Future therapeutic perspectives in nonalcoholic fatty liver disease: a focus on nuclear receptors, a promising therapeutic target.

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem worldwide, with an increasing incidence, secondary to the increasing incidence of obesity and diabetes, from a very young age. It is associated with metabolic and cardiovascular disorders, as components of the metabolic syndrome (MS). NAFLD is the hepatic manifestation of MS. The pathogenesis of the disease is multifactorial and complex, involving genetic, metabolic, but also environmental factors. Currently, nuclear receptors (NRs) represent a promising therapeutic target in the treatment of non-alcoholic steatohepatitis (NASH). Of these, the most studied receptor was the liver X receptor (LXR), which would have great potential in the treatment of metabolic diseases, namely hypercholesterolemia, atherosclerosis, and NAFLD. However, the therapeutic use of NRs is restricted in medical practice for two reasons: limited knowledge of the structure of the receptor and its inability to modulate certain actions in the target organs and genes. One problem is the understanding of the function and structure of the N-terminal domain which has a major transcriptional activation function (AF1).

Beyond the Cold: Activating Brown Adipose Tissue as an Approach to Combat Obesity.

With a dramatic increase in the number of obese and overweight people, there is a great need for new anti-obesity therapies. With the discovery of the functionality of brown adipose tissue in adults and the observation of beige fat cells among white fat cells, scientists are looking for substances and methods to increase the activity of these cells. We aimed to describe how scientists have concluded that brown adipose tissue is also present and active in adults, to describe where in the human body these deposits of brown adipose tissue are, to summarize the origin of both brown fat cells and beige fat cells, and, last but not least, to list some of the substances and methods classified as BAT promotion agents with their benefits and side effects. We summarized these findings based on the original literature and reviews in the field, emphasizing the discovery, function, and origins of brown adipose tissue, BAT promotion agents, and batokines. Only studies written in English and with a satisfying rating were identified from electronic searches of PubMed.

The therapeutic mechanisms and beneficial effects of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease: a systematic review.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, with an increasing prevalence in all regions of the world. Its spectrum includes hepatic steatosis (HS) and non-alcoholic steatohepatitis (NASH) with progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD may represent the hepatic manifestation of the metabolic syndrome (MS), with a prevalence directly proportional to the prevalence of obesity and MS. The standard treatment for patients with NAFLD is lifestyle modification, which in medical practice has many limitations. To overcome them, numerous drugs with benefits in the prevention and treatment of the disease have been studied. Currently, the most used substances are vitamin E and Pioglitazone, with numerous benefits. Furthermore, new strategies and beneficial treatments are needed for the prevention of the disease, which is currently a priority in both the health and research fields. One of the most studied agents in the last decades has been ursodeoxycholic acid (UDCA), which is of great interest in the treatment of NAFLD due to its hepatoprotective effects.

The Role of the Fatty Liver Index (FLI) in the Management of Non-Alcoholic Fatty Liver Disease: A Systematic Review.

Currently, non-alcoholic fatty liver disease is the most common liver disease worldwide, with a prevalence of 32%. It is much more common among men (40%) and among patients with metabolic comorbidities such as obesity, diabetes and dyslipidemia. Being an asymptomatic disease, the diagnosis is often established on the basis of imaging methods, with an important role given to abdominal ultrasonography, computed tomography and magnetic resonance imaging. In order to facilitate diagnosis, experts have introduced a series of blood biomarkers. Two biomarker panels are currently validated for the diagnosis of non-alcoholic fatty liver disease: the fatty liver index, and the hepatic steatosis index. The fatty liver index has been in use in medical practice for over 17 years and has demonstrated its accuracy in various studies that compared it with other diagnostic methods, highlighted its role in screening patients with cardiovascular risk and validated the effects of different diets and drugs that are proposed for the treatment of the disease. In the management of non-alcoholic fatty liver disease, the fatty liver index is an important algorithm in the diagnosis and prognosis of patients with metabolic risk. Taking into account the diversity of drugs to be approved in the treatment of non-alcoholic fatty liver disease, the fatty liver index will become an effective tool in monitoring the effects of these therapies.

