Current Pharmaceutical Design - Volume 26, Issue 32, 2020

Background: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic involving 20-40% of the general population. NAFLD is rapidly becoming the leading cause of hepatocellular carcinoma (HCC) worldwide. Knowledge about NAFLD-HCC peculiar features is needed to understand this emerging disease better. Objective: To review the current literature about the epidemiological, pathogenic and clinical features characterising the NAFLD and distinguishing it from HCC of other etiologies. Methods: A systematic review of the literature (PubMed and Medline) using the following string ("Non-alcoholic Fatty Liver Disease"[Mesh] and "Carcinoma, Hepatocellular"[Mesh]). Particular relevance was given to papers published in the last five years as well as previously published manuscript very relevant to this topic according to the experience of the authors. Results: A total of 244 original papers in humans in English literature were analysed. Inherent difficulties in the identification of high-risk subjects and the possibility of occurrence in non-cirrhotic livers are peculiar characteristics of NAFLD-HCC hampering surveillance programs. The consequently delayed diagnosis limits access to surgical procedures and impacts on survival. After correction for tumour burden, however, the survival is not different from that of viral HCC, suggesting that NAFLD-HCC is not intrinsically a more aggressive malignancy. Conclusion: A great deal of effort is needed to improve the clinical outcome of NAFLD-HCC, especially in terms of prevention, surveillance protocols, and identification of drug modifying the natural history of the underlying liver disease. The outcome of these efforts will significantly impact global HCC-related costs and mortality.

Nonalcoholic fatty liver disease (NAFLD) embraces histopathological entities ranging from the relatively benign simple steatosis to the progressive form nonalcoholic steatohepatitis (NASH), which is associated with fibrosis and an increased risk of progression to cirrhosis and hepatocellular carcinoma. NAFLD is the most common liver disease and is associated with extrahepatic comorbidities including a major cardiovascular disease burden. The non-invasive diagnosis of NAFLD and the identification of subjects at risk of progressive liver disease and cardio-metabolic complications are key in implementing personalized treatment schedules and follow-up strategies. In this review, we highlight the potential role of ultrasound semiquantitative scores for detecting and assessing steatosis severity, progression of NAFLD, and cardio-metabolic risk. Ultrasonographic scores of fatty liver severity act as sensors of cardio-metabolic health and may assist in selecting patients to submit to second-line non-invasive imaging techniques and/or liver biopsy.

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver diseases worldwide, involving about 25% of people. NAFLD incorporates a large spectrum of pathological conditions, from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and its complications include hepatic decompensation and hepatocellular carcinoma (HCC). This progression occurs, over many years, in an asymptomatic way, until advanced fibrosis appears. Thus, the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis are key issues. To date, the histological assessment of fibrosis with liver biopsy is the gold standard, but obviously, invasiveness is the greater threshold. In addition, rare but potentially life-threatening complications, poor acceptability, sampling variability and cost maybe restrict its use. Furthermore, due to the epidemic of NAFLD worldwide and several limitations of liver biopsy evaluation, noninvasive assessment tools to detect fibrosis in NAFLD patients are needed.

IGF2BP3 (also known as IMP3, KOC), a member of the insulin-like growth factor mRNA-binding protein family (IMPs), has been a research target in recent studies of promoting embryo development and exacerbating cancer. IGF2BP3 is ubiquitously expressed in early embryogenesis stages but limited in postembryonic stages, which is important in many physiological aspects such as stem cell renewal, morphological development and metabolism. A large number of studies show that IGF2BP3 interacts with many kinds of non-coding RNAs and proteins to promote cancer cell proliferation and metastasis and inhibit cancer cell apoptosis. As IGF2BP3 is highly expressed in advanced cancers and associated with poor overall survival rates of patients, it may be a potential molecular marker in cancer diagnosis for the detection of cancerous tissues and an indicator of cancer stages. Therefore, anti-IGF2BP3 drugs or monoclonal antibodies are expected as new therapeutic methods in cancer treatment. This review summarizes recent findings among IGF2BP3, RNA and proteins in cancer processes, with a focus on its cancer-promoting mechanisms and potential application as a new biomarker for cancer diagnosis and treatment.

