The compelling role of allopurinol in hyperuricemia-induced epilepsy: Unrecognized like tears in rain.

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.

Defective autophagy and autophagy activators in myasthenia gravis: a rare entity and unusual scenario.

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 (Treg) 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 Tregs. 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; Breg, regulatory B; IgG, immunoglobulin G; MG, myasthenia gravis; NMJ, neuromuscular junction; ROS, reactive oxygen species; Treg, regulatory T; Ubl, ubiquitin-like.

The therapeutic value of Myrtus communis L.: an updated review.

Myrtus communis L. (Family: Myrtaceae) is naturally found in the western part of Asia, Southern Europe, and North Africa. It has been reportedly applied in pharmaceutical industry, traditional medicine, cosmetics, spices, and food. Pubmed, Google scholar, Web of Science, and Scopus were utilized to seek out relevant content concerning the therapeutic potential of M. communis. Subsequently, we conducted a review to identity noteworthy updates pertaining to M. communis. Myrtle berries, leaves, seeds, and essential oils are natural sources of several nutrients and bioactive compounds with marked health effects. The chemical analysis showed that M. communis contained oils, alkaloids, flavonoids, phenolics, coumarins, saponosides, tannins, quinines, and anthraquinones. A pharmacological investigation revealed that M. communis possessed anti-inflammatory, analgesic, antimicrobial, antiparasitic, antioxidant, antidiabetic, anticancer, antimutagenic, immunomodulatory, dermatological, cardiovascular, central nervous system, and gastrointestinal protective effects, among numerous other biological effects. This current review focused on the biochemical, pharmacological, therapeutic effects, and various biological activities of different parts of M. communis. It signifies that M. communis is a therapeutic plant with numerous applications in medicine and could be used as a drug isolate based on its safety and effectiveness.

Metformin role in Parkinson's disease: a double-sword effect.

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.

The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review.

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-ß. As well, EAC-mediated inflammation promotes the expression of furin with further propagation of neoplastic growth and invasion.

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective.

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 (Aß). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aß. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aß and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aß. 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 Aß 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.

Therapeutic potential of Lawsonia inermis Linn: a comprehensive overview.

Lawsonia inermis Linn, commonly known as henna, is a member of the Lythraceae family and has been found to contain a variety of compounds with both industrial and medicinal applications in its stem, bark, roots, flowers, and seeds. This report provides a comprehensive review of the bioactive components, pharmacological activities, pharmacokinetics, and pharmacological side effects of Lawsonia inermis. Relevant materials were gathered from Google Scholar, PubMed, Scopus, and Web of Science and reviewed for important properties and updates about the plant. Lawsonia inermis contains a variety of bioactive compounds, including flavonoids, coumarins, triterpenoids, steroids, xanthones, polyphenols, fatty acids, alkaloids, quinones, tannins, leucocyandin, epicatechin, catechin, and quercetin. The plant is been traditionally used to treat numerous conditions, including ulcers, bronchitis, lumbago, hemicrania, leukoderma, scabies, boils, ophthalmic disorders, hair loss, and jaundice. It has also been found to possess a range of pharmacological activities, including antioxidant, anti-inflammatory, analgesic, antiparasitic, hepatoprotective, antifungal, antitumor, wound healing, and hypoglycemic effects. The potential of Lawsonia inermis for various biological applications is promising, and further studies are needed to fully explore its therapeutic benefits for various diseases of public health. Concern advances in drug development could enable the characterization of various bioactive constituents and facilitate their development and application for the benefit of humanity.

New insights on the potential effect of progesterone in Covid-19: Anti-inflammatory and immunosuppressive effects.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and sex hormones have immune-modulator effects during different viral infections, including SARS-CoV-2 infection. One of the essential sex hormones is progesterone (P4). AIMS: This review aimed to reveal the association between P4 and Covid-19. RESULTS AND DISCUSSION: The possible role of P4 in COVID-19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti-inflammatory cytokines, and inhibition release of pro-inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti-inflammatory Th2 with activation release of anti-inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon-gamma production that increased during SARS-CoV-2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS-CoV-2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ-aminobutyric acid (GABAA ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID-19 patients. CONCLUSION: Taken together, the anti-inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID-19.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

The potential link between acromegaly and risk of acute ischemic stroke in patients with pituitary adenoma: a new perspective.

