Search

Macroautophagy/autophagy is an essential degradation process that removes abnormal cellular components, maintains homeostasis within cells, and provides nutrition during starvation. Activated autophagy enhances cell survival during stressful conditions, although overactivation of autophagy triggers induction of autophagic cell death. Therefore, early-onset autophagy promotes cell survival whereas late-onset autophagy provokes programmed cell death, which can prevent disease progression. Moreover, autophagy regulates pancreatic β-cell functions by different mechanisms, although the precise role of autophagy in type 2 diabetes (T2D) is not completely understood. Consequently, this mini-review discusses the protective and harmful roles of autophagy in the pancreatic β cell and in the pathophysiology of T2D.

Objective: To examine the effect of using vitamin C and niclosamide together on liver damage caused by methotrexate., Methods: The study was conducted at the Pharmacology Department and the Iraqi Center for Cancer and Medical Genetics Research, College of Medicine, Mustansiriya University, Baghdad, Iraq, from November 2020 to July 2021, and comprised albino mice who were randomly assigned to 5 groups. Group 1 comprised controls, groups 2 to 5 was received methotrexate, niclosamide 70mg/kg/day, vitamin C 100mg/kg/day, and a combination of niclosamide and vitamin C, respectively. Mice in groups 3, 4 and 5 also received an intraperitoneal injection of methotrexate 20mg/kg to induce hepatotoxicity. After 48 hours of the injection, the mice were sacrificed under chloroform anaesthesia. Cardiac blood samples were drawn for biochemical examination. The liver, after being washed, was divided into two parts; one part was taken for histological examination, and the other was preserved in formalin 10% for histopathological analyses. Data was analysed using SPSS 16., Results: Of the 35 mice, there were 7(20%) in each of the 5 groups. The overall age ranged between 9-12 weeks and weight between 18-38gm. The results show significant hepatoprotection ( p-value <0.05) produced by both niclosamide and Vitamin C separately, reflected by a decrease in ALP, ALT, and LDH, while the combination of (niclosamide and Vitamin C) showed no additive effect (p>0.05) on enhancement of liver function., Conclusions: Niclosamide alone was found to be superior than in combination with vitamin C for treating methotrexate-induced liver damage.

Objective: To assess the hepatoprotective effect of curcumin and/or vitamin C in methotrexate-induced hepatotoxicity., Methods: The experimental study was conducted at the Department of Pharmacology, College of Medicine, and the Iraqi Centre for Cancer and Medical Genetic Research, Mustansiriya University, Baghdad, Iraq, from Nov 12, 2020, to June 1, 2021, and comprised Swiss albino female mice aged 3-4 months and weighing 30-40g each. The mice were divided into 5 groups and treated for 10 days. Group 1 received distilled water, group 2 received single-dose methotrexate on the 10th day of the trial, group 3 was treated with curcumin plus methotrexate, group 4 was treated with vitamin C plus methotrexate, and group 5 was treated with curcumin and vitamin C plus methotrexate. Parameters measured were serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase, as well as hepatic tissue malondialdehyde, superoxide dismutase and glutathione. Data was analysed using SPSS 16., Results: There were 35 mice; 7(20%) in each of the 5 groups. Hepatoprotection produced by curcumin as reflected by a decrease in lactate dehydrogenase and malondialdehyde levels was significant (p<0.05). Vitamin C also produced a significant hepatoprotection, demonstrated by a decrease in alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and malondialdehyde levels. The combination of curcumin and vitamin C reflected an additive effect demonstrated by a significant decrease in malondialdehyde (p<0.05)., Conclusions: Curcumin and/or vitamin C provided hepatoprotection against methotrexate-induced hepatotoxicity through modulation of oxidative stress biomarkers.

Objective: To evaluate the potential protective effect of metformin against osteoarthritis development in rats., Methods: The experimental study was conducted at the Iraqi Centre for Cancer Research and Medical Genetics, Mustansiriyah University, Baghdad, Iraq, from December 2021 to February 2022, and comprised male Sprague- Dawley mice who were divided into 5 equal groups: negative control group, osteoarthritis group subjected to monoiodoacetate induction, positive control group treated with celecoxib 30mg/kg, metformin 100mg/kg group, and metformin 200mg/kg group. Body mass index, inflammatory biomarkers, and serum C-terminal cross-linked telopeptide of type II collagen levels were noted for all the animals. Data was analysed using SPSS 24., Results: Of the 35 mice, 7(20%) were in each of the 5 groups. Compared to the osteoarthritis group, metformintreated mice showed significantly reduced body mass index, inflammatory biomarker levels, and blood levels of Cterminal cross-linked telopeptide of type II collagen (p=0.05). Metformin 200mg/kg treatment had more beneficial effects than 100mg/kg dose on inflammatory biomarkers and serum C-terminal cross-linked telopeptide of type II collagen (p=0.05)., Conclusions: A beneficial protective effect against the onset of osteoarthritis was produced by metformin in a dosedependent way. Additionally, metformin could lessen cartilage damage as demonstrated by a decrease in the serum levels of C-terminal cross-linked telopeptide of type II collagen in the osteoarthritis group.

