A Multidisciplinary Approach and Current Perspective of Nonalcoholic Fatty Liver Disease: A Systematic Review.

In recent times, nonalcoholic fatty liver disease (NAFLD) has been considered one of the major causes of liver disease across the world. NAFLD is defined as the deposition of triglycerides in the liver and is associated with obesity and metabolic syndrome. Hyperinsulinemia, insulin resistance (IR), fatty liver, hepatocyte injury, unbalanced proinflammatory cytokines, mitochondrial dysfunction, oxidative stress, liver inflammation, and fibrosis are the main pathogenesis in NAFLD. Recent studies suggest that the action of intestinal microbiota through chronic inflammation, increased intestinal permeability, and energy uptake plays a vital role in NAFLD. Moreover, polycystic ovarian syndrome also causes NAFLD development through IR. Age, gender, race, ethnicity, sleep, diet, sedentary lifestyle, and genetic and epigenetic pathways are some contributing factors of NAFLD that can exacerbate the risk of liver cirrhosis and hepatocellular carcinoma (HCC) and eventually lead to death. NAFLD has various presentations, including fatigue, unexplained weight loss, bloating, upper abdominal pain, decreased appetite, headache, anxiety, poor sleep, increased thirst, palpitation, and a feeling of warmth. Some studies have shown that NAFLD with severe coronavirus disease 2019 (COVID-19) has poor outcomes. The gold standard for NAFLD diagnosis is liver biopsy. Other diagnostic tools are imaging tests, serum biomarkers, microbiota markers, and tests for extrahepatic complications. There are no specific treatments for NAFLD. Therefore, the main concern for NAFLD is treating the comorbid conditions such as anti-diabetic agents for type 2 diabetes mellitus, statins to reduce HCC progression, antioxidants to prevent hepatocellular damage, and bariatric surgery for patients with a BMI of >40 kg/m2 and >35 kg/m2 with comorbidities. Lifestyle and dietary changes are considered preventive strategies against NAFLD advancement. Inadequate treatment of NAFLD further leads to cardiac consequences, sleep apnea, chronic kidney disease, and inflammatory bowel disease. In this systematic review, we have briefly discussed the risk factors, pathogenesis, clinical features, and numerous consequences of NAFLD. We have also reviewed various guidelines for NAFLD diagnosis along with existing therapeutic strategies for the management and prevention of the disease.

Role of Prophylactic Steroids in Differentiation Syndrome.

Acute promyelocytic leukemia (APML) is defined as a balanced chromosomal translocation between chromosomes 15 and 17 t(15;17)(q24;q21), which results in the formation of promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) fusion protein. A widespread recommendation for APML treatment is combined all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) therapy. Differentiation syndrome (DS), or retinoic acid syndrome, is one of the well-known complications of APML treated with ATRA or ATO. The presenting symptoms of APML-induced DS are diverse, and rare symptoms are easily misdiagnosed. However, unexplained fever, dyspnea, weight gain > 5 kg, leukocytosis, acute renal failure, and a chest radiograph demonstrating pleural or pericardial effusion are the most common manifestations of DS. Early recognition and prompt initiation of corticosteroids are key factors in the management of DS. As soon as ATRA/ATO therapy is started, prophylactic treatment with steroids has been recommended to minimize the severity of DS. It is proposed that ATRA/ATO should be stopped or held once the signs and symptoms of DS develop. This case report describes a 45-year-old male who was diagnosed with APML after he developed episodes of hematuria and nose bleeding at home. The patient was also given an empiric steroid along with ATRA/ATO to lessen the intensity of DS. Our study suggests that early initiation of prophylactic steroid treatment can improve the prognosis and mortality of patients with APML-induced DS.

Fournier's Gangrene: A Coexistence or Consanguinity of SGLT-2 Inhibitor Therapy.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) are a relatively new class of medications used for the management of type II diabetes mellitus targeting the kidneys. Within the last decade, several warnings have been issued regarding the development of severe genitourinary infections, including necrotizing fasciitis, or Fournier's gangrene, in those with pre-existing type II diabetes and concomitant use of this drug class. OBJECTIVE: The purpose of this review is to highlight and discuss the factors contributing to the development of Fournier's gangrene, its pathogenesis, and a review of existing literature describing patient outcomes, treatment, and future directions regarding early detection of this complication. METHODS: Articles and studies addressing effective treatment adherence and key factors contributing to Fournier's gangrene with SGLT2 inhibitors were identified by effective keyword searches in PubMed Central, Google Scholar, and Cochrane, as well as the references found within these articles. RESULTS: Using the keywords provided, 55 case reports, review articles, and meta-analysis reports written within the last 20 years were utilized as the source of the data presented in this systematic review article.

An Overview on Causes of Nonadherence in the Treatment of Rheumatoid Arthritis: Its Effect on Mortality and Ways to Improve Adherence.

Rheumatoid arthritis is one of the most prevalent musculoskeletal disorders that, when insufficiently treated, results in detrimental sequelae including joint damage and reduced quality of life. Poor patient adherence to medication is a significant blockade to effective management. The purpose of this review is to highlight and discuss the factors responsible for defiance of antirheumatic medication and ways to overcome these barriers. Education level, health literacy, cohabitation status, multi-morbidities, complicated drug regimen, intermittent co-payments, prescribed regimen adverse effects, and cognitive impairment are a few among many common barrier factors leading to poorer outcomes in rheumatoid arthritis. While there is an abundance of inhibitory factors leading to worsening disease progression, they each can be easily dealt with an effective approach at the beginning or during the treatment course to ensure a better outcome.