Diagnostic Performance of an Artificial Intelligence Model Based on Contrast-Enhanced Ultrasound in Patients with Liver Lesions: A Comparative Study with Clinicians.

Contrast-enhanced ultrasound (CEUS) is widely used in the characterization of liver tumors; however, the evaluation of perfusion patterns using CEUS has a subjective character. This study aims to evaluate the accuracy of an automated method based on CEUS for classifying liver lesions and to compare its performance with that of two experienced clinicians. The system used for automatic classification is based on artificial intelligence (AI) algorithms. For an interpretation close to the clinical setting, both clinicians knew which patients were at high risk for hepatocellular carcinoma (HCC), but only one was aware of all the clinical data. In total, 49 patients with 59 liver tumors were included. For the benign and malignant classification, the AI model outperformed both clinicians in terms of specificity (100% vs. 93.33%); still, the sensitivity was lower (74% vs. 93.18% vs. 90.91%). In the second stage of multiclass diagnosis, the automatic model achieved a diagnostic accuracy of 69.93% for HCC and 89.15% for liver metastases. Readers demonstrated greater diagnostic accuracy for HCC (83.05% and 79.66%) and liver metastases (94.92% and 96.61%) compared to the AI system; however, both were experienced sonographers. The AI model could potentially assist and guide less-experienced clinicians to discriminate malignant from benign liver tumors with high accuracy and specificity.

The Clinical Value of Multimodal Ultrasound for the Differential Diagnosis of Hepatocellular Carcinoma from Other Liver Tumors in Relation to Histopathology.

Recent advances in the field of ultrasonography offer promising tools for the evaluation of liver tumors. We aim to assess the value of multimodal ultrasound in differentiating hepatocellular carcinomas (HCCs) from other liver lesions. We prospectively included 66 patients with 72 liver tumors. The histological analysis was the reference standard for the diagnosis of malignant liver lesions, and partially for benign tumors. All liver lesions were assessed by multiparametric ultrasound: standard ultrasound, contrast-enhanced ultrasound (CEUS), the point shear wave elastography (pSWE) using shear wave measurement (SWM) method and real-time tissue elastography (RTE). To diagnose HCCs, CEUS achieved a sensitivity, specificity, accuracy and positive predictive value (PPV) of 69.05%, 92.86%, 78.57% and 93.55%, respectively. The mean shear-wave velocity (Vs) value in HCCs was 1.59 ± 0.29 m/s, which was lower than non-HCC malignancies (p < 0.05). Using a cut-off value of 1.58 m/s, SWM achieved a sensitivity of 54.76%, and 82.35% specificity, for differentiating HCCs from other malignant lesions. The combination of SWM and CEUS showed higher sensitivity (79.55%) compared with each technique alone, while maintaining a high specificity (89.29%). In RTE, most HCCs (61.53%) had a mosaic pattern with dominant blue areas corresponding to type "c" elasticity. Elasticity type "c" was 70.59% predictive for HCCs. In conclusion, combining B-mode ultrasound, CEUS, pSWE and RTE can provide complementary diagnostic information and potentially decrease the requirements for other imaging modalities.

An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma.

Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood-brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents.

Obesity and Myocardial Infarction-The Place of Obesity Among Cardiovascular Risk Factors-Retrospective Study.

Since the 21st century, the leading cause of death is cardiovascular disease, with myocardial infarction being the most common. The incidence and prevalence of obesity has risen sharply in recent years, and it is commonly recognised as a cardiovascular risk factor among tobacco smoking, dyslipidemia (high LDL-C, high triglycerides, low HDL-C), hypertension, diabetes, age, gender, hereditary predisposition. MATERIALS AND METHODS: This study is a retrospective study conducted at the Craiova Emergency Clinical Hospital between October 2020 and January 2023. Enrolled patients are 60, 36 patients with ST-segment elevation myocardial infarction and 24 patients with non-ST-segment elevation acute myocardial infarction. The data was collected from the hospital's official database and then analyzed using Microsoft Excel and the Toolbar Data Analysis. RESULTS: The mean age of the patients in the study was 62 years with a minimum of 34 years and a maximum of 84 years. 23(38.3%) of patients were smokers, 7(11.6%) were ex-smokers and 30(50%) were non-smokers. 49(81.6%) patients were hypertensive. 44(73%) had cholesterol greater than 200mg/dl. 54(90%) had LDL>100mg/dl, 18(30%) had HDL>45mg/gl, 24(40%) patients had serum TG>150mg/dl, 17(28%) were overweight and 13(22%) were obese, 30(50%) were normal weight. 18(30%) patients had type 2 diabetes. CONCLUSIONS: Among the cardiovascular risk factors in the patients studied, hypertension was the most common, followed by dyslipidemia, obesity, smoking, diabetes mellitus, and very rarely the use of drugs and anabolic substances.