Neurodegenerative diseases (NDs) such as Alzheimer disease (AD) and Parkinson disease (PD) are group of diseases affecting the central nervous system (CNS) characterized by progressive neurodegenerations and cognitive impairment. Findings from different studies highlighted the beneficial and detrimental effects of serum uric acid on the development and progression of NDs. Therefore, this mini-review aims to discuss the beneficial and detrimental effects of uric on NDs. The neuroprotective effect of uric acid is mainly related to the antioxidant effect of uric acid which alleviates oxidative stress-induced neurodegeneration in AD and PD. However, long-term effect of hyperuricemia prompts for the development and progression of cognitive impairment. Hyperuricemia is associated with cognitive impairment and dementia, and gout increases dementia risk. In addition, hyperuricemia can cause cerebral vascular injury which is a risk factor for vascular dementia and cognitive impairment. Taken together, the relationship between uric acid and NDs risk remains conflicting. Hence, preclinical and clinical studies are indicated in this regard., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Parkinson's disease (PD) is a progressive neurodegenerative disease of the brain due to degeneration of dopaminergic neurons in the substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3β) is implicated in the pathogenesis of PD. Therefore, the purpose of the present review was to revise the mechanistic role of GSK-3β in PD neuropathology, and how GSK-3β inhibitors affect PD neuropathology. GSK-3 is a conserved threonine/serine kinase protein that is intricate in the regulation of cellular anabolic and catabolic pathways by modulating glycogen synthase. Over-expression of GSK-3β is also interconnected with the development of different neurodegenerative diseases. However, the underlying mechanism of GSK-3β in PD neuropathology is not fully clarified. Over-expression of GSK-3β induces the development of PD by triggering mitochondrial dysfunction and oxidative stress in the dopaminergic neurons of the SN. NF-κB and NLRP3 inflammasome are activated in response to dysregulated GSK-3β in PD leading to progressive neuronal injury. Higher expression of GSK-3β in the early stages of PD neuropathology might contribute to the reduction of neuroprotective brain-derived neurotrophic factor (BDNF). Thus, GSK-3β inhibitors may be effective in PD by reducing inflammatory and oxidative stress disorders which are associated with degeneration of dopaminergic in the SN., (© 2024. The Author(s).)

Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP.

Endothelial dysfunction is considered one of the main causes of atherosclerosis and elevated blood pressure. Atherosclerosis (AS) formation is enhanced by different mechanisms including cytokine generation, vascular smooth muscle cell proliferation, and migration. One of the recent treatment toward endothelial dysfunction is vinpocetine (VPN). VPN is an ethyl apovincaminate used in the management of different cerebrovascular disorders and endothelial dysfunction through inhibition of atherosclerosis formation. VPN is a potent inhibitor of phosphodiesterase enzyme 1 (PDE1) as well it has anti-inflammatory and antioxidant effects through inhibition of the expression of nuclear factor kappa B (NF-κB). VPN has been shown to be effective against development and progression of AS. However, the underlying molecular mechanism was not fully clarified. Consequently, objective of the present narrative review was to clarify the mechanistic role of VPN in AS. Most of pro-inflammatory cytokines released from macrophages are inhibited by the action of VPN via NF-κB-dependent mechanism. VPN blocks monocyte adhesion and migration by inhibiting the expression of pro-inflammatory cytokines. As well, VPN is effective in reducing oxidative stress, a cornerstone in the pathogenesis of AS, through inhibition of NF-κB and PDE1. VPN promotes plaque stability and prevent erosion and rupture of atherosclerotic plaque. In conclusion, VPN through mitigation of inflammatory and oxidative stress with plaque stability effects could be effective agent in the management of endothelial dysfunction through inhibition of atherosclerosis mediators., (© 2024. The Author(s).)

In response to different viral infections, including SARS-CoV-2 infection, pro-inflammatory, anti-inflammatory cytokines, and bioactive lipids are released from infected and immune cells. One of the most critical bioactive lipids is prostaglandins (PGs) which favor perseverance of inflammation leading to chronic inflammation as PGs act as cytokine amplifiers. PGs trigger the release of pro-inflammatory cytokines, activate Th cells, recruit immune cells, and increase the expression of pro-inflammatory genes. Therefore, PGs may induce acute and chronic inflammations in various inflammatory disorders and viral infections like SARS-CoV-2. PGs are mainly inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) by blocking cyclooxygenase enzymes (COXs), which involve PG synthesis. NSAIDs reduce inflammation by selective or non-selective blocking activity of COX2 or COX1/2, respectively. In the Covid-19 era, there is a tremendous controversy regarding the use of NSAIDs in the management of SARS-CoV-2 infection. As well, the possible role of PGs in the pathogenesis of SARS-CoV-2 infection is not well-defined. Thus, the objective of the present study is to review the potential role of PGs and NSAIDs in Covid-19 in a narrative review regarding the preponderance of assorted views.

Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Coronavirus disease 2019 (Covid-19) is a recent and current infectious pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Covid-19 may lead to the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severe cases. Down-regulation of angiotensin-converting enzyme (ACE2) by the SARS-CoV-2 increases the production of angiotensin II (AngII), which increases the release of pro-inflammatory cytokines and placental growth factor (PlGF). PlGF is a critical molecule involved in vasculogenesis and angiogenesis. PlGF is stimulated by AngII in different inflammatory diseases through a variety of signaling pathways. PlGF and AngII are interacted in SARS-CoV-2 infection resulting in the production of pro-inflammatory cytokines and the development of Covid-19 complications. Both AngII and PlGF are interacted and are involved in the progression of inflammatory disorders; therefore, we aimed in this review to highlight the potential role of the PlGF/AngII axis in Covid-19.

Melatonin (MTN) is a neuro-hormone released from the pineal gland. MTN secretion is regulated by different neuronal circuits, including the retinohypothalamic tract and suprachiasmatic nucleus (SCN), which are affected by light. MTN is neuroprotective in various neurodegenerative diseases, including Parkinson's disease (PD). MTN circulating level is highly blunted in PD. However, the underlying causes were not fully clarified. Thus, the present review aims to discuss the potential causes of blunted MTN levels in PD. Distortion of MTN circadian rhythmicity in PD patients causies extreme daytime sleepiness. The underlying mechanism for blunted MTN response may be due to reduction for light exposure, impairment of retinal light transmission, degeneration of circadian pacemaker and dysautonomia. In conclusion, degeneration of SCN and associated neurodegeneration together with neuroinflammation and activation of NF-κB and NLRP3 inflammasome, induce dysregulation of MTN secretion. Therefore, low serum MTN level reflects PD severity and could be potential biomarkers. Preclinical and clinical studies are suggested to clarify the underlying causes of low MTN in PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Depression is a mood disorder that may increase risk for the development of insulin resistance (IR) and type 2 diabetes (T2D), and vice versa. However, the mechanistic pathway linking depression and T2D is not fully elucidated. The aim of this narrative review, therefore, was to discuss the possible link between depression and T2D. The coexistence of T2D and depression is twice as great compared to the occurrence of either condition independently. Hyperglycaemia and dyslipidaemia promote the incidence of depression by enhancing inflammation and reducing brain serotonin (5-hydroxytryptamine [5HT]). Dysregulation of insulin signalling in T2D impairs brain 5HT signalling, leading to the development of depression. Furthermore, depression is associated with the development of hyperglycaemia and poor glycaemic control. Psychological stress and depression promote the development of T2D. In conclusion, T2D could be a potential risk factor for the development of depression through the induction of inflammatory reactions and oxidative stress that affect brain neurotransmission. In addition, chronic stress in depression may induce the development of T2D through dysregulation of the hypothalamic-pituitary-adrenal axis and increase circulating cortisol levels, which triggers IR and T2D., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

LCZ696 blocks both angiotensin receptor type 1 (ATR1) and neprilysin (NEP), which are intricate in the degradation of natriuretic peptides (NPs) and other endogenous peptides. It has been shown NEP inhibitors and LCZ696 could be effectively in the management of atherosclerosis (AS). However, the underlying mechanism of LCZ696 in AS is needed to be clarified entirely. Hence, this review is directed to reconnoiter the mechanistic role of LCZ696 in AS. The anti-inflammatory role of LCZ696 is related to the inhibition of transforming growth factor beta (TGF-β)-activated kinase 1 (TAK) and nod-like receptor pyrin 3 receptor (NLRP3) inflammasome. Moreover, LCZ696, via inhibition of pro-inflammatory cytokines, oxidative stress, apoptosis and endothelial dysfunction can attenuate the development and progression of AS. In conclusion, LCZ696 could be effective in the management of AS through modulation of inflammatory and oxidative signaling. Preclinical and clinical studies are recommended in this regard., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid-related factor 2 (Nrf2) and Kruppel-like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti-inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin-sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long-term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti-inflammatory effect, may attenuate the development and progression of AS., Aims: Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation., Conclusion: In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory impairment and cognitive dysfunctions. It has been shown that hypoglycemia can adversely affect AD neuropathology. It is well-known that chronic hyperglycemia in type 2 diabetes (T2D) is regarded as a potential risk factor for the development and progression of AD. However, the effect of recurrent hypoglycemia on the pathogenesis of AD was not deeply discussed, and how recurrent hypoglycemia affects AD at cellular and molecular levels was not intensely interpreted by the previous studies. The underlying mechanisms for hypoglycaemia-induced AD are diverse such as endothelial dysfunction, thrombosis, and neuronal injury that causing tau protein hyperphosphorylation and the accumulation of amyloid beta (Aβ) in the brain neurons. Of note, the glucagon hormone, which controls blood glucose, can also regulate the cognitive functions. Glucagon increases blood glucose by antagonizing the metabolic effect of insulin. Therefore, glucagon, through attenuation of hypoglycemia, may prevent AD neuropathology. Glucagon/GLP-1 has been shown to promote synaptogenesis, hippocampal synaptic plasticity, and learning and memory, while attenuating amyloid and tau pathologies. Therefore, activation of glucagon receptors in the brain may reduce AD neuropathology. A recent glucagon receptor agonist dasiglucagon which used in the management of hypoglycemia may be effective in preventing hypoglycemia and AD neuropathology. This review aims to discuss the potential role of dasiglucagon in treating hypoglycemia in AD, and how this drug reduce AD neuropathology., (© 2024. The Author(s).)

