Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 2, 2021

Glioma comprises of a group of heterogeneous brain tumors originating from glial cells. Primary glioblastoma is among the most common glial cells that have a characteristic clinical and molecular profile. Advancement in the field of cancer research and inventions of various clinical methodologies could not improve the median survival of this deadly tumor from 12 months. The development of a non-invasive prognostic biomarker in blood would be a revolution in the diagnosis and therapeutic monitoring of this tumor. Extracellular vesicles (Evs) are released from the tumor microenvironment into the blood, which contains the genetic material that represents the genetics of tumor cells. It is also seen that these Evs contain a variety of RNA populations, including miRNAs. Several studies identified that circulating cell-free miRNAs, either free or present in Evs, could be considered as a potential biomarker in early diagnosis and prognosis of glioblastoma. Micro RNA studies in glioblastoma have found to be promising, as it reveals the biological pathway behind pathogenesis and helps in predicting the treatment targets. The literature says that various treatment methods change the type and quantity of miRNAs in biological fluids, which can be used to monitor the therapy. This review paper focuses on the role of circulating miRNAs as potential biomarkers in the diagnosis and clinical management of glioma patients.

Pancreatic cancer is one of the low vascular permeable tumors with a high mortality rate. The five-year survival period is ∼5%. The field of drug delivery is at its pace in developing unique drug delivery carriers to treat high mortality rate cancers such as pancreatic cancer. Theranostic nanoparticles are the new novel delivery carriers where the carrier is loaded with both diagnostic and therapeutic agents. The present review discusses various therapeutic and theranostic nanocarriers for pancreatic cancer.

Background: Microbe-host association has emerged as a modulator in modern medicine. Cancer and its associated host microbes are collectively referred to as the cancer microbiome. The cancer microbiome is complex, and many aspects remain unclear including metabolic plasticity, microenvironment remodeling, cellular communications, and unique signatures within the host, all of which have a vital role in homeostasis and pathogenesis of host physiology. However, the role of the microbiome in cancer initiation, progression, and therapy is still poorly understood and remains to be explored. Objective: The objective of this review is to elucidate the role of the microbiome in cancer metabolism and the tumor microenvironment. It also focuses on the importance of therapeutic opportunities and challenges in the manipulation of the cancer microbiome. Methods: A literature search was conducted on the role of the microbiome in cancer initiation, progression, and therapy. Conclusion: The tumor microenvironment and cancer metabolism are significant in host-microbiome interactions. The microbiome can modulate standard cancer therapies like chemotherapy and immunotherapy. Microbiome transplantation has also been demonstrated as an effective therapy against cancer. Furthermore, the modulation of the microbiome also has potential clinical outcomes in modern medicine.

The food industry is constantly shifting focus based on prebiotics as health-promoting substrates rather than just food supplements. A prebiotic is “a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health.” Prebiotics exert a plethora of health-promoting effects, which has lead to the establishment of multimillion food and pharma industries. The following are the health benefits attributed to prebiotics: mineral absorption, better immune response, increased resistance to bacterial infection, improved lipid metabolism, possible protection against cancer, relief from poor digestion of lactose, and reduction in the risk of diseases such as intestinal disease, non-insulin-dependent diabetes, obesity and allergy. Numerous studies in both animals and humans have demonstrated the health benefits of prebiotics.

Background: Scientific research continues to develop more efficacious drugs to treat and cure cancer, the dreadful disease threatening the human race. Chemotherapy is an essential means in cancer therapy, however, plant drugs having pharmacological safety, can be used alone or as additions to current chemotherapeutic agents to enhance therapeutic efficacy and minimize chemotherapyinduced adverse effects. Objective: A combination therapy where the synergistic effect on multiple targets is possible has gained significance because a one-drug one-target approach fails to yield the desired therapeutic effect. Therefore, a detailed description of important plant polyphenolic compounds with anticancer activity and their role in potentiating chemotherapeutic efficiency of existing anticancer drugs is provided in this review. Systematically screening combinations of active pharmaceutical ingredients for potential synergy with plant compounds may be especially valuable in cancer therapy. Methods: We extensively have gone through reviews and research articles available in the literature. We made use of databases such as Google Scholar, Research Gate, PubMed, Science Direct, etc. The following keywords were used in our literature search: “Chemotherapy, drug development, cancer drugs, plant-derived polyphenolics, synergistic studies, combination therapy, diagnosis and genetics.” Conclusion: Systematic research studies on screening combinations of plant phytochemicals with potential chemotherapeutic pharmaceuticals shed light on their synergistic effects, mechanisms of actions paving the way to develop more efficient anticancer therapeutics to treat and cure the cancer menace, to nullify chemotherapy-induced adverse effects and our review substantially contributes in this direction.

