Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development.

The formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies.

Emerging Targets for Modulation of Immune Response and Inflammation in Stroke.

The inflammatory and immunological responses play a significant role after stroke. The innate immune activation stimulated by microglia during stroke results in the migration of macrophages and lymphocytes into the brain and are responsible for tissue damage. The immune response and inflammation following stroke have no defined targets, and the intricacies of the immunological and inflammatory processes are only partially understood. Innate immune cells enter the brain and meninges during the acute phase, which can cause ischemia damage. Activation of systemic immunity is caused by danger signals sent into the bloodstream by injured brain cells, which is followed by a significant immunodepression that encourages life-threatening infections. Neuropsychiatric sequelae, a major source of post-stroke morbidity, may be induced by an adaptive immune response that is initiated by antigen presentation during the chronic period and is directed against the brain. Thus, the current review discusses the role of immune response and inflammation in stroke pathogenesis, their role in the progression of injury during the stroke, and the emerging targets for the modulation of the mechanism of immune response and inflammation that may have possible therapeutic benefits against stroke.

Targeting ferroptosis in ischemia/reperfusion renal injury.

Renal I/R injury is a severe medical condition contributing to acute kidney injury (AKI), leading to rapid kidney dysfunction and high mortality rates. It is generally observed during renal transplantation, shock, trauma, and urologic and cardiovascular surgery, for which there is no effective treatment. Cell death and damage are commonly linked to I/R. Cell death triggered by iron-dependent lipid peroxidation, such as ferroptosis, has been demonstrated to have a significant detrimental effect in renal IRI models, making it a new type of cell death currently being researched. Ferroptosis is a nonapoptotic type of cell death that occurs when free iron enters the cell and is a critical component of many biological processes. In ferroptosis-induced renal I/R injury, iron chelators such as Deferasirox, Deferiprone, and lipophilic antioxidants are currently suppressed lipid peroxidation Liproxstatin-1 (Lip-1), Ferrostatin-1 along with antioxidants like vitamin and quercetin. Ferroptosis has been considered a potential target for pharmaceutical intervention to alleviate renal IRI-associated cell damage. Thus, this review emphasized the role of ferroptosis and its inhibition in renal IRI. Also, Pharmacological modulation of ferroptosis mechanism in renal I/R injury has been conferred. Graphical abstract.

Therapeutic Insights on Ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that alters either motor or non-motor activities. Dopamine-based medications can help alleviate symptoms at an early stage, but the disease worsens due to fewer neuroprotective drugs. PD's pathogenic mechanism involves α-synuclein accumulations, lipid peroxidation damage, iron deposition, and enhanced oxidative stress. An iron-dependent method of programmed cell death known as ferroptosis, which results from the dangerous accumulation of lipid peroxides, is similar to PD. The interesting fact is that α-synuclein has been functionally connected to iron or lipid metabolism, suggesting that dysregulated α-syn may interact with other PD clinical traits associated with ferroptosis. Treatments aimed at restoring dopamine levels in the brain are already available; however, they only alleviate symptoms and do not stop the progression of neurodegeneration. Ferroptosis-related mechanisms that could be targeted for treatment will be discussed in this review. Researchers have found that anti-ferroptosis molecules such as iron chelators and anti-oxidants protect the brains of PD animal models and humans. The ferroptosis pathway in PD and the treatment prospects of addressing the molecular pathways engaged in ferroptosis are both examined in this review.

Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases.

It is considered a significant challenge to understand the neuronal cell death mechanisms with a suitable cure for neurodegenerative disorders in the coming years. Calpains are one of the best-considered "cysteine proteases activated" in brain disorders. Calpain is an important marker and mediator in the pathophysiology of neurodegeneration. Calpain activation being the essential neurodegenerative factor causing apoptotic machinery activation, it is crucial to develop reliable and effective approaches to prevent calpain-mediated apoptosis in degenerating neurons. It has been recently seen that the "inhibition of calpain activation" has appeared as a possible therapeutic target for managing neurodegenerative diseases. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was conducted. The present article reviews the basic pathobiology and role of selective calpain inhibitors used in various neurodegenerative diseases as a therapeutic target.

