Cyclin-dependent kinase 5 (CDK5) inhibitors in Parkinson disease.

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.

Open-label pilot study of ethosuximide as adjunctive therapy for relieving abdominal pain related to Irritable Bowel Syndrome.

WHAT IS KNOWN AND OBJECTIVES: There is clear evidence for an association between irritable bowel syndrome (IBS) and visceral hypersensitivity. This clinical study aimed to assess the adjunct role of ethosuximide, an antiepileptic drug with T-type calcium channel blocking activity, in the relieving of IBS-related abdominal pain. METHODS: This is a prospective, 3-month, randomized and controlled study of parallel groups. Fifty outpatients who met the inclusion criteria participated in the trial. Patients were allocated randomly: 25 received mebeverine 135 mg three times daily (t.i.d), whereas the other 25 received mebeverine 135 mg t.i.d and ethosuximide 500 mg t.i.d. At baseline and 12 weeks after starting the drug, patients were evaluated by a gastroenterologist. Serum tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), faecal myeloperoxidase and faecal neutrophile gelatinase-associated lipocalin (NGAL) levels were tested before and after treatment. The Numeric Pain Rating Scale (NRS) was assessed before and after three months of therapy. RESULTS AND DISCUSSION: After 12 weeks, the ethosuximide group showed a statistically and significantly greater reduction in the serum levels of TNF-α, IL-6, IL-8, faecal myeloperoxidase and faecal NGAL in comparison with the control group after the treatment. Moreover, the ethosuximide group showed a statistically significant decrease in NRS compared with the mebeverine group. WHAT IS NEW AND CONCLUSION: Ethosuximide could be a promising adjunct to antispasmodics in the treatment of IBS patients. Trial registration identifier: NCT04217733.

Repurposing metformin as adjuvant therapy in patients with ulcerative colitis treated with mesalamine: A randomized controlled double-blinded study.

BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease associated with persistent inflammation. Animal studies proved the efficacy of metformin in UC. AIM: To investigate the potential role of metformin and its protective pathways in patients with UC. METHODS: This is a randomized, controlled, and double-blinded clinical trial that included 60 participants with mild to moderate UC and was divided randomly into two groups (n = 30). For 6 months, the mesalamine group received 1 g of mesalamine three times daily (t.i.d.). For six months, the metformin group received mesalamine 1 g t.i.d. and metformin 500 mg twice daily. A gastroenterologist evaluated patients at baseline and 6 months after starting the treatment in order to measure serum levels of zonulin, sphingosine 1 phosphate (S1P), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Biopsies from the colon were used to measure gene expression of zonula occuldin-1 (ZO-1), signal transducer and activator of factor-3 (STAT-3), and intracellular adhesion molecule-1 (ICAM-1). The numeric pain rating scale (NRS) and partial Mayo score were also assessed for each patient. RESULTS: When compared to the mesalamine group, the metformin group demonstrated a statistical decrease in serum IL-6, zonulin, TNF-α, SIP, gene expression of ICAM-1 and STAT-3, and a significant increase in colonic ZO-1 when compared to the mesalamine group. The metformin group also showed a significant decrease in NRS and partial Mayo score index in comparison with the mesalamine group. CONCLUSION: Metformin may be a promising additional therapy for UC patients. Trial registration identifier: NCT05553704.

Calprotectin in Parkinsonian disease: Anticipation and dedication.

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.

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.

Correlation between depression scores and serum NF-ĸB/NLRP3 axis, biotinidase, and HMGB1 after treatment with isotretinoin in patients with acne vulgaris.

BACKGROUND: Acne vulgaris (AV) is an inflammatory skin disorder leading to scars and discomfort, its intensity has major psychological consequences such as depression. AIM: To investigate the effect of isotretinoin (ISO) on NF-κB/NLRP3, biotinidase, and HMGB and correlation with depression. PATIENTS AND METHODS: This was a case-control study that involved two groups. Group 1 is 20 healthy control, and group 2 is 20 patients diagnosed with AV according to Global Acne Grading System (GAGS) and received 20 mg ISO for 2 months. Before and after therapy, the Hamilton Depression Rating Scale (HDRS) was applied to assess each participant's level of depression. Nuclear factor kappa B (NF-ĸB), biotinidase, high mobility group box protein (HMGB1), nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP-3) were measured in serum samples. RESULTS: There was no significant difference in all measured markers of healthy group before and after 2 months. Regarding group 2, there was a statistically significant decrease in all measured markers after 2 months of treatment and significant correlations between GAGS, NF-ĸB, HMGB1, NLRP3, biotinidase, and depression score. CONCLUSION: Increased GAGS, HMGB1, NLRP3, and biotinidase were associated with depression severity in AV patients and ISO treatment significantly reduced these parameters and reduced depressive symptoms.

Effect of a high dose atorvastatin as added-on therapy on symptoms and serum AMPK/NLRP3 inflammasome and IL-6/STAT3 axes in patients with major depressive disorder: randomized controlled clinical study.