Prostate cancer is a multifactorial disease that mainly occurs due to the accumulation of somatic, genetic, and epigenetic changes, resulting in the inactivation of tumor-suppressor genes and activation of oncogenes. Mutations in genes, specifically those that control cell growth and division or the repair of damaged DNA, make the cells grow and divide uncontrollably to form a tumor. The risk of developing prostate cancer depends upon the gene that has undergone the mutation. Identifying such genetic risk factors for prostate cancer poses a challenge for the researchers. Besides genetic mutations, many epigenetic alterations, including DNA methylation, histone modifications (methylation, acetylation, ubiquitylation, sumoylation, and phosphorylation) nucleosomal remodeling, and chromosomal looping, have significantly contributed to the onset of prostate cancer as well as the prognosis, diagnosis, and treatment of prostate cancer. Chronic inflammation also plays a major role in the onset and progression of human cancer, via modifications in the tumor microenvironment by initiating epithelialmesenchymal transition and remodeling the extracellular matrix. In this article, the authors present a brief history of the mechanisms and potential links between the genetic aberrations, epigenetic changes, inflammation, and inflammasomes that are known to contribute to the prognosis of prostate cancer. Furthermore, the authors examine and discuss the clinical potential of prostate carcinogenesis in relation to epigenetics and inflammation for its diagnosis and treatment.

Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus characterized by gradually failing heart with detrimental cardiac remodelings, such as fibrosis and diastolic and systolic dysfunction, which is not directly attributable to coronary artery disease. Insulin resistance and resulting hyperglycemia is the main trigger involved in the initiation of diabetic cardiomyopathy. There is a constellation of many pathophysiological events, such as lipotoxicity, oxidative stress, inflammation, inappropriate activation of the renin-angiotensin-aldosterone system, dysfunctional immune modulation promoting increased rate of cardiac cell injury, apoptosis, and necrosis, which ultimately culminates into interstitial fibrosis, cardiac stiffness, diastolic dysfunction, initially, and later systolic dysfunction too. These events finally lead to clinical heart failure of DCM. Herein, The pathophysiology of DCM is briefly discussed. Furthermore, potential therapeutic strategies currently used for DCM are also briefly mentioned.

Background: Medicine has gone through many schools of thought before arriving in the version we see in our world today. In the beginning, it was based on religion, superstition, and magic plants for therapy. This approach was practiced for many centuries until a period of cultural development arrived. This change occurred in the ancient Greek era, when new theories on nature arose: physiokratia emerged to describe the nature of humanity, including its genesis and supporting phenomena. From the various mystical traditions, we have come to understand the natural phenomena that surround the universe, thanks to the knowledge of the "hidden causes" that emerged due to this trend of philosophical thought. Methods: We studied ancient texts to determine the common roots between myth, therapy, and religion of medical cultures in the pre-Hippocratic era and the era of pre-Socratic philosophers. Results: This study is focused on the period of time before and during pre-Socratic thought, showing that there are many similarities in the approach of therapy for various diseases in that era. The Greek contribution to Western medicine was in the development of a rational system of thought that has been transmitted in medical culture. This attempt to interpret humanity was called philosophy. Hippocrates, who came after the pre-Socratics, changed the old approach to patients. When the approach to medical diagnosis and healing changed, it affected the therapy of other ancient cultures. The ancient Greeks were influenced by other civilizations’ approaches to therapy, especially with the use of plants and the different mythological and religious outlooks connected to this use. Despite the emergence of pre- Socratic rationalism, supernatural beliefs remained even when the use of herbs was no longer practiced in direct connection to their origins in myth and magic. The first detachment of magic therapy occurred later with the father of medicine, Hippocrates. Conclusion: The ancient Greeks invented the rationalist doctrine, which influenced medicine. Thus, the birth of philosophy, through its many stages, has influenced therapeutic patterns in medicine, especially with medicinal herbs.