Background: Erectile dysfunction (ED) is an evolving health problem in the aging male population. Chronic low-grade inflammation is a critical component of ED pathogenesis and a probable intermediate stage of endothelial dysfunction, especially in metabolic diseases, with the inclusion of obesity, metabolic syndrome, and diabetes. Objective: This review will present an overview of preclinical and clinical data regarding common inflammatory mechanisms involved in the pathogenesis of ED associated with metabolic diseases and the effect of antiinflammatory drugs on ED. Methods: A literature search of existing pre-clinical and clinical studies was performed on databases [Pubmed (MEDLINE), Scopus, and Embase] from January 2000 to October 2019. Results: Low-grade inflammation is a possible pathological role in endothelial dysfunction as a consequence of ED and other related metabolic diseases. Increased inflammation and endothelial/prothrombotic markers can be associated with the presence and degree of ED. Pharmacological therapy and modification of lifestyle and risk factors may have a significant role in the recovery of erectile response through reduction of inflammatory marker levels. Conclusion: Inflammation is the least common denominator in the pathology of ED and metabolic disorders. The inflammatory process of ED includes a shift in the complex interactions of cytokines, chemokines, and adhesion molecules. These data have established that anti-inflammatory agents could be used as a therapeutic opportunity in the prevention and treatment of ED. Further research on inflammation-related mechanisms underlying ED and the effect of therapeutic strategies aimed at reducing inflammation is required for a better understanding of the pathogenesis and successful management of ED.

Background: Glioma is one of the most commonly observed tumours, representing about 75% of brain tumours in the adult population. Generally, glioma treatment includes surgical resection followed by radiotherapy and chemotherapy. The current chemotherapy for glioma involves the use of temozolomide, doxorubicin, monoclonal antibodies, etc. however, the clinical outcomes in patients are not satisfactory. Primarily, the blood-brain barrier hinders these drugs from reaching the target leading to the recurrence of glioma post-surgery. In addition, these drugs are not target-specific and affect the healthy cells of the body. Therefore, glioma-targeted drug delivery is essential to reduce the rate of recurrence and treat the condition with more reliable alternatives. Methods: A literature search was conducted to understand glioma pathophysiology, its current therapeutic approaches for targeted delivery using databases like Pub Med, Web of Science, Scopus, and Google Scholar, etc. Results: This review gives an insight to challenges associated with current treatments, factors influencing drug delivery in glioma, and recent advancements in targeted drug delivery. Conclusion: The promising results could be seen with nanotechnology-based approaches, like polymeric, lipidbased, and hybrid nanoparticles in the treatment of glioma. Biotechnological developments, such as carrier peptides and gene therapy, are future prospects in glioma therapy. Therefore, these targeted delivery systems will be beneficial in clinical practices for glioma treatment.

Background: The diagnosis and prognosis of pathological conditions, such as age-related macular degeneration (AMD) and cancer still need improvement. AMD is primarily caused due to the dysfunction of retinal pigment epithelium (RPE), whereas endothelial cells (ECs) play one of the major roles in angiogenesis; an important process which occurs in malignant progression of cancer. Several reports suggested the augmented release of nano-vesicles under pathological conditions, including from RPE as well as cancer-associated ECs, which take part in various biological processes, including intercellular communication in disease progression. Importantly, these nano-vesicles are around 30-1000 nm and carry the fingerprint of their initiating parent cells (IPCs). Therefore, these nano-vesicles could be utilized as the diagnostic tool for AMD and cancer, respectively. However, the analysis of nano-vesicles for biomarker study is confounded by their extensive heterogeneous nature. Methods: To confront this challenge, we utilized artificial intelligence (AI) based machine learning (ML) algorithms such as support vector machine (SVM) and decision tree model on the dataset of nano-vesicles from RPE and ECs cell lines with low dimensionality. Results: Overall, Gaussian SVM demonstrated the highest prediction accuracy of the IPCs of nano-vesicles, among all the chosen SVM classifiers. Additionally, the bagged tree showed the highest prediction among the chosen decision tree-based classifiers. Conclusion: Therefore, the overall bagged tree showed the best performance for the prediction of IPCs of nanovesicles, suggesting the applicability of AI-based prediction approach in diagnosis and prognosis of pathological conditions, including non-invasive liquid biopsy via various biofluids-derived nano-vesicles.

Background: Hypoxic-ischemic (HI) brain injury is a leading cause of long-term neurodevelopmental morbidities in neonates. Human plasma-derived Inter-Alpha Inhibitor Proteins (hIAIPs) are neuroprotective after HI brain injury in neonatal rats. The light chain (bikunin) of hIAIPs inhibits proteases involved in the coagulation of blood. Newborns exposed to HI can be at risk for significant bleeding in the brain and other organs. Objective: The objectives of the present study were to assess the pharmacokinetics (PK) and the duration of bleeding after intraperitoneal (IP) administration of hIAIPs in HI-exposed male and female neonatal rats. Methods: HI was induced with the Rice-Vannucci method in postnatal (P) day-7 rats. After the right common carotid artery ligation, rats were exposed to 90 min of 8% oxygen. hIAIPs (30 mg/kg, IP) were given immediately after Sham or HI exposure in the PK study and serum was collected 1, 6, 12, 24, or 36 h after the injections. Serum hIAIP concentrations were measured with a competitive ELISA. ADAPT5 software was used to fit the pooled PK data considering first-order absorption and disposition. hIAIPs (60 mg/kg, IP) were given in the bleeding time studies at 0, 24 and 48 h after HI with tail bleeding times measured 72 h after HI. Results: IP administration yielded significant systemic exposure to hIAIPs with PK being affected markedly including primarily faster absorption and reduced elimination as a result of HI and modestly of sex-related differences. hIAIP administration did not affect bleeding times after HI. Conclusion: These results will help to inform hIAIP dosing regimen schedules in studies of neuroprotection in neonates exposed to HI.