Acromegaly is an endocrine disorder due to the excess production of growth hormone (GH) from the anterior pituitary gland after closed epiphyseal growth plates. Acromegaly is mainly caused by benign GH-secreting pituitary adenoma. Acute ischemic stroke (AIS) is one of the most common cardiovascular complications. It ranks second after ischemic heart disease (IHD) as a cause of disability and death in high-income countries globally. Thus, this review aimed to elucidate the possible link between acromegaly and the development of AIS. The local effects of acromegaly in the development of AIS are related to the development of pituitary adenoma and associated surgical and radiotherapies. Pituitary adenoma triggers the development of AIS through different mechanisms, particularly aneurysmal formation, associated thrombosis, and alteration of cerebral microcirculation. Cardiovascular complications and mortality were higher in patients with pituitary adenoma. The systemic effect of acromegaly-induced cardio-metabolic disorders may increase the risk for the development of AIS. Additionally, acromegaly contributes to the development of endothelial dysfunction (ED), inflammatory and oxidative stress, and induction of thrombosis that increases the risk for the development of AIS. Moreover, activated signaling pathways, including activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB), nod-like receptor pyrin 3 (NLRP3) inflammasome, and mitogen-activated protein kinase (MAPK) in acromegaly may induce systemic inflammation with the development of cardiovascular complications mainly AIS. Taken together, acromegaly triggers the development of AIS through local and systemic effects by inducing the formation of a cerebral vessel aneurysm, the release of pro-inflammatory cytokines, the development of oxidative stress, ED, and thrombosis correspondingly.

The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS).

Acute ischemic stroke (AIS) is a focal neurological disorder that accounts for 85% of all stroke types, due to occlusion of cerebral arteries by thrombosis and emboli. AIS is also developed due to cerebral hemodynamic abnormality. AIS is associated with the development of neuroinflammation which increases the severity of AIS. Phosphodiesterase enzyme (PDEs) inhibitors have neuro-restorative and neuroprotective effects against the development of AIS through modulation of the cerebral cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP)/nitric oxide (NO) pathway. PDE5 inhibitors through mitigation of neuroinflammation may decrease the risk of long-term AIS-induced complications. PDE5 inhibitors may affect the hemodynamic properties and coagulation pathway which are associated with thrombotic complications in AIS. PDE5 inhibitors reduce activation of the pro-coagulant pathway and improve the microcirculatory level in patients with hemodynamic disturbances in AIS. PDE5 inhibitors mainly tadalafil and sildenafil improve clinical outcomes in AIS patients through the regulation of cerebral perfusion and cerebral blood flow (CBF). PDE5 inhibitors reduced thrombomodulin, P-selectin, and tissue plasminogen activator. Herein, PDE5 inhibitors may reduce activation of the pro-coagulant pathway and improve the microcirculatory level in patients with hemodynamic disturbances in AIS. In conclusion, PDE5 inhibitors may have potential roles in the management of AIS through modulation of CBF, cAMP/cGMP/NO pathway, neuroinflammation, and inflammatory signaling pathways. Preclinical and clinical studies are recommended in this regard.

Graphene oxide-induced, reactive oxygen species-mediated mitochondrial dysfunctions and apoptosis: high-dose toxicity in normal cells.

Aim: The cytotoxic effects of graphene oxide nanoparticles (GONPs) using MTT assays, observance of apoptotic markers, and oxidative stress were outlined. Materials & methods: Rat embryonic fibroblasts (REFs) and human epithelial breast cells (HBLs) were used at 250, 500 and 750 µg/ml concentrations. Results: Significant cytotoxic and apoptotic effects were observed. Analyses of CYP2E1 and malondialdehyde concentrations in REF and HBL-100 cell lines after exposing to GONPs confirmed the nanomaterials toxicity. However, the glutathione levels in REF and HBL-100 cell lines showed a substantial reduction compared with the control. The cytochrome CYP2E1, glutathione, malondialdehyde and caspase-3 alterations provided a plausible interlinked relationship. Conclusion: The study confirmed the GONPs cytotoxic effects on REF and HBL-100 cell lines. The outcome suggested caution in wide-spread applications of GONPs, which could have implications for occupational health also.

New insights on the potential effect of vinpocetine in Parkinson's disease: one of the neglected warden and baffling topics.