Several different proteins regulate, directly or indirectly, the production of growth hormones from the pituitary gland, thereby complex genetics is involved. Defects in these genes are related to the deficiency of growth hormones solely, or deficiency of other hormones, secreted from the pituitary gland including growth hormones. These studies can aid clinicians to trace the pattern of the disease between the families, start early treatment and predict possible future consequences. This paper highlights some of the most common and novel genetic anomalies concerning growth hormones, which are responsible for various genetic defects in isolated growth and combined pituitary hormone deficiency disease.

Aim: To investigate the effect of smoking and alcohol intake on the association between betel nut chewing and each metabolic abnormality. Background: Betel nut chewing has been associated with metabolic syndrome. Objective: Whether the association is affected by tobacco or alcohol use is not clarified so far. Methods: The authors conducted a cross-sectional study using 6,657 military males, aged 18-50 years in eastern Taiwan in 2013-2014. Metabolic syndrome was defined according to the International Diabetes Federation’s ethnic criteria for Asians. The population was classified as non-betel nut chewers (N =5,749), current chewers with both tobacco and alcohol use (N =615), and current chewers without tobacco and/or alcohol use (N =293). Multiple logistic regression analyses were stepwise adjusted for the confounders including alcohol and tobacco use to determine the association of betel chewing with the metabolic abnormalities. Results: As compared to the non-current chewers, the current chewers with both tobacco/alcohol use and those without had a higher risk of metabolic syndrome (odds ratios (OR) and 95% confidence intervals: 2.46 (2.00-3.02), and 2.04 (1.53-2.73), respectively) after controlling for age, service specialty, total cholesterol levels ≥200 mg/dL and exercise frequency (model 1). The association did not change much in the two chewing groups after additionally adjusting for alcohol consumption (model 2) (OR: 2.49 (1.99-3.12), and 2.04 (1.52-2.73), respectively), whereas the relationship reduced significantly in the chewers with both tobacco/alcohol use rather than those without after further adjusting for smoking (model 3) (OR: 2.18 (1.71-2.78) and 2.02 (1.51-2.71), respectively). This was in parallel with the pattern for the association of betel nut chewing with serum triglycerides >150 mg/dL in the chewers with both tobacco/alcohol use and those without in model 1 (OR: 2.90 (2.40-3.51) and 1.90 (1.45-2.49), respectively, p =0.011), in model 2 (OR: 2.82 (2.30-3.46) and 1.89 (1.44-2.49), respectively, p =0.040), and in model 3 (2.26 (1.81-2.81) and 1.87 (1.42-2.45), respectively, p =0.76). Conclusion: Our findings suggest that tobacco smoking but not alcohol intake could increase the relationship of betel nut chewing with metabolic syndrome, which is likely mediated by a synergic effect on increasing serum triglycerides levels.

Aims: The aim of the study was to experimentally investigate the antihypertensive effect of Ruta Montana. Background: Ruta montana L. is traditionally used in Moroccan herbal medicine to treat hypertension. This study aimed to experimentally evaluate the hypotensive and vasoactive properties of this plant. Objective: The objective of the study was to evaluate the effect of the aqueous extract of Ruta Montana on blood pressure parameters in LNAME-induced hypertensive rats and to determine the vasorelaxant activity of this aqueous extract. Methods: The antihypertensive effect of the aqueous extract obtained from Ruta montana aerial parts (RMAPAE) (200 mg/kg) was evaluated in normal and anesthetized hypertensive rats. Blood pressure parameters (systolic blood pressure (SBP), mean blood pressure (MBP) and diastolic blood pressure (DBP)) and heart rate were measured using a tail-cuff and a computer-assisted monitoring device. The acute and chronic effect of RMAPAE was recorded for 6 hours for the acute experiment and for 7 days for the sub-chronic test. In the other set, the vasorelaxant effect of RMAPAE on the contractile response was observed in the isolated thoracic aorta. Results: The results indicated that the RMAPAE extract significantly decreased SBP, MBP, DBP and heart rate in L-NAME-induced hypertensive rats. Furthermore, RMAPAE was demonstrated to induce a dose-dependent relaxation in the aorta precontracted with Epinephrine or KCl. More interestingly, this vasorelaxant activity of RMAPAE seems to be probably mediated through the prostaglandins pathway. Conclusion: The present study illustrates the beneficial action of Ruta montana on hypertension and supports its use as an antihypertensive agent.