Epilepsy is a common neurological disease characterized by the recurrent, paroxysmal, and unprovoked seizures. It has been shown that hyperuricemia enhances and associated with the development and progression of epilepsy through induction of inflammation and oxidative stress. In addition, uric acid is released within the brain and contributes in the development of neuronal hyperexcitability and epileptic seizure. Brain uric acid acts as damage associated molecular pattern (DAMP) activates the immune response and induce the development of neuroinflammation. Therefore, inhibition of xanthine oxidase by allopurinol may reduce hyperuricemia-induced epileptic seizure and associated oxidative stress and inflammation. However, the underlying mechanism of allopurinol in the epilepsy was not fully elucidated. Therefore, this review aims to revise from published articles the link between hyperuricemia and epilepsy, and how allopurinol inhibits the development of epileptic seizure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) that results from autoantibodies against nicotinic acetylcholine receptors (nAchRs) at NMJs. These autoantibodies are mainly originated from autoreactive B cells that bind and destroy nAchRs at NMJs preventing nerve impulses from activating the end-plates of skeletal muscle. Indeed, immune dysregulation plays a crucial role in the pathogenesis of MG. Autoreactive B cells are increased in MG due to the defect in the central and peripheral tolerance mechanisms. As well, autoreactive T cells are augmented in MG due to the diversion of regulatory T (T reg ) cells or a defect in thymic anergy leading to T cell-mediated autoimmunity. Furthermore, macroautophagy/autophagy, which is a conserved cellular catabolic process, plays a critical role in autoimmune diseases by regulating antigen presentation, survival of immune cells and cytokine-mediated inflammation. Abnormal autophagic flux is associated with different autoimmune disorders. Autophagy regulates the connection between innate and adaptive immune responses by controlling the production of cytokines and survival of T regs . As autophagy is involved in autoimmune disorders, it may play a major role in the pathogenesis of MG. Therefore, this mini-review demonstrates the potential role of autophagy and autophagy activators in MG. Abbreviations: Ach, acetylcholine; B reg , regulatory B; IgG, immunoglobulin G; MG, myasthenia gravis; NMJ, neuromuscular junction; ROS, reactive oxygen species; T reg , regulatory T; Ubl, ubiquitin-like.

Primary hypothyroidism (PHT) is associated with an increased risk for the development of atherosclerosis (AS) and other cardiovascular disorders. PHT induces atherosclerosis (AS) through the induction of endothelial dysfunction, and insulin resistance (IR). PHT promotes vasoconstriction and the development of hypertension. However, patients with subclinical PHT with normal thyroid hormones (THs) are also at risk for cardiovascular complications. In subclinical PHT, increasing thyroid stimulating hormone (TSH) levels could be one of the causative factors intricate in the progression of cardiovascular complications including AS. Nevertheless, the mechanistic role of PHT in AS has not been fully clarified in relation to increased TSH. Therefore, in this review, we discuss the association between increased TSH and AS, and how increased TSH may be involved in the pathogenesis of AS. In addition, we also discuss how L-thyroxine treatment affects the development of AS., (© 2024. The Author(s).)

Atherosclerosis (AS) formation is enhanced by different mechanisms including cytokine generation, vascular smooth muscle cell proliferation, and migration. One of the recent treatments towards endothelial dysfunction and AS is Vinpocetine (VPN). VPN is a potent inhibitor of phosphodiesterase enzyme 1 (PDE-1) and has anti-inflammatory and antioxidant effects through inhibition the expression of nuclear factor kappa B (NF-κB). VPN has been shown to be effective against the development and progression of AS. However, the underlying molecular mechanism was not fully clarified. Consequently, objective of the present review was to discuss the mechanistic role of VPN in the pathogenesis AS. Most of pro-inflammatory cytokines that released from macrophages are inhibited by action of VPN through NF-κB-dependent mechanism. VPN blocks monocyte adhesion and migration by constraining the expression and action of pro-inflammatory cytokines. As well, VPN is effective in reducing of oxidative stress a cornerstone in the pathogenesis of AS through inhibition of NF-κB and PDE1. VPN promotes plaque stability and prevents the erosion and rupture of atherosclerotic plaque. In conclusion, VPN through mitigation of inflammatory and oxidative stress, and improvement of plaque stability effects could be effective agent in the management of AS., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Al-kuraishy, Jabir, Sulaiman, Mohammed, Al-Gareeb, Albuhadily, Jawad, Swelum and Abomughaid.)

Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Cyclin-dependent kinase 5 (Cdk5) is a protein expressed in postmitotic neurons in the central nervous system (CNS). Cdk5 is activated by p35 and p39 which are neuron regulatory subunits. Cdk5/p35 complex is activated by calpain protease to form Cdk5/p35 which has a neuroprotective effect by regulating the synaptic plasticity and memory functions. However, exaggerated Cdk5 is implicated in different types of neurodegenerative diseases including Parkinson disease (PD). Therefore, modulation of Cdk5 signalling may mitigate PD neuropathology. Therefore, the aim of the present review was to discuss the critical role of Cdk5 in the pathogenesis of PD, and how Cdk5 inhibitors are effectual in the management of PD. In conclusion, overactivated Cdk5 is involved the development of neurodegeneration, and Cdk5/calpain inhibitors such as statins, metformin, fenofibrates and rosiglitazone can attenuate the progression of PD neuropathology., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non-motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α-Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long-term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease of the brain. PD is characterized by motor and non-motor symptoms. The p75 neurotrophin receptor (p75NTR) is a functional receptor for different growth factors including pro-brain derived neurotrophic factor (pro-BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Consequently, this review aimed to illustrate the detrimental and beneficial role of p75NTR in PD. Diverse studies showed that p75NTR and its downstream signaling are intricate in the pathogenesis of PD. Nevertheless, pro-apoptotic and pro-survival pathways mediated by p75NTR in PD were not fully clarified. Of note, p75NTR plays a critical role in the regulation of dopaminergic neuronal survival and apoptosis in the CNS. Particularly, p75NTR can induce selective apoptosis of dopaminergic neurons and progression of PD. In addition, p75NTR signaling inhibits the expression of transcription factors which are essential for the survival of dopaminergic neurons. Also, p75NTR expression is connected with the severity of dopaminergic neuronal injury. These verdicts implicate p75NTR signaling in the pathogenesis of PD, though the underlying mechanistic pathways remain not elucidated. Collectively, the p75NTR signaling pathway induces a double-sword effect either detrimental or beneficial depending on the ligands and status of PD neuropathology. Therefore, p75NTR signaling seems to be protective via phosphoinositide 3-kinase (PI3K)/AKT and Bcl-2 and harmful via activation of JNK, caspase 3, nuclear factor kappa B (NF-κB), and RhoA pathways., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epilepsy is a chronic neurological disorder manifested by recurring unprovoked seizures resulting from an imbalance in the inhibitory and excitatory neurotransmitters in the brain. The process of epileptogenesis involves a complex interplay between the reduction of inhibitory gamma-aminobutyric acid (GABA) and the enhancement of excitatory glutamate. Pro-BDNF/p75 NTR expression is augmented in both glial cells and neurons following epileptic seizures and status epileptics (SE). Over-expression of p75 NTR is linked with the pathogenesis of epilepsy, and augmentation of pro-BDNF/p75 NTR is implicated in the pathogenesis of epilepsy. However, the precise mechanistic function of p75 NTR in epilepsy has not been completely elucidated. Therefore, this review aimed to revise the mechanistic pathway of p75 NTR in epilepsy., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Parkinson's disease (PD) is considered one of the most common neurodegenerative brain diseases which involves the deposition of α-synuclein. Irisin hormone, a newly discovered adipokine, has a valuable role in diverse neurodegenerative diseases. Therefore, this review aims to elucidate the possible role of the irisin hormone in PD neuropathology. Irisin hormone has a neuroprotective effect against the development and progression of various neurodegenerative disorders by increasing the expression of brain-derived neurotrophic factor (BDNF). Irisin hormone has anti-inflammatory, anti-apoptotic, and anti-oxidative impacts, thereby reducing the expression of the pro-inflammatory cytokines and the progression of neuroinflammation. Irisin-induced PGC-1α could potentially prevent α-synuclein-induced dopaminergic injury, neuroinflammation, and neurotoxicity in PD. Inhibition of NF-κB by irisin improves PGC-1α and FNDC5 signaling pathway with subsequent attenuation of PD neuropathology. Therefore, the irisin/PGC-1α/FNDC5 pathway could prevent dopaminergic neuronal injury. In conclusion, the irisin hormone has a neuroprotective effect through its anti-inflammatory and antioxidant impacts with the amelioration of brain BDNF levels. Further preclinical and clinical studies are recommended in this regard., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Parkinson's disease (PD) is a common neurodegenerative disease developed due to the degeneration of dopaminergic neurons in the substantia nigra. There is no single effective treatment in the management of PD. Therefore, repurposing effective and approved drugs like metformin could be an effective strategy for managing PD. However, the mechanistic role of metformin in PD neuropathology was not fully elucidated. Metformin is an insulin-sensitizing agent used as a first-line therapy in the management of type 2 diabetes mellitus (T2DM) and has the ability to reduce insulin resistance (IR). Metformin may have a beneficial effect on PD neuropathology. The neuroprotective effect of metformin is mainly mediated by activating adenosine monophosphate protein kinase (AMPK), which reduces mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation. As well, metformin mitigates brain IR a hallmark of PD and other neurodegenerative diseases. However, metformin may harm PD neuropathology by inducing hyperhomocysteinemia and deficiency of folate and B12. Therefore, this review aimed to find the potential role of metformin regarding its protective and detrimental effects on the pathogenesis of PD. The mechanistic role of metformin in PD neuropathology was not fully elucidated. Most studies regarding metformin and its effectiveness in PD neuropathology were observed in preclinical studies, which are not fully translated into clinical settings. In addition, metformin effect on PD neuropathology was previously clarified in T2DM, potentially linked to an increasing PD risk. These limitations hinder the conclusion concerning the therapeutic efficacy of metformin and its beneficial and detrimental role in PD. Therefore, as metformin does not cause hypoglycemia and is a safe drug, it should be evaluated in non-diabetic patients concerning PD risk., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is the most common type of dementia associated with amyloid beta (Aβ) deposition. Dysfunction of the neuronal clearance pathway promotes the accumulation of Aβ. The plasminogen-activating system (PAS) is controlled by various enzymes like tissue plasminogen activators (tPA). Neuronal tPA enhances the conversion of plasminogen to plasmin, which cleaves Aβ; this function is controlled by many inhibitors of PAS, including a plasminogen-activating inhibitor (PAI-1) and neuroserpin. Therefore, the objective of the present narrative review was to explore the potential role of tPA/neuroserpin in the pathogenesis of AD. PAI-1 activity is increased in AD, which is involved in accumulating Aβ. Progressive increase of Aβ level during AD neuropathology is correlated with the over-production of PAI-1 with subsequent reduction of plasmin and tPA activities. Reducing plasmin and tPA activities promote Aβ by reducing Aβ clearance. Neuroserpin plays a critical role in the pathogenesis of AD as it regulates the expression and accumulation of Aβ. Higher expression of neuroserpin inhibits the neuroprotective tPA and the generation of plasmin with subsequent reduction in the clearance of Aβ. These observations raise conflicting evidence on whether neuroserpin is neuroprotective or involved in AD progression. Thus, neuroserpin over-expression with subsequent reduction of tPA may propagate AD neuropathology., (© 2023. The Author(s).)

