efficacy profile. Novel drug delivery strategies provide target-specific drug delivery, improved pharmacokinetic behaviour, and sustained release leading to lower doses and dosing frequency with significantly reduced side effects. Along with basic aspects of tyrosine kinase, this review discusses various aspects related to the application of tyrosine kinase inhibitors in clinical oncological setting. Furthermore, the limitations/challenges and formulation advancements related to this class of candidates particularly for cancer management have been reviewed. It is expected that innovations in drug delivery approaches for TK inhibitors using novel techniques will surely provide a new insights for improved cancer treatment and patients' life quality.

Abstract: Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, was approved by the US FDA to entered clinical trials in 2019 to treat patients suffering from locally advanced or metastatic ER-positive/HER2-negative breast cancer, and has since been approved by the US FDA. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.

Significance: Traumatic spinal cord injury (SCI) causes significant disruption of neuronal, glial, vascular and extracellular elements. The spinal cord extracellular matrix (ECM) comprises structur...

More than half of cancer patients need radiotherapy during the course of their treatment. Despite the beneficial aspects, the destructive effects of radiation beams on normal tissues lead to oxidative stress, inflammation, and cell injury. Kidneys are affected during radiotherapy of abdominal malignancies. Radiation nephropathy eventually leads to the release of factors triggering systemic inflammation. Currently, there is no proven prophylactic or therapeutic intervention for the management of radiation-induced nephropathy. This article reviews the biomarkers involved in the pathophysiology of radiation-induced nephropathy and its underlying molecular mechanisms. The efficacy of compounds with potential radioprotective properties on amelioration of inflammation and oxidative stress is also discussed. By outlining the approaches for preventing and treating this critical side effect, we evaluate the potential treatment of radiation-induced nephropathy. Available preclinical and clinical studies on these compounds are also scrutinized.

Drug repurposing is an attractive strategy for identifying new indications for existing drugs. Three approved antidepressants have advanced into clinical trials for cancer therapy. In particular, further medicinal chemistry efforts with tranylcypromine (TCP) have led to the discovery of several TCP-based histone lysine specific demethylase 1 (LSD1) inhibitors that display therapeutic promise for treating cancer in the clinic. Thus repurposing antidepressants could be a promising strategy for cancer treatment. In this review, we illustrate the anticancer mechanisms of action of antidepressants and also discuss the challenges and future directions of repurposing antidepressants for anticancer drug discovery, to provide an overview of approved antidepressant cancer therapies.

Major depressive disorder (MDD) is a disease associated with many factors; specifically, environmental, genetic, psychological, and biological factors play critical roles. Recent studies have demonstrated that histone modification may occur in the human brain in response to severely stressful events, resulting in transcriptional changes and the development of MDD. In this review, we discuss five different histone modifications, histone methylation, histone acetylation, histone phosphorylation, histone crotonylation and histone β-hydroxybutyrylation, and their relationships with MDD. The utility of histone deacetylase (HDAC) inhibitors (HDACis) for MDD treatment is also discussed. As a large number of MDD patients in China have been treated with traditional Chineses medicine (TCM), we also discuss some TCM therapies, such as Xiaoyaosan (XYS), and their effects on histone modification. In summary, targeting histone modification may be a new strategy for elucidating the mechanism of MDD and a new direction for MDD treatment.

Background: Endocrine Disrupting Chemicals (EDCs) are ubiquitous and may significantly contribute in environmental pollution, thus contaminating humans and wildlife. Environmental pollutants could interfere with bone homeostasis by means of different mechanisms, which include hormonal imbalance, direct osteoblasts toxicity and enanchment of osteoclasts activity, thus leading to osteopenia or osteoporosis. Among these, bisphenols, dioxins, polycyclic aromatic hydrocarbons, polychlorobiphenyls, poly- and perfluoroalkyls, phthalates, parabens, organotins and cadmium may play a role in bone distuption. Methods: PubMed/MEDLINE, ISI-web of knowledge and Google scholar databases were searched for medical subject headings terms and free-text word related to the aforementioned classes of chemicals and bone metabolism and remodelling for better clarifying and understanding the main mechanisms of bone disruption. Results: Several of EDCs act as xenoestrogens. Considering that estrogens play a significant role in regulating bone remodeling, most of these chemicals generate hormonal imbalance with possible detrimental consequences on bone tissue structure and its mechanical and non-mechanical properties. Discussion: A lot of evidences about bone distruptors came from in vitro studies or animal models, and conduct to equivocal results. In addition, a few data derived form humans and most of these data focused on the impact of EDCs on bone mineral density without considering their influence on long-term fracture risk. Moreover, it should be taken into account that humans are exposed to a mixture of EDCs and the final effect on bone metabolism might be the result of either a synergism or antagonist effects among them. Age of first exposure, cumulative dose exposure over time, and the usually observed non-monotonic dose-response curve for EDCs should be considered as other important variable influencing the final effect on bone metabolism. Conclusion: Taking into account these variables, observational studies are needed to better analyze this issue both for echological purpose and to preserve bone health.

SIGNIFICANCE: Alzheimer disease (AD) is an all-too-common condition in the aging population. However, aging does not automatically equal neurodegeneration and memory decline. RECENT ADVANCES: This review article involves metabolic changes in the AD brain that are related to oxidative stress. Selected pathways are identified as potential targets for intervention in AD. CRITICAL ISSUES: One of the main factors of AD is the oxidative imbalance within the central nervous system, causing a disruption in metabolic processes. Reactive oxygen species (ROS) are a natural consequence of many cellular processes, especially those associated with mitochondria, such as the electron transport chain. Some ROS, when kept under control and maintained at reasonable levels, often play roles in cell signaling. The cellular damage of ROS arises when oxidative imbalance occurs, in which case ROS are not controlled, leading to a myriad of alterations in cellular metabolic processes. These altered pathways include, among others, dysfunctional glycolysis, calcium regulation, lipid metabolism, mitochondrial processes, and mammalian target of rapamycin pathway dysregulation. FUTURE DIRECTIONS: Understanding how ROS can lead to these alterations can, ideally, elucidate therapeutic options for retarding AD progression in the aging population. Antioxid. Redox Signal. 36, 1289–1305.

The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.

Background: Oxidative stress is one of the main contributing factors involved in cerebral biochemical impairment. The higher susceptibility of the central nervous system to reactive oxygen species mediated damage could be attributed to several factors. For example, neurons use a greater quantity of oxygen, many parts of the brain have higher concentraton of iron, and neuronal mitochondria produce huge content of hydrogen peroxide. In addition, neuronal membranes have polyunsaturated fatty acids, which are predominantly vulnerable to oxidative stress (OS). OS is the imbalance between reactive oxygen species generation and cellular antioxidant potential. This may lead to various pathological conditions and diseases, especially neurodegenerative diseases such as, Parkinson’s, Alzheimer’s, and Huntington’s diseases. Objectives: In this study, we explored the involvement of OS in neurodegenerative diseases. Methods: We used different search terms like “oxidative stress and neurological disorders” “free radicals and neurodegenerative disorders” “oxidative stress, free radicals, and neurological disorders” and “association of oxidative stress with the name of disorders taken from the list of neurological disorders. We tried to summarize the source, biological effects, and physiologic functions of ROS. Results: Finally, it was noted that more than 190 neurological disorders are associated with oxidative stress. Conclusion: More elaborated studies in the future will certainly help in understanding the exact mechanism involved in neurological diseases and provide insight into revelation of therapeutic targets.