Background: Although the importance of mast cells in asthma has been studied, mast cellsinduced global changes in lungs are largely unknown. Data-driven identification contributes to discovering significant biomarkers or therapeutic targets, which are the basis of effective clinical medications. Objective: This study aims to explore the effects of mast cells on gene expression in asthmatic lungs, and to assess the curative effects of inhaled budesonide (BUD). Methods: Pulmonary gene expression in KitWsh mice with or without mast cell engraftment was analyzed with R software. Functional enrichment of Gene Ontology and KEGG was carried out through the DAVID online tool. Hub genes were identified with String and Cytoscape software. Results: The array analyses showed that the mast cell engraftment enhanced inflammation/immune response, cytokine/chemokine signal, and monocyte/neutrophil/lymphocyte chemotaxis. Interleukin (IL)-6 was identified to be a significant hub gene with the highest interaction degree. Based on this, the effects of BUD were investigated on the aspects of anti-inflammation. BUD’s treatment was found to reduce serum IL-6 content and pulmonary inflammation in ovalbumin-induced asthma rats. The treatment also downregulated beta-tryptase expression both in lung tissues and serum. Morphologically, the accumulation and degranulation of mast cells were significantly suppressed. Notably, the effects of BUD on inflammation and degranulation were comparable with Tranilast (a classic mast cell inhibitor), while a remarkable synergy was not observed. Conclusion: This study presented a unique pulmonary gene profile induced by mast cell engraftment, which could be reversed through blockage of mast cells or inhaled BUD.

Background: Fabry Disease (FD, OMIM#301500) is a progressive, life-threatening, multisystemic, rare lysosomal storage disease. Today, approximately 1000 mutations are recorded in the Human Gene Mutation Database (www.hgmd.org) for GLA. Among the identified mutations, genetic variants of unknown significance (GVUS) and novel mutations cause problems in terms of diagnosis and treatment approach. Methods: In our study, 510 high-risk patients were enrolled. 229 out of 510 were Male (45%) (Mean age was 40.8 ±15.0) and 281 of were Female (55%) (Mean age was 39, 7±15.5). The definite diagnosis of the FD was confirmed by GLA gene sequence analysis. GLA mutation was found in 15 cases (3.4%). Family members of the relevant indexes were included in the screening programs according to the X-linked inheritance pattern. And then we conducted family screening on 74 family members of 15 index cases. Of those 74 cases, 39 had mutations (53%). In males, α-GalA activity and in both gender Lyso-Gb3 levels were measured and multisystem evaluation was performed in all cases with the mutation. Results: We found six different familial mutation types; two of them pathogenic; p.D170N (1), p.P205S (13), one of them GVUS; p.Q330R (1), three of them likely benign; p.D313Y (12), p.S126G (25), c.-30G>A (2) mutations were detected. Conclusion: The purpose of this retrospective study is to approach Fabry disease on a genetic basis and to improve its management and to draw attention to the importance of early diagnosis. We also aimed to evaluate the appropriate algorithms to determine whether the mutation is the FD-causing mutation or not.