COVID-19-Associated acute respiratory distress syndrome (CARDS): Mechanistic insights on therapeutic intervention and emerging trends.

AIMS: The novel Coronavirus disease 2019 (COVID-19) has caused great distress worldwide. Acute respiratory distress syndrome (ARDS) is well familiar but when it happens as part of COVID-19 it has discrete features which are unmanageable. Numerous pharmacological treatments have been evaluated in clinical trials to control the clinical effects of CARDS, but there is no assurance of their effectiveness. MATERIALS AND METHODS: A systematic review of the literature of the Medline, Scopus, Bentham, PubMed, and EMBASE (Elsevier) databases was examined to understand the novel therapeutic approaches used in COVID-19-Associated Acute Respiratory Distress Syndrome and their outcomes. KEY FINDINGS: Current therapeutic options may not be enough to manage COVID-19-associated ARDS complications in group of patients and therefore, the current review has discussed the pathophysiological mechanism of COVID-19-associated ARDS, potential pharmacological treatment and the emerging molecular drug targets. SIGNIFICANCE: The rationale of this review is to talk about the pathophysiology of CARDS, potential pharmacological treatment and the emerging molecular drug targets. Currently accessible treatment focuses on modulating immune responses, rendering antiviral effects, anti-thrombosis or anti-coagulant effects. It is expected that considerable number of studies conducting globally may help to discover effective therapies to decrease mortality and morbidity occurring due to CARDS. Attention should be also given on molecular drug targets that possibly will help to develop efficient cure for COVID-19-associated ARDS.

Cyclic nucleotide phosphodiesterase inhibition as a potential therapeutic target in renal ischemia reperfusion injury.

AIMS: Ischemia/reperfusion (I/R) occurs in renal artery stenosis, partial nephrectomy and most commonly during kidney transplantation. It brings serious consequences such as DGF (Delayed Graft Function) or organ dysfunction leading to renal failure and ultimate death. There is no effective therapy to handle the consequences of Renal Ischemia/Reperfusion (I/R) injury. Cyclic nucleotides, cAMP and cGMP are the important second messengers that stimulate intracellular signal transduction for cell survival in response to growth factors and peptide hormones in normal tissues and in kidneys plays significant role that involves vascular tone regulation, inflammation and proliferation of parenchymal cells. Renal ischemia and subsequent reperfusion injury stimulate signal transduction pathways involved in oxidative stress, inflammation, alteration in renal blood flow leading to necrosis and apoptosis of renal cell. MATERIALS AND METHODS: An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out. To understand the functioning of Phosphodiesterases (PDEs) and its pharmacological modulation in Renal Ischemia-Reperfusion Injury. KEY FINDINGS: Current therapeutic options may not be enough to treat renal I/R injury in group of patients and therefore, the current review has discussed the general characteristics and physiology of PDEs and preclinical-studies defining the relationship between PDEs expression in renal injury due to I/R and its outcome on renal function. SIGNIFICANCE: The role of PDE inhibitors in renal I/R injury and the clinical status of drugs for various renal diseases have been summarized in this review.

Traumatic Brain Injury: Mechanistic Insight on Pathophysiology and Potential Therapeutic Targets.

Traumatic brain injury (TBI) causes brain damage, which involves primary and secondary injury mechanisms. Primary injury causes local brain damage, while secondary damage begins with inflammatory activity followed by disruption of the blood-brain barrier (BBB), peripheral blood cells infiltration, brain edema, and the discharge of numerous immune mediators including chemotactic factors and interleukins. TBI alters molecular signaling, cell structures, and functions. Besides tissue damage such as axonal damage, contusions, and hemorrhage, TBI in general interrupts brain physiology including cognition, decision-making, memory, attention, and speech capability. Regardless of the deep understanding of the pathophysiology of TBI, the underlying mechanisms still need to be assessed with a desired therapeutic agent to control the consequences of TBI. The current review gives a brief outline of the pathophysiological mechanism of TBI and various biochemical pathways involved in brain injury, pharmacological treatment approaches, and novel targets for therapy.

Therapeutic modulation of the phosphatidylinositol 3-kinases (PI3K) pathway in cerebral ischemic injury.