Vinpocetine (VPN) is an ethyl apovincaminate that has anti-inflammatory and antioxidant effects by inhibiting the expression of nuclear factor kappa B (NF-κB) and phosphodiesterase enzyme 1 (PDE-1). VPN is used in the management of stroke, dementia, and other neurodegenerative brain diseases. VPN may be effective in treating Parkinson's disease (PD). Therefore, this review aimed to clarify the mechanistic role of VPN in the management of PD. VPN has protective and restorative effects against neuronal injury by reducing neuroinflammation, and improvement of synaptic plasticity and cerebral blood flow. VPN protects dopaminergic neurons by reducing oxidative stress, lipid peroxidation, glutamate neurotoxicity, and regulation of Ca+ 2 overloads. VPN can alleviate PD neuropathology through its anti-inflammatory, antioxidant, antiapoptotic and neurogenic effects. VPN through inhibition of PDE1 improves cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling in the dopaminergic neurons of the substantia nigra (SN). VPN improves PD neuropathology through PDE1 inhibition with a subsequent increase of the cAMP/cGMP signaling pathway. Therefore, increasing cAMP leads to antioxidant effects, while augmentation of cGMP by VPN leads to anti-inflammatory effects which reduced neurotoxicity and development of motor severity in PD. In conclusion, this review indicated that VPN could be effective in the management of PD.

Potential role of tirzepatide towards Covid-19 infection in diabetic patients: a perspective approach.

In Covid-19, variations in fasting blood glucose are considered a distinct risk element for a bad prognosis and outcome in Covid-19 patients. Tirazepatide (TZT), a dual glucagon-like peptide-1 (GLP-1)and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist may be effective in managing Covid-19-induced hyperglycemia in diabetic and non-diabetic patients. The beneficial effect of TZT in T2DM and obesity is related to direct activation of GIP and GLP-1 receptors with subsequent improvement of insulin sensitivity and reduction of body weight. TZT improves endothelial dysfunction (ED) and associated inflammatory changes through modulation of glucose homeostasis, insulin sensitivity, and pro-inflammatory biomarkers release. TZT, through activation of the GLP-1 receptor, may produce beneficial effects against Covid-19 severity since GLP-1 receptor agonists (GLP-1RAs) have anti-inflammatory and pulmoprotective implications in Covid-19. Therefore, GLP-1RAs could effectively treat severely affected Covid-19 diabetic and non-diabetic patients. Notably, using GLP-1RAs in T2DM patients prevents glucose variability, a common finding in Covid-19 patients. Therefore, GLP-1RAs like TZT could be a therapeutic strategy in T2DM patients with Covid-19 to prevent glucose variability-induced complications. In Covid-19, the inflammatory signaling pathways are highly activated, resulting in hyperinflammation. GLP-1RAs reduce inflammatory biomarkers like IL-6, CRP, and ferritin in Covid-19 patients. Therefore, GLP-1RAs like TZ may be effective in Covid-19 patients by reducing the inflammatory burden. The anti-obesogenic effect of TZT may reduce Covid-19 severity by ameliorating body weight and adiposity. Furthermore, Covid-19 may induce substantial alterations in gut microbiota. GLP-1RA preserves gut microbiota and prevents intestinal dysbiosis. Herein, TZT, like other GLP-1RA, may attenuate Covid-19-induced gut microbiota alterations and, by this mechanism, may mitigate intestinal inflammation and systemic complications in Covid-19 patients with either T2DM or obesity. As opposed to that, glucose-dependent insulinotropic polypeptide (GIP) was reduced in obese and T2DM patients. However, activation of GIP-1R by TZT in T2DM patients improves glucose homeostasis. Thus, TZT, through activation of both GIP and GLP-1, may reduce obesity-mediated inflammation. In Covid-19, GIP response to the meal is impaired, leading to postprandial hyperglycemia and abnormal glucose homeostasis. Therefore, using TZT in severely affected Covid-19 patients may prevent the development of glucose variability and hyperglycemia-induced oxidative stress. Moreover, exaggerated inflammatory disorders in Covid-19 due to the release of pro-inflammatory cytokines like IL-1ß, IL-6, and TNF-α may lead to systemic inflammation and cytokine storm development. Besides, GIP-1 inhibits expression of IL-1ß, IL-6, MCP-1, chemokines and TNF-α. Therefore, using GIP-1RA like TZT may inhibit the onset of inflammatory disorders in severely affected Covid-19 patients. In conclusion, TZT, through activation of GLP-1 and GIP receptors, may prevent SARS-CoV-2-induced hyperinflammation and glucose variability in diabetic and non-diabetic patients.

