Potential Protective Effects of Antioxidants against Cyclophosphamide-Induced Nephrotoxicity.

Cyclophosphamide is an alkylating antineoplastic agent, and it is one of the most successful drugs with wide arrays of clinical activity. It has been in use for several types of cancer treatments and as an immunosuppressive agent for the management of autoimmune and immune-mediated diseases. Nowadays, its clinical use is limited due to various toxicities, including nephrotoxicity. Even though the mechanisms are not well understood, cyclophosphamide-induced nephrotoxicity is reported to be mediated through oxidative stress. This review focuses on the potential role of natural and plant-derived antioxidants in preventing cyclophosphamide-induced nephrotoxicity.

Antileishmanial Activity of Tamoxifen by Targeting Sphingolipid Metabolism: A Review.

Leishmaniasis is a widespread group of neglected parasitic diseases caused by protozoa of the genus Leishmania. Around 2 million new cases are reported each year and around 12 million people are at risk of being infected. Although various therapies have been used to treat leishmaniasis, they have been associated with increased cytotoxicity and drug resistance problems. Hence, the present review was intended to show the potential of tamoxifen as an alternative option for the treatment of leishmaniasis. Tamoxifen is a known selective estrogen receptor modulator and has been widely used for the treatment of early-stage breast cancer. Various experimental and clinical studies revealed that it has an antileishmanial effect by decreasing parasitic burden, with low cost and few side effects. The antileishmanial action of tamoxifen has been related to its potential effect on sphingolipid metabolism. Besides, it affects mitochondrial function by inducing alterations in the plasma membrane potential. However, further detailed studies are required to show the ultimate effects on health outcomes.

Montelukast: The New Therapeutic Option for the Treatment of Epilepsy.

Currently, there is no definitive cure for epilepsy. The available medications relieve symptoms and reduce seizure attacks. The major challenge with the available antiepileptic medication is safety and affordability. The repurposing of montelukast for epilepsy can be an alternative medication with a better safety profile. Montelukast is a leukotriene receptor antagonist that binds to the cysteinyl leukotrienes (CysLT) receptors used in the treatment of bronchial asthma and seasonal allergies. Emerging evidence suggests that montelukast's anti-inflammatory effect can help to maintain BBB integrity. The drug has also neuroprotective and anti-oxidative activities to reduce seizure incidence and epilepsy. The present review summarizes the neuropharmacological actions of montelukast in epilepsy with an emphasis on the recent findings associated with CysLT and cell-specific effects.

Anti-Diabetic Effect of Telmisartan Through its Partial PPARγ-Agonistic Activity.

Telmisartan is an angiotensin II receptor antagonist, which selectively inhibits the angiotensin II type 1 receptor. Thus, it is widely used for hypertension management. Nowadays, telmisartan's effect on peroxisome proliferator-activated receptors (PPARs) is gaining wider attention. PPARs are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Telmisartan is reported to have a partial PPARγ-agonistic effect while avoiding the safety concerns found with full PPARγ agonists (thiazolidinediones). Telmisartan could be an alternative treatment option, with dual benefit for diabetes mellitus (DM) and hypertension. This review summarizes the anti-diabetic activity of telmisartan via its partial PPARγ-agonistic activity.

A Systematic Review on Rho-Kinase as a Potential Therapeutic Target for the Treatment of Erectile Dysfunction.

BACKGROUND: Erectile dysfunction (ED) is a common clinical condition with limited treatment options. The main aim of the present systematic review was to synthesize information on Rho-kinase as a novel therapeutic approach for the treatment of ED. METHODS: We performed a systematic literature study in PubMed, Google Scholar and Scopus. Included studies were original articles studied the role of Rho-kinase in the pathogenesis and/or new treatment approach for ED in animal models and clinical studies, published between 2014 and 2019. Data derived from each study were study design used, interventions applied and main treatment outcomes. The quality of the selected articles was assessed by CAMARADES criteria and data were analyzed using descriptive statistics. RESULTS: A total of 1067 original articles were retrieved in the given period and eighteen papers met our inclusion criteria. Five articles explain the role of Rho-kinase in ED pathogenesis using different models such as cavernous nerve crush injury, heart failure-induced ED, vasculogenic and post-radical prostatectomy ED, diabetes-induced ED and age-related ED. Other ten papers explain the role of novel drugs evaluated for ED treatment by targeting Rho-kinase as a new approach for ED therapy. The rest three papers discuss the role of plant extracts used by traditional society for the treatment of ED and assess their potential function in targeting Rho-kinase in animal models. The penile erectile functional index has shown that the ratio of intracavernosal pressure to mean arterial pressure (ICP/MAP) was decreased due to age and various chronic diseases. Whilst, ROCK I and ROCK II expression were increased. Western blot findings have also shown that ROCK II and MYPT-1 phosphorylation rates increased in cavernous tissue after ED induction. Besides, compounds which can inhibit the action of Rho-kinase activity showed relaxation of the corpus cavernosum, decrease in corporal fibrosis, and alleviate increased apoptosis and caspase-3 activity in an NO-independent manner. Moreover, histological and molecular dysregulation have been improved by inhibition of Rho-kinase. CONCLUSION: Targeting Rho-kinase may be a possible target for the treatment of ED secondary to specific causes, and Rho-kinase inhibitors may be a new drug family for the treatment of ED. However, this requires further studies for in-depth understanding.