Objective: Fetuin-A serves a dual function; its high levels are associated with metabolic syndrome, type 2 diabetes, obesity, insulin resistance, and nonalcoholic fatty liver disease, and on the other hand, it serves as a potent inhibitor of ectopic vascular calcification. Due to the opposing findings, the aim of the current study was to investigate serum fetuin-A levels in men with coronary artery disease (CAD). Methods: In the case-control study, anthropometric and biochemical parameters were determined in 83 men (43 CAD patients and 40 control subjects). At last, the serum fetuin-A levels were measured using the fetuin-A human enzyme-linked immunosorbent assay (ELISA) kit. Results: A significant difference was detected among the two groups for triglyceride and cholesterol levels (P=0.003 and P=0.002, respectively). The mean fetuin-A levels were determined 230.57 ± 63.76 and 286.35 ± 64.07 μg/ml for the control group and the CAD patients, respectively (P<0.001). Fetuin- A was significantly correlated to the severity of CAD (r 0.393, P<0.001) and associated with the risk of CAD in subjects (OR [CI] = 1. 144 [1.060-1. 235]; p = 0.001). A cut-off value of 237.4 μg/ml had good sensitivity (76.7%) and specificity (65.0%) for differentiating between two groups [area under curve (AUC) = 0.732 (CI=0.621-0.842); p < 0.001]. Conclusion: Our results indicated that fetuin-A levels were positively correlated to the severity of CAD. The findings suggest that there is a possible link between pathogenic mechanisms of atherosclerosis and fetuin-A; however, more investigations are needed in this regard.

Background and Objective: Carpal tunnel syndrome (CTS) is the most common form of nerve entrapment. Clinically, various signs and symptoms compare due to overexposure to mechanical vibrations transmitted to the wrist bones and cartilage, resulting in compression of the sensory and motor nerve fibers of the median nerve. Early symptoms include nocturnal paresthesia and electromyography reveals reduced sensory nerve conduction velocity. Aim of this study was to evaluate the efficacy of a dietary integrator composed of acetyl-L-carnitine, α-lipoic acid, quercetin, bromelain, pantothenic acid, C and B1 and B2 and B6 and B12 vitamins in patients with early (minimal) carpal tunnel syndrome. Methods: 36 patients (28 female and 8 male) with early CTS characterized by sensory nerve demyelination and inflammation of the transverse carpal ligament. Patients were divided into two groups, group A (18 patients received physical therapy) and group B (18 patients received physical therapy and an oral integrator). Clinical (sleep quality questionnaire to measure severity of paresthesia) and neurophysiological assessment (Sensory Nerve Conduction Velocity) performed at baseline, and then at 30 and 60 days after treatment. Results: Sleep quality and Sensory Nerve Conduction Velocity data analysis show improvement in both groups at 30 and 60 days, with statistical difference between them in both time of analysis. Conclusion: In the early CTS, with sensory fibers damage, use of dietary integrator, such as Micronil Dol®, composed of acetyl-L-carnitine, α-lipoic acid, quercetin, bromelain, pantothenic acid, C and B1 and B2 and B6 and B12 vitamins can be effective in quick recovery of median nerve sensory.

Background: Endothelial nitric oxide synthase (eNOS) plays a major role in the response of anti-hypercholesterol statin drugs. Genetic polymorphisms in the eNOS gene affect the activity of eNOS thereby modulating the statin response. Objective: This study investigated the influence of major functional eNOS gene polymorphisms (rs2070744, rs1799983, and rs61722009) on the lipid profile of type 2 diabetes mellitus (T2DM) Jordanian patients treated with atorvastatin. Methods: The sample comprised 103 T2DM patients who attended the diabetes clinic of Jordan University Hospital. The T2DM patients had regularly been taking 20 mg atorvastatin. The atorvastatin response was calculated by measuring the lipid profile before and after three months of atorvastatin treatment. The eNOS genotypes of the subjects were analyzed using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) assay. Results: No significant association was found between eNOS genetic polymorphisms and the response to atorvastatin (ANOVA, p > 0.05). In addition, no significant difference in the frequency of eNOS genotypes was found between T2DM patients and healthy subjects. However, patients with eNOS rs1799983, 4a/4a, and rs61722009 G/G genotypes showed significantly lower levels of baseline total cholesterol (TC) and low density lipoprotein (LDL) than did patients carrying the rs1799983 4b/4b or rs61722009 T/T genotype (p < 0.05). The eNOS rs1799983 and rs61722009 polymorphisms were in complete linkage disequilibrium (D' = 1). Conclusion: Although no association was found between eNOS genetic polymorphisms and atorvastatin response, there was a significant association between the rs1799983 and rs61722009 genotypes and baselines levels of TC and LDL in Jordanian T2DM patients. These genetic variants affect cholesterol levels and may play a role in the susceptibility to cardiovascular diseases in T2DM patients. Further studies are needed to validate these findings.