The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer's diseases.

Human Islet amyloid polypeptide (hIAPP) from pancreatic ß cells in the islet of Langerhans has different physiological functions including inhibiting the release of insulin and glucagon. Type 2 diabetes mellitus (T2DM) is an endocrine disorder due to relative insulin insufficiency and insulin resistance (IR) is associated with increased circulating hIAPP. Remarkably, hIAPP has structural similarity with amyloid beta (Aß) and can engage in the pathogenesis of T2DM and Alzheimer's disease (AD). Therefore, the present review aimed to elucidate how hIAPP acts as a link between T2DM and AD. IR, aging and low ß cell mass increase expression of hIAPP which binds cell membrane leading to the aberrant release of Ca2+ and activation of the proteolytic enzymes leading to a series of events causing loss of ß cells. Peripheral hIAPP plays a major role in the pathogenesis of AD, and high circulating hIAPP level increase AD risk in T2DM patients. However, there is no hard evidence for the role of brain-derived hIAPP in the pathogenesis of AD. Nevertheless, oxidative stress, mitochondrial dysfunction, chaperon-mediated autophagy, heparan sulfate proteoglycan (HSPG), immune response, and zinc homeostasis in T2DM could be the possible mechanisms for the induction of the aggregation of hIAPP which increase AD risk. In conclusion, increasing hIAPP circulating levels in T2DM patients predispose them to the development and progression of AD. Dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists attenuate AD in T2DM by inhibiting expression and deposition of hIAP.

Effects of neprilysin and neprilysin inhibitors on glucose homeostasis: Controversial points and a promising arena.

Neprilysin (NEP) is a transmembrane zinc-dependent metalloproteinase that inactivates various peptide hormones including glucagon-like peptide 1 (GLP-1). NEP inhibitors may be effective in the management of type 2 diabetes mellitus (T2DM) by increasing the circulating level of GLP-1. However, acute-effect NEP inhibitors may lead to detrimental effects by increasing blood glucose independent of GLP-1. These findings suggest a controversial point regarding the potential role of NEP inhibitors on glucose homeostasis in T2DM patients. Therefore, this perspective aimed to clarify the controversial points concerning the role of NEP inhibitors on glucose homeostasis in T2DM. NEP inhibitors may lead to beneficial effects by inhibition of NEP, which is involved in the impairment of glucose homeostasis through modulation of insulin resistance. NEP increases dipeptidyl peptidase-4 (DPP4) activity and contributes to increasing active GLP-1 proteolysis so NEP inhibitors may improve glycemic control through increasing endogenous GLP-1 activity and reduction of DPP4 activity. Thus, NEP inhibitors could be effective alone or in combination with antidiabetic agents in treating T2DM patients. However, long-term and short-term effects of NEP inhibitors may lead to a detrimental effect on insulin sensitivity and glucose homeostasis through different mechanisms including augmentation of substrates and pancreatic amyloid deposition. These findings are confirmed in animal but not in humans. In conclusion, NEP inhibitors produce beneficial rather than detrimental effects on glucose homeostasis and insulin sensitivity in humans though most of the detrimental effects of NEP inhibitors are confirmed in animal studies.

Morus alba: a comprehensive phytochemical and pharmacological review.

Morus alba is a fast-growing shrub or medium-sized tree with a straight, cylindrical trunk. Medicinally, whole plants, leaves, fruits, branches, and roots have been employed. Google Scholar, PubMed, Scopus, and Web of Science were used to search for relevant material on the phytochemical components and pharmacologic and mechanism of action of the Morus alba. This was reviewed to assess important updates about Morus alba. The fruits of Morus alba have traditionally been used as an analgesic, anthelmintic, antibacterial, anti-rheumatic, diuretic, hypotensive, hypoglycemia, purgative, restorative, sedative tonic, and blood stimulant. Various plant parts were used as a cooling, sedating, diuretic, tonic, and astringent agent to treat nerve disorders. The plant contained tannins, steroids, phytosterols, sitosterol, glycosides, alkaloids, carbohydrates, proteins, and amino acids, as well as saponins, triterpenes, phenolics, flavonoids, benzofuran derivatives, anthocyanins, anthraquinones, glycosides, vitamins, and minerals. Previous pharmacological research identified antimicrobial, anti-inflammatory, immunological, analgesic, antipyretic, antioxidant, anti-cancer, antidiabetic, gastrointestinal, respiratory, cardiovascular, hypolipidemic, anti-obesity, dermatological, neurological, muscular, and protecting effects. This study looked at Morus alba's traditional uses, chemical components, and pharmacological effects.