The cerebral ischemic reperfusion injury may leads to morbidity and mortality in patients. phosphatidylinositol 3-kinase (PI3K) signaling pathway has been believed to work in association with its downstream targets, other receptors, and pathways that may offer antioxidant, anti-inflammatory, anti-apoptotic effects, neuroprotective role in neuronal excitotoxicity. This review elaborates the mechanistic interventions of the PI3K pathway in cerebral ischemic injury in context to nuclear factor erythroid 2-related factor 2 (Nrf2) regulation, Hypoxia-inducible factor 1 signaling (HIF-1), growth factors, Endothelial NOS (eNOS) proinflammatory cytokines, Erythropoietin (EPO), Phosphatase and tensin homologous protein of chromosome 10 gene (PTEN) signaling, NF-κB/Notch signaling, c-Jun N-terminal kinase (JNK) and Glycogen synthase kinase-3ß (GSK-3ß) signaling pathway. Evidences showing the activation of PI3K inhibits apoptotic pathway, which results in its neuroprotective effect in ischemic injury. Despite discussing the therapeutic role of the PI3K pathway in treating cerebral ischemic injury, the review also enlighten the selective modulation of PI3K pathway with activators and inhibitors which may provide promising results in clinical and preclinical settings.

Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases.

AIMS: Poly (ADP-ribose) polymerase- (PARP)-1 is predominantly triggered by DNA damage. Overexpression of PARP-1 is known for its association with the pathogenesis of several CNS disorders, such as Stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington (HD) and Amyotrophic lateral sclerosis (ALS). NAD+ depletion resulted PARP related cell death only happened when the trial used extreme high oxidization treatment. Inhibition of PARP1/2 may induce replication related cell death due to un-repaired DNA damage. This review has discussed PARP-1 modulated downstream pathways in neurodegeneration and various FDA approved PARP-1 inhibitors. MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on mechanistic role of Poly (ADP-ribose) polymerase and its inhibition in Neurodegenerative diseases. KEY FINDINGS: Several researchers have put forward number of potential treatments, of which PARP-1 enzyme has been regarded as a potent target intended for the handling of neurodegenerative ailments. Targeting PARP using its chemical inhibitors in various neurodegenerative may have therapeutic outcomes by reducing neuronal death mediated by PARPi. Numerous PARP-1 inhibitors have been studied in neurodegenerative diseases but they haven't been clinically evaluated. SIGNIFICANCE: In this review, the pathological role of PARP-1 in various neurodegenerative diseases has been discussed along with the therapeutic role of PARP-1 inhibitors in various neurodegenerative diseases.

Natural Compounds as Source of Aldose Reductase (AR) Inhibitors for the Treatment of Diabetic Complications: A Mini Review.

BACKGROUND: Aldol reductase (AR) is the polyol pathway's main enzyme that portrays a crucial part in developing 'complications of diabetes' involving cataract, retinopathy, nephropathy, and neuropathy. These diabetic abnormalities are triggered tremendously via aggregation of sorbitol formation (catalyzed by AR) in the polyol pathway. Consequently, it represents an admirable therapeutic target and vast research was done for the discovery of novel molecules as potential AR inhibitors for diabetic complications. OBJECTIVE: This review article has been planned to discuss an outline of diabetic complications, AR and its role in diabetic complications, natural compounds reported as AR inhibitors, and benefits of natural/plant derived AR inhibitors for the management of diabetic abnormalities. RESULTS: The goal of AR inhibition remedy is to stabilize the increased flux of blood glucose and sorbitol via the 'polyol pathway' in the affected tissues. A variety of synthetic inhibitors of AR have been established such as tolrestat and sorbinil, but both of these face limitations including low permeability and health problems. Pharmaceutical industries and other scientists were also undertaking work to develop newer, active, and 'safe' AR inhibitors from natural sources. Therefore, several naturally found molecules were documented to possess a potent inhibitory action on AR activity. CONCLUSION: Natural inhibitors of AR appeared as harmless pharmacological agents for controlling diabetic complications. The detailed literature throughout this article shows the significance of herbal extracts and phytochemicals as prospective useful AR inhibitors in treating diabetic complications.

Alcoholic and Non-Alcoholic Liver Diseases: Promising Molecular Drug Targets and their Clinical Development.

Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.