Decrease of glutathione peroxidase in arrhythmic cardiac pathology in young individuals and its therapeutic implications.

Glutathione peroxidase (GPx), as an antioxidant enzyme, is involved in the regulation of processes that cause cellular oxidative stress, with implications in various pathologies. The aim of the present study was to evaluate GPx variations in patients with arrhythmic, non-structural cardiac disorders. The research was performed on 120 patients, with a mean age of 33 years old, divided into 3 equal groups, of which 2 groups included patients with cardiac arrhythmias, the first group, associated with dyslipidemia and the second one, without dyslipidemia, and a control group consisting of healthy individuals. The method for determining GPx was based on the GPx enzyme catalysis reaction of the reduced glutathione (GSH) oxidation reaction by cumene hydroperoxide. The results revealed that GPx variation was decreased in patients with cardiac arrhythmias, with or without dyslipidemia, up to 66 and 74% of mean control values, respectively, the differences being statistically significant, showing the existence of an oxidative stress imbalance, that may be involved in triggering arrhythmogenic electrochemical mechanisms. The GPx deficiency determined in relation to cardiac arrhythmias was in dyslipidemic and non-lipidemic patients as follows: 29-35% in sinus bradycardia, 31-35% in associated cardiac arrhythmias, 30-33% in sinus tachycardia, 27-33% in atrial fibrillation, 32-33% in atrial flutter, 27-32% in atrial extrasystolic arrhythmia, 28-30% in ventricular extrasystolic arrhythmia and 18-26% in paroxysmal supraventricular tachycardia. Collectively, the results revealed that GPx, an antioxidant enzyme, is a specific biomarker, whose decrease indicated the existence of oxidative stress in young individuals with cardiac arrhythmias and its involvement in arrhythmogenic electrochemical processes. In addition, GPx deficiencies were between 18-35% in all types of cardiac arrhythmias, the highest being recorded in sinus bradycardia and the lowest in paroxysmal supraventircular tachycardia. Furthermore, the oxidative stress favored by the decrease of GPx induced lipid oxidation, regardless of the presence or absence of dyslipidemia, which triggered the formation of anti-lipid antibodies and a subclinical endothelial aggression, with early atherosclerotic potential. GPx evaluation may argue for the existence of oxidative stress in non-structural cardiac arrhythmias, and by its proper correction (antioxidants), prophylaxis of atherogenic dysfunction.

Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy.

Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.

Hepatocellular Carcinoma with Gastrointestinal Involvement: A Systematic Review.

In this paper, we aimed to evaluate clinical and imagistic features, and also to provide a diagnostic algorithm for patients presenting with gastrointestinal involvement from hepatocellular carcinoma (HCC). We conducted a systematic search on the PubMed, Scopus and Web of Science databases to identify and collect papers oncases of HCC with gastrointestinal involvement. This search was last updated on 29 April 2022. One hundred and twenty-three articles were included, corresponding to 197 patients. The majority of the patients were male (87.30%), with a mean age of 61.21 years old. The analysis showed large HCCs located mainly in the right hepatic lobe, and highly elevated alfa-fetoprotein (mean = 15,366.18 ng/mL). The most frequent etiological factor was hepatitis B virus (38.57%). Portal vein thrombosis was present in 27.91% of cases. HCC was previously treated in most cases by transarterial chemoembolization (32.99%) and surgical resection (28.93%). Gastrointestinal lesions, developed mainly through direct invasion and hematogenous routes, were predominantly detected in the stomach and duodenum in equal measure-27.91%. Gastrointestinal bleeding was the most common presentation (49.74%). The main diagnostic tools were esophagogastroduodenoscopy (EGD) and computed tomography. The mean survival time was 7.30 months. Gastrointestinal involvement in HCC should be included in the differential diagnosis of patients with underlying HCC and gastrointestinal manifestations or pathological findings in EGD.