Dantrolene and ryanodine receptors in COVID-19: The daunting task and neglected warden.

Dantrolene (DTN) is a ryanodine receptor (RyR) antagonist that inhibits Ca2+ release from stores in the sarcoplasmic reticulum. DTN is mainly used in the management of malignant hyperthermia. RyRs are highly expressed in immune cells and are involved in different viral infections, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), because Ca2+ is necessary for viral replication, maturation and release. DTN can inhibit the proliferation of SARS-CoV-2, indicating its potential role in reducing entry and pathogenesis of SARS-CoV-2. DTN may increase clearance of SARS-CoV-2 and promote coronavirus disease 2019 (COVID-19) recovery by shortening the period of infection. DTN inhibits N-methyl-D-aspartate (NMDA) mediated platelets aggregations and thrombosis. Therefore, DTN may inhibit thrombosis and coagulopathy in COVID-19 through suppression of platelet NMDA receptors. Moreover, DTN has a neuroprotective effect against SARS-CoV-2 infection-induced brain injury through modulation of NMDA receptors, which are involved in excitotoxicity, neuronal injury and the development of neuropsychiatric disorders. In conclusion, DTN by inhibiting RyRs may attenuate inflammatory disorders in SARS-CoV-2 infection and associated cardio-pulmonary complications. Therefore, DNT could be a promising drug therapy against COVID-19. Preclinical and clinical studies are warranted in this regards.

The phytochemical profiling, pharmacological activities, and safety of malva sylvestris: a review.

Malva sylvestris is a plant commonly found in Europe, Asia, and Africa. The leaves and flowers of this plant have been used for centuries in traditional medicine to treat various ailments such as cough, cold, diarrhoea, and constipation. Google Scholar, PubMed, Scopus, and Web of Science were used to search for relevant material on the phytochemical profiling and pharmacologic activities of Malva sylvestris. The techniques used in phytochemical profiling and the pharmacologic activity of each compound were extracted from the included studies, including in vitro, in vivo, and clinical studies. The phytochemical analysis of Malva sylvestris revealed that the leaves and flowers are the most commonly used parts of the plant and contain various bioactive compounds such as flavonoids, mucilages, terpenoids, phenol derivatives, coumarins, sterols, tannins, saponins, and alkaloids. These phytochemicals are responsible for the many pharmacological activities of Malva sylvestris, such as anti-inflammatory, antimicrobial, hepatoprotective, laxative, antiproliferative and antioxidant properties. This review has presented an overview of the antinociceptive and anti-inflammatory activities and the cytotoxic effects of Malva sylvestris on different types of cancer cells. It has also summarised the work on developing copper oxide nanoparticles using Malva sylvestris leaf extract and its potential use in food and medicine. This review aims to highlight the traditional uses, phytochemistry, pharmacological activities, and safety of Malva sylvestris.

Targeting of neuroinflammation by glibenclamide in Covid-19: old weapon from arsenal.

In coronavirus disease 2019 (Covid-19) era, neuroinflammation may develop due to neuronal tropism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and/or associated immune activation, cytokine storm, and psychological stress. SARS-CoV-2 infection and linked cytokine storm may cause blood-brain barrier (BBB) injury through which activated immune cells and SARS-CoV-2 can pass into the brain causing activation of glial cells with subsequent neuroinflammation. Different therapeutic regimens were suggested to alleviate Covid-19-induced neuroinflammation. Since glibenclamide has anti-inflammatory and neuroprotective effects, it could be effective in mitigation of SARS-CoV-2 infection-induced neuroinflammation. Glibenclamide is a second-generation drug from the sulfonylurea family, which acts by inhibiting the adenosine triphosphate (ATP)-sensitive K channel in the regulatory subunit of type 1 sulfonylurea receptor (SUR-1) in pancreatic ß cells. Glibenclamide reduces neuroinflammation and associated BBB injury by inhibiting the nod-like receptor pyrin 3 (NLRP3) inflammasome, oxidative stress, and microglial activation. Therefore, glibenclamide through inhibition of NLRP3 inflammasome, microglial activation, and oxidative stress may attenuate SARS-CoV-2-mediated neuroinflammation.