Hepatoprotective activity of Lactéol® forte and quercetin dihydrate against thioacetamide-induced hepatic cirrhosis in male albino rats.

Liver cirrhosis is a silent disease in humans and is experimentally induced by many drugs and toxins as thioacetamide (TAA) in particular, which is the typical model for experimental induction of hepatic fibrosis. Thus, the objective of the present study was to elucidate the possible protective effects of lactéol® forte (LF) and quercetin dihydrate (QD) against TAA-induced hepatic damage in male albino rats. Induction of hepatotoxicity was performed by TAA injection (200 mg/kg I/P, twice/ week) in rats. LF (1 × 109 CFU/rat 5 times/week) and QD (50 mg/kg 5 times/week) treated groups were administered concurrently with TAA injection (200 mg/kg I/P, twice/ week). The experimental treatments were conducted for 12 weeks. Hepatotoxicity was evaluated biochemically by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) in the serum and histopathologically with the scoring of histopathological changes besides histochemical assessment of collagen by Masson's trichrome and immunohistochemical analysis for α-smooth muscle actin (α-SMA), Ki67 and caspase-3 expression in liver sections. Our results indicated that LF and QD attenuated some biochemical changes and histochemical markers in TAA-mediated hepatotoxicity in rats by amelioration of biochemical markers and collagen, α-SMA, Ki67 and caspase3 Immunoexpression. Additionally, LF and QD supplementation downregulated the proliferative, necrotic, fibroblastic changes, eosinophilic intranuclear inclusions, hyaline globules and Mallory-like bodies that were detected histopathologically in the TAA group. In conclusion, LF showed better hepatic protection than QD against TAA-induced hepatotoxicity in rats by inhibiting inflammatory reactions with the improvement of some serum hepatic transaminases, histopathological picture and immunohistochemical markers.

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.

The potential role of brain renin-angiotensin system in the neuropathology of Parkinson disease: Friend, foe or turncoat?

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.

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy.

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.

COVID-19 and ß-thalassemia: in lieu of evidence and vague nexus.

Coronavirus disease 19 (COVID-19) is an infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) causing acute systemic disorders and multi-organ damage. ß-thalassemia (ß-T) is an autosomal recessive disorder leading to the development of anemia. ß-T may lead to complications such as immunological disorders, iron overload, oxidative stress, and endocrinopathy. ß-T and associated complications may increase the risk of SARS-CoV-2, as inflammatory disturbances and oxidative stress disorders are linked with COVID-19. Therefore, the objective of the present review was to elucidate the potential link between ß-T and COVID-19 regarding the underlying comorbidities. The present review showed that most of the ß-T patients with COVID-19 revealed mild to moderate clinical features, and ß-T may not be linked with Covid-19 severity. Though patients with transfusion-dependent ß-T (TDT) develop less COVID-19 severity compared to non-transfusion-depend ß-T(NTDT), preclinical and clinical studies are recommended in this regard.

The Possible Role of Brain-derived Neurotrophic Factor in Epilepsy.

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.

Depression and type 2 diabetes: A causal relationship and mechanistic pathway.

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.

NF-κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. NF-κB is implicated in the pathogenesis of T2DM, and activation of NF-κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α-synuclein and degeneration of dopaminergic neurons in the SN. Increasing α-synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)-1ß followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF-κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic ß-cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF-κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.

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.

Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator.

Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy's involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy.

Primary Hypothyroidism and Alzheimer's Disease: A Tale of Two.

Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer's disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aß) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aß and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true.

Pathogenic Role of Fibrinogen in the Neuropathology of Multiple Sclerosis: A Tale of Sorrows and Fears.

Multiple sclerosis (MS) is an autoimmune demyelinating neurodegenerative disease of the central nervous system (CNS) due to injury of the myelin sheath by immune cells. The clotting factor fibrinogen is involved in the pathogenesis of MS by triggering microglia and the progress of neuroinflammation. Fibrinogen level is correlated with MS severity; consequently, inhibition of the fibrinogen cascade may reduce MS neuropathology. Thus, this review aimed to clarify the potential role of fibrinogen in the pathogenesis of MS and how targeting of fibrinogen affects MS neuropathology. Accumulation of fibrinogen in the CNS may occur independently or due to disruption of blood-brain barrier (BBB) integrity in MS. Fibrinogen acts as transduction and increases microglia activation which induces the progression of inflammation, oxidative stress, and neuronal injury. Besides, brain fibrinogen impairs the remyelination process by inhibiting the differentiation of oligodendrocyte precursor cells. These findings proposed that fibrinogen is associated with MS neuropathology through interruption of BBB integrity, induction of neuroinflammation, and demyelination with inhibition of the remyelination process by suppressing oligodendrocytes. Therefore, targeting of fibrinogen and/or CD11b/CD18 receptors by metformin and statins might decrease MS neuropathology. In conclusion, inhibiting the expression of CD11b/CD18 receptors by metformin and statins may decrease the pro-inflammatory effect of fibrinogen on microglia which is involved in the progression of MS.

A Potential Link Between Visceral Obesity and Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aß) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aß. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aß formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aß formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

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.

The potential role of cholesterol in Parkinson's disease neuropathology: perpetrator or victim.