Targeting Netrin-1 and -4 as a Novel Diagnostic Parameter and Treatment Option for Diabetic Retinopathy.

Diabetic retinopathy (DR) is a retinal vascular disorder associated with both type 1 and type 2 diabetes mellitus (DM). It is characterized by specific loss of pericytes, which leads to an augmented blood vessel permeability, and development of new blood vessels (retinal neovascularization). Moreover, stiffening of eye membrane, inflammation, and apoptosis of endothelial cells also lead to damage of the blood-retinal barrier and blindness in most cases unless it's detected and managed early. Hence, this review was intended to assess the potential roles of Netrin-1 and -4 as new/alternative biomarkers and therapeutic options for DR. Netrin-1 and -4 have been the most known ligands and are well known for their role in neural guidance. DR has both neural and vascular components; therefore, biomarkers used for both neural and vascular retinal tissues are potentially important. According to different experimental and clinical studies, as compared to the normal groups, there was a significant increment in both retinal Netrin-1 and -4 mRNA and protein levels in the retinopathy groups. In addition, exogenous supplementation of these proteins is also used as a therapeutic agent for DR.

Evaluation of in-vivo antidiarrhoeal and in-vitro antibacterial activities of the root extract of Brucea antidysenterica J. F. Mill (Simaroubaceae).

BACKGROUND: Diarrhoea has been the major cause of death especially in children of developing countries. Brucea antidysenterica is one of the several medicinal plants used traditionally for the treatment of diarrhoea in Ethiopia. Hence, the present study was undertaken to investigate the antidiarrhoeal and antibacterial activities of the root extract of B. antidysenterica. METHODS: Plant material was extracted by maceration technique using 80% methanol. The antidiarrhoeal activity was tested using castor oil-induced diarrhoea, castor oil-induced charcoal meal test, and castor oil-induced enteropooling models in mice. Whilst, the antibacterial activity of the crude extract was evaluated using agar well diffusion and broth microdilution methods. RESULTS: The 80% methanolic crude extract significantly delayed the diarrhoeal onset at the two higher doses (p < 0.001) and it has also inhibited the number and weight of faecal output at all tested doses as compared with the negative control. Moreover, it showed a significant anti-motility effect (p < 0.001) at all tested doses. Whereas it displayed a significant reduction in the weight and volume of intestinal contents at the doses of 200 and 400 mg/kg (p < 0.01). The highest concentration (800 mg/mL) of test extract showed maximum zone of inhibition in all tested standard strains of bacteria (18.3 mm-22 mm). While MIC and MBC values (0.39 mg/mL and 1.56 mg/mL) showed that S. flexneri was the most susceptible pathogen for test extract. CONCLUSION: The study revealed that the root extract of B. antidysenterica has antidiarrhoeal and antibacterial activities.

Plasma Adipsin as a Biomarker and Its Implication in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) is a worldwide health threat affecting millions of people, which is associated with different micro- and macro-vascular complications. Type 2 diabetes mellitus (T2DM) is one of the different types of DM caused by insulin resistance and/or reduced secretion of insulin from the pancreas. A validated novel biomarker is required to enhance the accuracy of disease prediction, provide novel insights into pathophysiology and contribute to future prevention of T2DM. Various newer diagnostic methods have been developed by targeting endogenous proteins among which Adipsin is one of the promising target. Therefore, this review discusses Adipsin as a potential biomarker and its implication in T2DM. Adipsin is one of the adipokines secreted by adipose tissues which is involved in maintaining adipose tissue homeostasis and increasing insulin secretion in response to glucose. According to different experimental and clinical studies, plasma Adipsin concentrations are low in animals and patients with DM which support its use as a biomarker in combination to the other diagnostic modalities for DM. Additionally, the existence of Adipsin could be important in improving hyperglycemia by preserving ß-cell mass through improving ß-cell survival and maintaining their transcriptional identity.

The Role of Antioxidants in Ameliorating Cyclophosphamide-Induced Cardiotoxicity.

The chemotherapeutic and immunosuppressive agent cyclophosphamide has previously been shown to induce complications within the setting of bone marrow transplantation. More recently, cardiotoxicity has been shown to be a dose-limiting factor during cyclophosphamide therapy, and cardiooncology is getting wider attention. Though mechanism of cyclophosphamide-induced cardiotoxicity is not completely understood, it is thought to encompass oxidative and nitrative stress. As such, this review focuses on antioxidants and their role in preventing or ameliorating cyclophosphamide-induced cardiotoxicity. It will give special emphasis to the cardioprotective effects of natural, plant-derived antioxidants that have garnered significant interest in recent times.