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin-angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS-induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain-derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non-classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a progressive neurodegenerative disease as a result of the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental features of PD are motor and non-motor symptoms. PD symptoms develop due to the disruption of dopaminergic neurotransmitters and other neurotransmitters such as γ-aminobutyric acid (GABA). The potential role of GABA in PD neuropathology concerning the motor and non-motor symptoms of PD was not precisely discussed. Therefore, this review intended to illustrate the possible role of GABA in PD neuropathology regarding motor and non-motor symptoms. The GABA pathway is essential in regulating the inhibitory tone to prevent excessive stimulation of the cerebral cortex. Degeneration of dopaminergic neurons in PD is linked with reducing GABAergic neurotransmission. Decreasing GABA activity promotes mitochondrial dysfunction and oxidative stress, which are highly related to PD neuropathology. Hence, restoring GABA activity by GABA agonists may attenuate the progression of PD motor symptoms. Therefore, dysregulation of GABAergic neurons in the SNpc contributes to developing PD motor symptoms. Besides, PD non-motor symptoms are also related to the dysfunction of the GABAergic pathway, and amelioration of this pathway may reduce PD non-motor symptoms. In conclusion, the deregulation of the GABAergic pathway in PD might be intricate in developing motor and non-motor symptoms. Improving this pathway might be a novel, beneficial approach to control PD symptoms., (© 2024. The Author(s).)

The ketogenic diet (KD) is a low-carbohydrate, adequate protein and high-fat diet. KD is primarily used to treat refractory epilepsy. KD was shown to be effective in treating different neurodegenerative diseases. Alzheimer disease (AD) is the first common neurodegenerative disease in the world characterized by memory and cognitive impairment. However, the underlying mechanism of KD in controlling of AD and other neurodegenerative diseases are not discussed widely. Therefore, this review aims to revise the fundamental mechanism of KD in different neurodegenerative diseases focusing on the AD. KD induces a fasting-like which modulates the central and peripheral metabolism by regulating mitochondrial dysfunction, oxidative stress, inflammation, gut-flora, and autophagy in different neurodegenerative diseases. Different studies highlighted that KD improves AD neuropathology by regulating synaptic neurotransmission and inhibiting of neuroinflammation and oxidative stress. In conclusion, KD improves cognitive function and attenuates the progression of AD neuropathology by reducing oxidative stress, mitochondrial dysfunction, and enhancing neuronal autophagy and brain BDNF., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epilepsy is a neurological disease characterized by repeated seizures. Despite of that the brain-derived neurotrophic factor (BDNF) is implicated in the pathogenesis of epileptogenesis and epilepsy, BDNF may have a neuroprotective effect against epilepsy. Thus, the goal of the present review was to highlight the protective and detrimental roles of BDNF in epilepsy. In this review, we also try to find the relation of BDNF with other signaling pathways and cellular processes including autophagy, mTOR pathway, progranulin (PGN), and α-Synuclein (α-Syn) which negatively and positively regulate BDNF/tyrosine kinase receptor B (TrkB) signaling pathway. Therefore, the assessment of BDNF levels in epilepsy should be related to other neuronal signaling pathways and types of epilepsy in both preclinical and clinical studies. In conclusion, there is a strong controversy concerning the potential role of BDNF in epilepsy. Therefore, preclinical, molecular, and clinical studies are warranted in this regard., (© 2023. The Author(s).)