Parkinson's disease (PD) is a neurodegenerative disease characterized by deposition of α-synuclein and aggregation of Lewy bodies. Cholesterol is involved with PD neuropathology in bidirectional ways that could be protective or harmful. Thus, the objective of the present review was to verify the potential role of cholesterol in PD neuropathology. Deregulation of ion channels and receptors induced by cholesterol alteration suggests a possible mechanism for the neuroprotective effects of cholesterol against PD development. However, high serum cholesterol level increases PD risk indirectly by 27-hydroxycholesterol which induces oxidative stress, inflammation, and apoptosis. Besides, hypercholesterolemia triggers the accumulation of cholesterol in macrophages and immune cells leading to the release of pro-inflammatory cytokines with progression of neuroinflammation subsequently. Additionally, cholesterol increases aggregation of α-synuclein and induces degeneration of dopaminergic neurons (DN) in the substantia nigra (SN). Hypercholesterolemia may lead to cellular Ca2+ overload causing synaptic and the development of neurodegeneration. In conclusion, cholesterol has bidirectional effects on PD neuropathology and might be protective or harmful.

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.

Long-term use of metformin and Alzheimer's disease: beneficial or detrimental effects.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by extracellular deposition of amyloid beta (Aß) leading to cognitive decline. Evidence from epidemiological studies has shown the association between type 2 diabetes mellitus (T2DM) and the development of AD. T2DM and peripheral insulin resistance (IR) augment the risk of AD with the development of brain IR with inhibition of neuronal insulin receptors. These changes impair clearance of Aß, increase secretion of Aß1-42, reduce brain glucose metabolism, and abnormal deposition of Aß plaques. Insulin-sensitizing drug metformin inhibits aggregation of Aß by increasing the activity of the insulin-degrading enzyme (IDE) and neprilysin (NEP) levels. Additionally, different studies raised conflicting evidence concerning long-term metformin therapy in T2DM patients, as it may increase the risk of AD or it may prevent the progression of AD. Therefore, the objective of this review was to clarify the beneficial and detrimental effects of long-term metformin therapy in T2DM patients and risk of AD. Evidence from clinical trial studies revealed the little effect of metformin on AD. Various animal studies showed that metformin increases Aß formation by activation of amyloid precursor protein (APP)-cleaving enzymes with the generation of insoluble tau species. Of note, the metformin effect on cognitive function relative to AD pathogenesis is mostly assessed in animal model studies. The duration of metformin therapy was short in most animal studies, this finding cannot apply to the long-term duration of metformin in humans. Therefore, large-scale prospective and comparative studies involving long-term metformin therapy in both diabetic and non-diabetic patients are required to exclude the effect of T2DM-induced AD.

Benzodiazepines in Alzheimer's disease: beneficial or detrimental effects.

Dementia is considered a clinical syndrome characterized by cognitive dysfunction and memory loss. Alzheimer's disease (AD) is the most common type of dementia. AD is linked with the turbulence of diverse neurotransmitters including gamma-aminobutyric acid (GABA). Notably, GABA in the brain and cerebrospinal fluid was reduced in AD. Thus, allosteric modulation of the GABA effect by benzodiazepines (BDZs) may improve the clinical outcomes of AD patients. Therefore, the objective of the present review was to reveal the possible role of BDZs on the pathogenesis and clinical outcomes in AD patients. Though BDZs may adversely affect cognitive functions mainly in elderly patients, herein it was postulated that BDZs may have beneficial, neutral, or detrimental effects in AD. Taken together, there is strong controversy regarding the use of BDZs and the risk for the development of AD. Therefore, experimental, preclinical and clinical studies are critical to determine the potential protective or detrimental effects of BDZs on AD neuropathology.

The potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus (T2DM).

Fibroblast growth factor 21 (FGF21) is a peptide hormone mainly synthesized and released from the liver. FGF21 acts on FGF21 receptors (FGFRs) and ß-Klotho, which is a transmembrane co-receptor. In type 2 diabetes mellitus (T2DM), inflammatory disorders stimulate the release of FGF21 to overcome insulin resistance (IR). FGF21 improves insulin sensitivity and glucose homeostasis. Metformin which is used in the management of T2DM may increase FGF21 expression. Accordingly, the objective of this review was to clarify the metformin effect on FGF21 in T2DM. FGF21 level and expression of FGF2Rs are dysregulated in T2DM due to the development of FGF21 resistance. Metformin stimulates the hepatic expression of FGF21/FGF2Rs by different signaling pathways. Besides, metformin improves the expression of ß-Klotho which improves FGF21 sensitivity. In conclusion, metformin advances FGF21 signaling and decreases FGF21 resistance in T2DM, and this might be an innovative mechanism for metformin in the enhancement of glucose homeostasis and metabolic disorders in T2DM patients.

The potential therapeutic effect of statins in multiple sclerosis: beneficial or detrimental effects.

Multiple sclerosis (MS) is a chronic progressive disabling disease of the central nervous system (CNS) characterized by demyelination and neuronal injury. Dyslipidemia is observed as one of the imperative risk factors involved in MS neuropathology. Also, chronic inflammation in MS predisposes to the progress of dyslipidemia. Therefore, treatment of dyslipidemia in MS by statins may attenuate dyslipidemia-induced MS and avert MS-induced metabolic changes. Therefore, the present review aimed to elucidate the possible effects of statins on the pathogenesis and outcomes of MS. Statins adversely affect the cognitive function in MS by decreasing brain cholesterol CoQ10, which is necessary for the regulation of neuronal mitochondrial function. However, statins could be beneficial in MS by shifting the immune response from pro-inflammatory Th17 to an anti-inflammatory regulatory T cell (Treg). The protective effect of statins against MS is related to anti-inflammatory and immunomodulatory effects with modulation of fibrinogen and growth factors. In conclusion, the effects of statins on MS neuropathology seem to be conflicting, as statins seem to be protective in the acute phase of MS through anti-inflammatory and antioxidant effects. However, statins lead to detrimental effects in the chronic phase of MS by reducing brain cholesterol and inhibiting the remyelination process.