Background: Gastrointestinal symptoms are often the first symptoms of hypopituitarism. However, pseudo-intestinal obstruction is not a common manifestation of hypopituitarism. Some patients presenting with gastrointestinal symptoms as their chief complaint were admitted to the Department of Gastroenterology and were accurately diagnosed with hypopituitarism at the Department of Endocrinology. Case Summary: This case pertains to a 57-year-old man with poor appetite, fatigue, weakness, and recent onset recurring abdominal pain. An erect, abdominal X-ray indicated flatulence and gas-fluid levels in the midsection of the abdomen, and pseudo-intestinal obstruction was diagnosed. Subsequently, the patient was referred to the Department of Gastroenterology to identify the cause of the pseudo-intestinal obstruction. An examination of the digestive system did not reveal any abnormalities, but the patient developed hyponatremia and exhibited drowsiness. The patient was transferred to the Department of Endocrinology for further treatment. The patient was eventually diagnosed with hypopituitarism, caused by empty sella syndrome. The patient received prednisone and euthyrox replacement therapy, and pseudo-intestinal obstruction did not occur again. Conclusion: In general, endocrine diseases, including hypopituitarism, hypothyroidism, and hyponatremia, should be considered for patients with pseudo-intestinal obstruction combined with hyponatremia and drowsiness, especially if the symptoms of the digestive system are not complicated and the drowsiness is obvious.

Background and Objectives: Migraine is an exhausting neuro-inflammatory disorder recognized as recurrent headache attacks. Evidence has shown that Interleukin (IL)-1β plays a substantial role in the neuro-immunity pathogenicity of migraine. n-3 fatty acids and curcumin revealed neuromodulatory and anti-inflammatory effects through several pathways, of which the suppression of IL-1β gene expression is an important inflammatory pathway. The aim of this study was the investigation of synergistic relation of n -3 fatty acids and nano-curcumin on IL-1β gene expression and serum levels in migraine patients. Methods: This study was performed as a randomized, double-blind, placebo-controlled trial in a period of two months. A total of 80 episodic migraines were assigned into 4 groups of 1) n-3 fatty acids and curcumin combination; 2) n -3 fatty acids; 3) nano-curcumin; and 4) n-3 fatty acids and curcumin placebo. The gene expression and serum level of IL-1β were measured by real-time PCR and ELISA methods respectively, at the beginning and the end of the interventions. Results: Results showed the n-3 fatty acids and nano-curcumin combination significantly reduced the attack frequency in a synergistic status (P < 0.001). A significantly greater reduction in the serum level of IL-1β was observed in the combination group, and the differences in the other groups were not statistically significant. The IL-1β gene expression in the combination group showed a significant reduction for other treatment groups (P < 0.05), but these significant differences were absent after multiple testing Bonferroni corrections. Conclusion: Present findings revealed that n -3 fatty acids and curcumin co-supplementation can be suggested as a promising new approach in migraine headache management, but further studies are needed to confirm these findings.

Background: Our previous findings demonstrated that in vitro supplementation of polyphenols, extracted from seeds of red grape (Nero di Troia cultivar), to peripheral lymphomonocytes from patients affected by allergic contact dermatitis (ACD) to nickel (Ni) could reduce the release of proinflammatory cytokines and nitric oxide (NO), while increasing the levels of interleukin (IL)-10, an anti-inflammatory cytokine. Objective: To assess whether an intervention with oral administration of polyphenols leads to a reduction of peripheral biomarkers in ACD patients. Methods: At T0, 25 patients affected by ACD to Ni were orally administered with 300 mg polyphenols prodie extracted from seeds of red grape (Nero di Troia cultivar) (NATUR-OX®) for 3 months (T1). The other 25 patients affected by ACD to Ni received placebo only for the same period of time. Serum biomarkers were analyzed at T0 and T1. In both groups, seven dropouts were recorded. Results: At T1 in comparison to T0, in treated patients, values of interferon-γ, IL-4, IL-17, pentraxin 3 and NO decreased, while IL-10 levels increased when compared with T0 values. Conversely, in placebo- treated patients, no modifications of biomarkers were evaluated at T1. Conclusion: Present laboratory data rely on the anti-oxidant, anti-inflammatory and anti-allergic properties of polyphenols.