Vascular Parkinsonism (VP) is clinical term represents a progressive ischemic changes and subcortical lacunar infarct leading to Parkinsonism mainly in the lower limbs so called lower body Parkinsonism. The VP neuropathology is differed from that of PD neuropathology which rarely associated with basal ganglion lesions. Dopamine transporters are normal in VP but are highly reduced in PD, and dopaminergic agonists had no effective role on VP. The neuropathological mechanisms of VP are related to vascular injury which induces the interruption of the neural connection between basal ganglion and cerebral cortex. Hyperlipidemia and other cardiometabolic risk factors augment VP risk and the related neuropathology. Targeting of these cardiometabolic disorders by lipid-lowering statins may be effective in the management of VP. Therefore, this mini-review aims to clarify the possible role of statins in the management of VP. Statins have neuroprotective effects against different neurodegenerative diseases by anti-inflammatory, antioxidant and antithrombotic effects with enhancement of endothelial function. In conclusion, statins can prevent and treat VP by inhibiting inflammatory and oxidative stress disorders, mitigating of white matter hyperintensities and improving of neuronal signaling pathways. Additional preclinical, clinical trials and prospective studies are warranted in this regard., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD., Aim: Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms., Conclusion: There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the central nervous system (CNS). The underlying pathophysiology of MS is the destruction of myelin sheath by immune cells. The formation of myelin plaques, inflammation, and injury of neuronal myelin sheath characterizes its neuropathology. MS plaques are multiple focal regions of demyelination disseminated in the brain's white matter, spinal cords, deep grey matter, and cerebral cortex. Fenofibrate is a peroxisome proliferative activated receptor alpha (PPAR-α) that attenuates the inflammatory reactions in MS. Fenofibrate inhibits differentiation of Th17 by inhibiting the expression of pro-inflammatory signaling. According to these findings, this review intended to illuminate the mechanistic immunoinflammatory role of fenofibrate in mitigating MS neuropathology. In conclusion, fenofibrate can attenuate MS neuropathology by modulating different pathways, including oxidative stress, autophagy, mitochondrial dysfunction, inflammatory-signaling pathways, and neuroinflammation., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS) due to an increase of abnormal peripherally auto-reactive T lymphocytes which elicit autoimmunity. The main pathophysiology of MS is myelin sheath damage by immune cells and a defect in the generation of myelin by oligodendrocytes. Macroautophagy/autophagy is a critical degradation process that eliminates dysfunctional or superfluous cellular components. Autophagy has the property of a double-edged sword in MS in that it may have both beneficial and detrimental effects on MS neuropathology. Therefore, this review illustrates the protective and harmful effects of autophagy with regard to this disease. Autophagy prevents the progression of MS by reducing oxidative stress and inflammatory disorders. In contrast, over-activated autophagy is associated with the progression of MS neuropathology and in this case the use of autophagy inhibitors may alleviate the pathogenesis of MS. Furthermore, autophagy provokes the activation of different immune and supporting cells that play an intricate role in the pathogenesis of MS. Autophagy functions in the modulation of MS neuropathology by regulating cell proliferation related to demyelination and remyelination. Autophagy enhances remyelination by increasing the activity of oligodendrocytes, and astrocytes. However, autophagy induces demyelination by activating microglia and T cells. In conclusion, specific autophagic activators of oligodendrocytes, and astrocytes, and specific autophagic inhibitors of dendritic cells (DCs), microglia and T cells induce protective effects against the pathogenesis of MS. Abbreviations: ALS: amyotrophic lateral sclerosis; APCs: antigen-presenting cells; BBB: blood-brain barrier; CSF: cerebrospinal fluid; CNS: central nervous system; DCs: dendritic cells; EAE: experimental autoimmune encephalomyelitis; ER: endoplasmic reticulum; LAP: LC3-associated phagocytosis; MS: multiple sclerosis; NCA: non-canonical autophagy; OCBs: oligoclonal bands; PBMCs: peripheral blood mononuclear cells; PD: Parkinson disease; ROS: reactive oxygen species; UPR: unfolded protein response.

Parkinson disease (PD) is a common brain neurodegenerative disease due to progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Of note, the cardio-metabolic disorders such as hypertension are adversely affect PD neuropathology through exaggeration of renin-angiotensin system (RAS). The RAS affects the stability of dopaminergic neurons in the SNpc, and exaggeration of angiotensin II (AngII) is implicated in the development and progression of PD. RAS has two axes classical including angiotensin converting enzyme (ACE)/AngII/AT1R, and the non-classical axis which include ACE2/Ang1-7/Mas receptor, AngIII, AngIV, AT2R, and AT4R. It has been shown that brain RAS is differs from that of systemic RAS that produce specific neuronal effects. As well, there is an association between brain RAS and PD. Therefore, this review aims to revise from published articles the role of brain RAS in the pathogenesis of PD focusing on the non-classical pathway, and how targeting of this axis can modulate PD neuropathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative brain disease (NBD) developed due to dopaminergic neuron loss in the substantia nigra (SN). Vitamin D (VD), VD receptor (VDR), and VD metabolites are highly expressed in the human brain and play a critical role in maintaining different brain functions. VDRs are highly expressed in the SN that regulates the activity of dopaminergic neurons and synaptic plasticity. VD exerts protective and therapeutic effects against the development of PD by modulating dopaminergic neurons of SN. VD reduces oxidative stress and neuroinflammation in PD because of its anti-inflammatory and antioxidant activities. Different studies revealed the protective effect of VD in the management of PD. However, the potential therapeutic effect of VD in well-established PD remains controversial. Therefore, this review aims to elucidate VD's preventive and therapeutic roles in PD. In conclusion, VD deficiency is associated with increased PD risk, but VD supplementation in well-established PD plays little role., (© 2023. The Author(s).)