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review).

Due to its localisation, rapid onset, high relapse rate and resistance to most currently available treatment methods, glioblastoma multiforme (GBM) is considered to be the deadliest type of all gliomas. Although surgical resection, chemotherapy and radiotherapy are among the therapeutic strategies used for the treatment of GBM, the survival rates achieved are not satisfactory, and there is an urgent need for novel effective therapeutic options. In addition to single-target therapy, multi-target therapies are currently under development. Furthermore, drugs are being optimised to improve their ability to cross the blood-brain barrier. In the present review, the main strategies applied for GBM treatment in terms of the most recent therapeutic agents and approaches that are currently under pre-clinical and clinical testing were discussed. In addition, the most recently reported experimental data following the testing of novel therapies, including stem cell therapy, immunotherapy, gene therapy, genomic correction and precision medicine, were reviewed, and their advantages and drawbacks were also summarised.

The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer.

Cancer and viruses have a long history that has evolved over many decades. Much information about the interplay between viruses and cell proliferation and metabolism has come from the history of clinical cases of patients infected with virus-induced cancer. In addition, information from viruses used to treat some types of cancer is valuable. Now, since the global coronavirus pandemic erupted almost a year ago, the scientific community has invested countless time and resources to slow down the infection rate and diminish the number of casualties produced by this highly infectious pathogen. A large percentage of cancer cases diagnosed are strongly related to dysregulations of the tyrosine kinase receptor (TKR) family and its downstream signaling pathways. As such, many therapeutic agents have been developed to strategically target these structures in order to hinder certain mechanisms pertaining to the phenotypic characteristics of cancer cells such as division, invasion or metastatic potential. Interestingly, several authors have pointed out that a correlation between coronaviruses such as the SARS-CoV-1 and -2 or MERS viruses and dysregulations of signaling pathways activated by TKRs can be established. This information may help to accelerate the repurposing of clinically developed anti-TKR cancer drugs in COVID-19 management. Because the need for treatment is critical, drug repurposing may be an advantageous choice in the search for new and efficient therapeutic compounds. This approach would be advantageous from a financial point of view as well, given that the resources used for research and development would no longer be required and can be potentially redirected towards other key projects. This review aims to provide an overview of how SARS-CoV-2 interacts with different TKRs and their respective downstream signaling pathway and how several therapeutic agents targeted against these receptors can interfere with the viral infection. Additionally, this review aims to identify if SARS-CoV-2 can be repurposed to be a potential viral vector against different cancer types.

Updated Insights on EGFR Signaling Pathways in Glioma.

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood-brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

Variation of Total Antioxidant Activity in Young People with Non-Lesional Cardiac Arrhythmias.

Total antioxidant activity status (TAS) represents the body's response to oxidative stress, important in the pathogenic assessment of oxidations. AIM: To determine TAS variations in young subjects, with non-lesional cardiac arrhythmias, with/without dyslipidemia and to assess the risk of lipid oxidation. PATIENTS AND METHODS: The research was performed on 120 young subjects (mean age 33 years), with various types of cardiac arrhythmias, on normal heart, without co-existing lesions. Subjects were divided into 3 groups (40 persons). The first 2 groups included subjects with cardiac arrhythmias. Group I also associated dyslipidemia; group II, without dyslipidemia and group III: control. Determination of TAS values was performed using ABTS (2-azino-di-3-ethylbenzthiazoline sulfonate) colorimetic method. Results were statistically processed. RESULTS: TAS values were decreased in all patients with cardiac arrhythmias, representing 52-54% of the values of healthy controls, the data being highly statistically significant. The variation of TAS decrease by types of arrhythmias was thus found in patients with arrhythmias and associated dyslipidemia and, respectively, without dyslipidemia, compared to controls. The deficit of antioxidant activity, between 48%-46% triggers electrochemical processes with implications in arrhythmogenesis and lipid oxidation. Coffee and vegetables-rich diet have antioxidant effect, reducing TAS deficiency. CONCLUSIONS: 1. TAS was decreased in all subjects with non-lesional arrhythmias. The study showed decreasing TAS level at 52-54% in patients with arrhythmias, with/without dyslipidemia, compared to controls. 2. TAS deficiency was associated with various types of dysrhythmias, ranging from 62% to 33%. 3. Decreased TAS also triggers lipid oxidation, as risk factor for early atherosclerotic lesions.