Potential Effect of Hydroxychloroquine in Diabetes Mellitus: A Systematic Review on Preclinical and Clinical Trial Studies.

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia. It affects millions of people globally. In spite of many antidiabetic drugs that are available, an adequate level of control remains challenging. Hydroxychloroquine is an immunomodulatory drug that has been used for the treatment of malaria and autoimmune diseases. There is an emerging evidence that suggests its beneficial effect against diabetes mellitus. Therefore, this systematic review is aimed at discoursing the role of hydroxychloroquine against diabetes mellitus and its potential mechanisms of actions. METHODS: A systematic and manual searching was carried out to retrieve relevant articles (preclinical and clinical studies) published from January 2014 to July 2019. Electronic databases including PubMed and Scopus as well as clinicaltrials.gov have been searched using different searching terms: "hydroxychloroquine," "diabetes mellitus," "hyperglycemia," and "insulin resistance." The MeSH terms (PubMed) and text words were combined with "AND" or "OR." In addition, manual searching of Google Engine and Google Scholar was conducted. Quality assessment of all the included studies was performed using CAMARADES (preclinical studies) and the Newcastle-Ottawa Scale and Cochrane Collaboration's tools (clinical studies). RESULTS: A total of eighteen studies (three experimental and fifteen clinical studies) were found to be eligible for the present systematic review. Among the included clinical studies (six randomized control trials, five observational studies, and four cohort studies), about 55,776 study participants were involved. Most of these studies showed significant improvement of lipid profile and insulin levels and substantial diminution of hemoglobin A1c, fasting plasma glucose, and postprandial blood glucose levels. Reduction in lysosomal degradation of the internal insulin-insulin receptor complex and enhancement in insulin sensitivity and adiponectin levels are some of the hypothesized mechanisms for the antidiabetic effect of hydroxychloroquine. CONCLUSION: The current review provides preliminary evidence for potential antidiabetic properties of hydroxychloroquine. Though the provided available data were promising, further clinical trials and mechanistic studies are needed to determine its long-term effects.

Thioredoxin-Interacting Protein as a Novel Potential Therapeutic Target in Diabetes Mellitus and Its Underlying Complications.

Diabetes mellitus (DM) is a common metabolic disorder which is characterized by a persistent increment of blood glucose. Globally, DM affects millions of people and the prevalence is increasing alarmingly. The critical step in the pathophysiology of DM is the loss of ß-cells of the pancreas, which are responsible for the secretion of insulin. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of the pancreatic ß-cells. TXNIP is an α-arrestin that can bind and inhibit thioredoxin (the antioxidant protein) which is produced in the pancreatic islet after glucose intake. Numerous studies illustrated that elevated TXNIP levels were found to induce ß-cell apoptosis; whereas TXNIP deficiency protects against type I and type II diabetes by promoting ß-cell survival. Nowadays, TXNIP depletion is becoming a key factor in pancreatic ß-cell survival enhancement. In the present review, targeting TXNIP is found to be relevant as a unique therapeutic opportunity, not only to improve insulin secretion and sensitivity, but also ameliorating the long term microvascular and macrovascular complications of the disease. Thus, TXNIP inhibitors that could reduce the expression and/or activity of TXNIP to non-diabetic levels are promising agents to halt the alarming rate of diabetes and its related complications.

Netrin as a Novel Biomarker and Its Therapeutic Implications in Diabetes Mellitus and Diabetes-Associated Complications.

Diabetes is a multifactorial metabolic syndrome and is one of the shared long-lasting illnesses globally. It is linked to long-term microvascular and macrovascular complications that contribute to disability, compromised quality of life, and reduction in lifespan, which eventually leads to death. This disease is not only incurring significant economic burden but also adversely affects the patients, caregivers, communities, and the society at large. The interruption of diabetes progress and its complications is a primary focus of scientific communities. In spite of various diagnostic modalities for diabetes, there is a limited marker to investigate the risk and progress of its complications. Netrin has recently received more attention as a biomarker of diabetes and a broader range of long-term complication. Therefore, the impetus of this review is to exhaustively discuss the role of Netrin as a potential biomarker and its therapeutic implication in diabetes and diverse sets of microvascular and macrovascular complications of diabetes. It also discourses the possible mechanisms of Netrin for the said pharmacological effect for a better understanding of the development and progression of diabetes and its complications in relation to this protein. It enables protective measures to be applied at the subclinical stage and the responses to preventive or therapeutic measures to be scrutinized. Besides, it might also facilitate the appraisal of novel therapeutic options for diabetes and various complications through modifying the endogenous Netrin and provide surrogate endpoints for intervention.