Background: Some studies have revealed an improvement in glucose metabolism after proton-pump inhibitors (PPI) therapy; however, this evidence is inconclusive and limited. Objective: The study aimed to examine the effect of PPI on glucose and insulin metabolism in patients with type 2 diabetes through a systematic review and meta-analysis. Methods: Only randomized controlled trials evaluating the impact of PPI on glucose or insulin concentrations in type 2 diabetes were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases. A meta-analysis was conducted using a random-effects model and generic inverse variance method. Sensitivity analysis was performed using the leave-one-out method. Results: Meta-analysis revealed no significant effect of PPI intervention on fasting glucose (mean difference [MD] -11.42 [95% CI, -29.68 to 6.83], I2 = 80%, p = 0.22), fasting insulin (MD 1.51 [95% CI, -0.36 to 3.37], I2 = 32%, p = 0.11), HOMA-IR (MD -0.16 [-0.98 to 0.65], I2 = 0%, p = 0.70), HOMA-β (MD 19.97 [-21.59 to 61.52], I2 = 71%, p = 0.35), and HbA1c concentrations (MD -0.34 [-0.99 to 0.31], I2 = 89%, p = 0.30). Conclusion: The treatment with PPI, in the short term, had no significant effects on glucose and insulin metabolism in patients with type 2 diabetes.

Objective: High prevalence of Dental and periodontal problems during the gestation period may have a negative effect on oral health-related quality of life (OHRQoL) in pregnant women. This systematic review aimed to perform a quality assessment and provide a critical overview of the current research available on OHRQoL in pregnant women. Methods: For this systemic review, all original and peer-reviewed human studies, which investigated OHRQoL of women during pregnancy or post- partum period, were searched. Studies were screened in title and abstract for the relevance by two independent investigators. Methodological quality was assessed using modified items recommended by the Newcastle–Ottawa Scale for observational studies. Results: All of the eight included studies had a cross-sectional design. Meta-analysis was not possible due to the heterogeneity of key aspects among the included studies. Thus, the data from the studies were evaluated qualitatively. The overall risk of bias of the included studies was low. Conclusion: The main conclusion of this review is that the presence of signs and symptoms of dental and gingival disease negatively affects the self-perception of OHRQoL in pregnant women. The most affected domains of OHRQoL in pregnant women were related to mental and psychological discomfort, followed by physical and functional problems.

Background: Osteoporosis presents a major threat to the health of women older than 65 years. Bisphosphonates (BPs) are now the principal class of medications for osteoporosis. Objective: To evaluate the efficacy and safety of BPs in women older than 65 years. Methods: A comprehensive search in the PubMed, EMBASE, Web of Science and Cochrane Central databases was undertaken for randomized controlled trials (RCTs) on the efficacy and safety of BPs in women older than 65 years. The primary outcome measures were the change in bone mass density (BMD), serum bone turnover marker levels, fracture rate and the adverse effect (AE) rate. The final search was performed in August 2019. Results: Seven RCTs were included. A total of 23287 patients met the inclusion criteria. BPs significantly increased the BMD of the posteroanterior (PA) spine, lateral spine and femoral neck, and reduced the fracture, vertebrate fracture and hip fracture rates in women older than 65 years. In addition, BPs increased the risks for pyrexia, myalgia, arthralgia, headache and influenza-like symptoms and had no statistical effect on any AEs, any serious AEs, discontinuation due to AEs, oesophagitis, any upper gastrointestinal adverse event, atrial fibrillation and myocardial infarction occurrence in women older than 65 years. Finally, intravenous BPs reduced hip fracture risk but increased AEs in women older than 65 years. Conclusion: Despite the fact that AEs significantly increased after drug delivery, BPs are highly effective and safe for managing osteoporosis in women older than 65 years. Zoledronic acid caused an increased rate of AEs in women older than 65 years, but these AEs seemed to be mild to moderate. In addition, the hip fracture rate in women older than 80 years old treated with BPs was different than that in the other included patients. Therefore, doctors may prescribe BPs for women older than 65 years in order to increase BMD, and AEs and hip fractures in women older than 80 years should be given attention.