COVID-19 is caused by a novel SARS-CoV-2 leading to pulmonary and extra-pulmonary manifestations due to oxidative stress (OS) development and hyperinflammation. COVID-19 is primarily asymptomatic though it may cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), systemic inflammation, and thrombotic events in severe cases. SARS-CoV-2-induced OS triggers the activation of different signaling pathways, which counterbalances this complication. One of these pathways is nuclear factor erythroid 2-related factor 2 (Nrf2), which induces a series of cellular interactions to mitigate SARS-CoV-2-mediated viral toxicity and OS-induced cellular injury. Nrf2 pathway inhibits the expression of pro-inflammatory cytokines and the development of cytokine storm in COVID-19. Therefore, Nrf2 activators may play an essential role in reducing SARS-CoV-2 infection-induced inflammation by suppressing NLRP3 inflammasome in COVID-19. Furthermore, Nrf2 activators can attenuate endothelial dysfunction (ED), renin-angiotensin system (RAS) dysregulation, immune thrombosis, and coagulopathy. Thus this mini-review tries to clarify the possible role of the Nrf2 activators in the management of COVID-19. Nrf2 activators could be an effective therapeutic strategy in the management of Covid-19. Preclinical and clinical studies are recommended in this regard., (© 2023 Wiley Periodicals LLC.)

Severe SARS-CoV-2 infection is linked with an overstated immune response with the succeeding release of pro-inflammatory cytokines and progression of the cytokine storm. In addition, severe SARS-CoV-2 infection is associated with the development of oxidative stress and coagulopathy. Dapsone (DPS) is a bacteriostatic antibiotic that has a potent anti-inflammatory effect. Thus, this mini-review aimed to elucidate the potential role of DPS in mitigating inflammatory disorders in COVID-19 patients. DPS inhibits neutrophil myeloperoxidase, inflammation, and neutrophil chemotaxis. Therefore, DPS could be effective against neutrophilia-induced complications in COVID-19. In addition, DPS could be effective in mitigating inflammatory and oxidative stress disorders by suppressing the expression of inflammatory signaling pathways and the generation of reactive oxygen species (ROS) correspondingly. In conclusion, DPS might be effective in the management of COVID-19 through the attenuation of inflammatory disorders. Therefore, preclinical and clinical studies are reasonable in this regard., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Endometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium. EAC is the most common female malignancy following the menopause period. About 40% of patients with EAC are linked with obesity and interrelated with hypertension, diabetes mellitus, and high circulating estrogen levels. Proprotein convertase (PC) furin was involved in the progression of EAC., Recent Findings: Furin is a protease enzyme belonging to the subtilisin PC family called PC subtilisin/kexin type 3 that converts precursor proteins to biologically active forms and products. Aberrant activation of furin promotes abnormal cell proliferation and the development of cancer. Furin promotes angiogenesis, malignant cell proliferation, and tissue invasion by malignant cells through its pro-metastatic and oncogenic activities. Furin activity is correlated with the malignant proliferation of EAC. Higher expression of furin may increase the development of EAC through overexpression of pro-renin receptors and disintegrin and metalloprotease 17 (ADAM17). As well, inflammatory signaling in EAC promotes the expression of furin with further propagation of malignant transformation., Conclusion: Furin is associated with the development and progression of EAC through the induction of proliferation, invasion, and metastasis of malignant cells of EAC. Furin induces ontogenesis in EAC through activation expression of ADAM17, pro-renin receptor, CD109, and TGF-β. As well, EAC-mediated inflammation promotes the expression of furin with further propagation of neoplastic growth and invasion., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Parkinson's disease (PD) is a neurodegenerative disease due to degeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc). PD is characterized by motor and non-motor symptoms. Non-motor symptoms such as constipation and dysfunction of gastrointestinal tract (GIT) motility together with medications used in the management of PD affect gut microbiota. Alterations of gut microbiota with development of gut dyspiosis can induce momentous changes in gut barrier with subsequent systemic inflammation and induction of neuroinflammation. It has been shown that calprotectin which reflect intestinal inflammation and gut barrier injury are augmented in PD. Therefore, this review aims to elucidate the possible role of gut barrier injury and associated dysbiois in PD neuropathology, and how calprotectin reflects gut barrier injury in PD. Benefit of this review was to elucidate that high fecal calprotectin level in PD patients indicated gut dysbiosis and intestinal inflammation. Early increment of fecal calprotectin indicates the development of gut dysbiosis and/or gut-barrier injury which may precede motor symptoms by decades. Thus, fecal calprotectin could be a diagnostic and prognostic biomarker in PD. preclinical and clinical studies are warranted in this regard to emphasize the potential role of fecal calprotectin in PD neuropathology., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)