Diagnostic and prognostic significance of hepatic steatosis in patients with chronic hepatitis C.

Knowing that hepatic steatosis (HS) is a common occurrence in patients with chronic hepatitis C (CHC), it is essential to establish what are the factors that predispose to its occurrence and what is the role of HS in the evolution and prognosis of patients with CHC who develop this feature. To achieve these aims, we performed a retrospective clinical study in 33 patients with CHC hospitalized, diagnosed, and monitored in the 2nd Medical Department of the Emergency County Hospital, Craiova, Romania, in a period of two years (2011-2012). Following clinical, hematological, biochemical, immunological, and pathological investigations of the 33 patients with CHC selected, only 14 patients showed pathological changes of the HS. The appearance of steatosis in patients with CHC results from a complex interaction between the particularities of the host and viral factors. The main risk factors of the host, which contributed to the appearance of HS were sex, age, body mass index (BMI), body weight, and personal history of pathology (obesity, metabolic syndrome). Virus-related factors involved in HS were viremia and viral genotype. In conclusion, HS is a common finding (42.42%) in patients with CHC, particularly genotypes 1 and 2. Early detection of HS by invasive or non-invasive methods is an important objective of monitoring patients with CHC, because HS is correlated with a high degree of fibrosis. Therefore, early correction of metabolic factors and early introduction of antiviral therapy are important targets for treating of patients with CHC.

The effect of temozolomide in combination with doxorubicin in glioblastoma cells in vitro.

BACKGROUND: Prior to 2000, the DNA alkylating agents nitrosoureas were used as standard treatment of glioblastoma. Current treatments for glioblastoma patients consist of surgery followed by radiation in combination with temozolomide. Despite therapeutic advances, the prognosis for glioblastoma patients remains grim, with a five-year overall survival below 15%. In this study, our team analyzed the interaction between temozolomide and doxorubicin in a glioblastoma cell line, in vitro. MATERIALS AND METHOD: The cell line, established from a patient who underwent surgery at the "Bagdasar Arseni Emergency Hospital", was exposed to 10 µM and 100 µM of temozolomide and 10 nM and 100 nM of doxorubicin, respectively, over a period of 7, 10 and 14 days, in monotherapy and in combination. RESULTS: The results showed that both temozolomide (66.5% cytotoxicity for the 10 µM dose at 14 days) de and doxorubicin (66.8% cytotoxicity for the 10 nM dose after 14 days) were very effective in killing cancer cells in monotherapy, but failed to produce a synergistic effect when used in combination. CONCLUSION: While the results may be discouraging, they present an interesting prospect into how certain drug interactions can impact treatment response.

Corpuscular Haemolytic Anaemias - Lepore Haemoglobinopathy.

Haemoglobinopathies are hereditary conditions in which the fundamental lesion affects the synthesis rate or the structure of the globin in normal hemoglobin. The synthesis of the polypeptide chains in globin is genetically coded. Clinically, haemoglobinopathies manifest most commonly in the form of hemolytic anemia and, more rarely, cyanosis and polyglobulia. They differ from "acquired haemoglobinopathies", such as methemoglobinemia, in which hemoglobin is usually compromised due to the action of toxic substances. The clinical aspects are in close relationship to the nature and level of the structural anomaly of the Hb molecule. The heterozygous form of the Lepore syndrome is hematologically characterized by a similar pattern to minor ß-thalassemia and electrophoretically by abnormal Hb D fractions at a rate of 5-10% and a decreased percentage of HbA. In homozygous forms, Lepore Hb represents 10-20% on electrophoresis, the rest consisting of HbF; HbA and HbA2 are completely absent. From a clinical point of view, Hb Lepore heterozygotes are similar to those with minor ß - thalassemia.