Background: Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been demonstrated to have significance in the pathophysiology of depression. Aim: To investigate the mechanistic pathways of high dose atorvastatin in MDD. Patients and methods: This trial included 60 patients with MDD who met the eligibility requirements. Two groups of patients (n = 30) were recruited by selecting patients from the Psychiatry Department. Group 1 received 20 mg of fluoxetine plus a placebo once daily. Group 2 received fluoxetine and atorvastatin (80 mg) once daily. All patients were assessed by a psychiatrist using the Hamilton Depression Rating Scale (HDRS). A HDRS score of ≤7 indicates remission or partial remission [HDRS<17 and>7]. Response was defined as ≥ 50% drop in the HDRS score. The serum concentrations of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP-3), interleukin-6 (IL-6), adenosine monophosphate activated protein kinase (AMPK), and signal transducer and activator of transcription factor-3 (STAT-3) were measured. Results: The atorvastatin group showed a significant reduction in the levels of all measured markers along with a statistical increase in the levels of AMPK when compared to the fluoxetine group. The atorvastatin group displayed a significant decrease in HDRS when compared to its baseline and the fluoxetine group. The response rate and partial remission were higher in the atorvastatin group than fluoxetine (p = 0.03, and p = 0.005), respectively. Conclusion: These results imply that atorvastatin at high doses may be a promising adjuvant therapy for MDD patients by altering the signaling pathways for AMPK/NLRP3 and IL-6/STAT-3. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05792540.

Pentoxifylline, a nonselective phosphodiesterase inhibitor, in adjunctive therapy in patients with irritable bowel syndrome treated with mebeverine.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal condition marked by chronic bowel pain or discomfort, as well as changes in abdominal motility. Despite its worldwide prevalence and clinical impact, the cause of IBS is unknown. Inflammation could play a fundamental role in the development of IBS. The aim of this study was to examine whether pentoxifylline, a competitive nonselective phosphodiesterase inhibitor, is useful in alleviating abdominal pain in IBS patients treated with mebeverine. METHODS: A randomized, controlled, and prospective clinical study that included 50 outpatients who met the inclusion criteria for IBS. Patients are allocated randomly into two groups (n = 25). Group 1 (mebeverine group) received mebeverine 135 mg three times daily (t.i.d) for three months. Group 2 (pentoxifylline group) received mebeverine 135 mg t.i.d and pentoxifylline 400 mg two times daily for three months. Patients were assessed by a gastroenterologist at baseline and three months after the medication had been started. The serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-alpha, fecal Neutrophil Gelatinase Associated Lipocalin (NGAL), and fecal myeloperoxidase were measured at the start and after three months of therapy. The Numeric Pain Rating scale (NRS) was assessed at baseline and after therapy. RESULTS: the pentoxifylline group showed a significant decrease in the level of measured biomarkers and a significant decrease in NRS. CONCLUSION: Pentoxifylline could be a promising adjuvant anti-inflammatory drug in the treatment of abdominal pain in IBS patients treated with mebeverine.

A Potential Role of Ethosuximide and Pentoxifylline in Relieving Abdominal Pain in Irritable Bowel Syndrome Patients Treated with Mebeverine: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Irritable bowel syndrome (IBS) is defined as an association of chronic abdominal pain with bowel habit abnormalities, without clear organic dysfunction. T-type calcium channels and low-grade mucosal inflammation are linked to abdominal pain; however, medical treatments for IBS abdominal pain are largely ineffective. In this study, we investigated if pentoxifylline (PTX) and ethosuximide could potentially alleviate abdominal pain in patients with IBS treated with mebeverine. METHODS: We recruited 150 patients from Tanta University Hospital to this randomized, prospective, and double blinded study. Patients were randomly allocated to three groups (n = 50). Group 1 (mebeverine) received 135 mg mebeverine three times/day (t.i.d). Group 2 (ethosuximide group) received 135 mg mebeverine t.i.d plus 250 mg ethosuximide twice daily (b.i.d) and group 3 (PTX group) received 135 mg mebeverine t.i.d plus 400 mg PTX b.i.d. Patients were assessed by a gastroenterologist at baseline and 6 months after therapy. Serum interleukin-8 (IL-8), IL-6, tumor necrosis-α (TNF-α), fecal myeloperoxidase, and fecal neutrophil gelatinase associated lipocalin (NGAL) levels were measured before and after therapy. The numeric pain rating scale (NRS) was also assessed before and after therapy. PRIMARY OUTCOMES: Reduced NRS scores and abdominal pain relief. SECONDARY OUTCOMES: Decreased inflammatory biomarkers. RESULTS: After 6 months, groups 2 and 3 showed a significantly greater reduction in serum IL-8, IL-6, TNF-α, fecal myeloperoxidase, and fecal NGAL levels when compared to group 1 after therapy. Both groups 2 and 3 showed significant reductions in NRS scores when compared to the group 1. CONCLUSION: Ethosuximide and PTX may be promising, novel adjunct drugs to antispasmodics for relieving abdominal pain in patients with IBS. TRIAL REGISTRATION: Identifier: NCT04217733.

COVID-19: Vaccine Delivery System, Drug Repurposing and Application of Molecular Modeling Approach.

The acute respiratory syndrome coronavirus (SARS-CoV-2) has spread across the world, resulting in a pandemic COVID-19 which is a human zoonotic disease that is caused by a novel coronavirus (CoV) strain thought to have originated in wild or captive bats in the initial COVID outbreak region. The global COVID-19 outbreak started in Guangdong Province, China's southernmost province. The global response to the COVID-19 pandemic has been hampered by the sheer number of infected people, many of whom need intensive care before succumbing to the disease. The epidemic is being handled by a combination of disease control by public health interventions and compassionate treatment for those who have been impacted. There is no clear anti-COVID-19 medication available at this time. However, the need to find medications that can turn the tide has led to the development of a number of investigational drugs as potential candidates for improving outcomes, especially in the severely and critically ill. Although many of these adjunctive medications are still being studied in clinical trials, professional organizations have attempted to define the circumstances in which their use is deemed off-label or compassionate. It is important to remind readers that new information about COVID-19's clinical features, treatment options, and outcomes is released on a regular basis. The mainstay of treatment remains optimized supportive care, and the therapeutic effectiveness of the subsequent agents is still being studied.