Rapid Turn From Cirrhosis to Encephalopathy Following COVID-19 Infection: A Cautionary Tale.

The coronavirus disease 2019 (COVID-19) infection has most commonly led to patients presenting with pulmonary disease, including severe acute respiratory syndrome. However, in about 14-53% of patients with a newly diagnosed COVID-19 infection, the liver is the organ most drastically affected, as opposed to the lungs. In patients with preexisting liver damage, the first symptom of a COVID-19 infection may come from worsening liver failure such as hepatic encephalopathy or worsening ascites. This case report highlights this unusual presentation of a COVID-19 infection in a patient with preexisting alcoholic liver cirrhosis. We report this case to heed warning that acutely worsening liver failure may be the first presenting symptom of a superimposed COVID-19 infection on preexisting liver disease.

CAPERalpha is a novel Rel-TAD-interacting factor that inhibits lymphocyte transformation by the potent Rel/NF-kappaB oncoprotein v-Rel.

The Rel/NF-kappaB transcription factors are constitutively activated in many human cancers. The Rel proteins in this family are implicated in leukemia/lymphomagenesis, but the mechanism is not completely understood. Previous studies showed that the transcription activation domains (TADs) of the viral oncoprotein v-Rel and its cellular Rel/NF-kappaB homologues c-Rel and RelA are key determinants of their different transforming activities in primary lymphocytes. Substitution of a Rel TAD for that of RelA conferred a strong transforming phenotype upon RelA, which otherwise failed to transform cells. To gain insights into protein interactions that influence cell transformation by the Rel TADs, we identified factors that interact with the TAD of v-Rel, the most oncogenic member of the Rel/NF-kappaB family. We report that the coactivator for transcription factors AP-1 and estrogen receptors, CAPERalpha, interacts with the v-Rel TAD and potently synergizes v-Rel-mediated transactivation. Importantly, coexpression of CAPERalpha markedly reduced and delayed v-Rel's transforming activity in primary lymphocytes, whereas a dominant-negative mutant enhanced the kinetics of v-Rel-mediated transformation. Furthermore, small interfering RNA-mediated knockdown of CAPERalpha in v-Rel-transformed lymphocytes significantly enhanced colony formation in soft agar. Since the potency of Rel-mediated transactivation is an important determinant of lymphocyte transformation, as is Rel's ability to induce transcriptional repression, these data suggest that CAPERalpha's interaction with the Rel TAD could modulate Rel/NF-kappaB's transforming activity by facilitating expression or dampening repression of specific gene subsets important for oncogenesis. Overall, this study identifies CAPERalpha as a new transcriptional coregulator for v-Rel and reveals an important role in modulating Rel's oncogenic activity.

Regulation of programmed cell death by NF-kappaB and its role in tumorigenesis and therapy.

The Rel/NF-kappaB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-kappaB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. While NF-kappaB is best characterized for its protective activity in response to proapoptotic stimuli, its role in suppressing programmed necrosis has come to light more recently. NF-kappaB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types. It is therefore important to understand the pathways that control NF-kappaB activation in different settings and the mechanisms that regulate its anti- vs pro-death activities. Here, we review the role of NF-kappaB in apoptotic and necrotic PCD, the mechanisms involved, and how its activity in the cell death response impacts cancer development, progression, and therapy. Given the role that NF-kappaB plays both in tumor cells and in the tumor microenvironment, recent findings underscore the NF-kappaB signaling pathway as a promising target for cancer prevention and treatment.

Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma.

Multiple myeloma (MM) is an invariably fatal form of cancer characterized by clonal proliferation of malignant plasma cells in the bone marrow. The canonical Wnt signaling pathway is activated in MM cells through constitutively active beta-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. The identification of a number of small molecular compounds, such as PKF115-584, which disrupt the interaction of the transcriptionally active beta-catenin/TCF protein complex, provides valuable new therapeutic tools to target an alternative pathway in MM independent of the proteasome. Here we evaluated the transcriptional, proteomic, signaling changes, and biological sequelae associated with the inhibition of Wnt signaling in MM by PKF115-584. The compound blocks expression of Wnt target genes and induces cytotoxicity in both patient MM cells and MM cell lines without a significant effect in normal plasma cells. In xenograft models of human MM, PKF115-584 inhibits tumor growth and prolongs survival. Taken together, these data demonstrate the efficacy of disrupting the beta-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM.

Induction of apoptosis by benzamide and its inhibition by aurin tricarboxylic acid (ATA) in Chinese hamster V79 cells.

To investigate the effect of benzamide and nicotinamide, well known inhibitors of poly(ADP-ribose) polymerase, in Chinese hamster V79 cells at the physiological condition of cell growth, we have tested the ability of the inhibitors to induce apoptosis. Apoptosis was detected by nuclear fragmentation, nucleosomal ladder formation, cytochrome-c release from the mitochondria and caspase-3 activation. Benzamide treatment alone increased nuclear fragmentation in dose (2.5-10 mM) and time (4-48 h)-dependent manner. Such treatment also increased nucleosomal ladders. However, 5 mM benzamide pre-treatment inhibited the nucleosomal ladders induced by gamma-irradiation indicating the role of poly(ADP-ribose) polymerase was different in irradiated cells and in un-irradiated cells. Release of cytochrome-c from the mitochondria and caspase-3 activity were also increased by such treatment. Treatment with 200 microM of aurin tricarboxylic acid (ATA), an inhibitor of DNases, inhibited the nucleosomal ladders induced by benzamide or gamma-irradiation without changing the cytochrome-c release or caspase-3 activation. This result showed that ATA inhibited the nucleosomal ladders possibly by inhibiting DNase(s) involved in apoptosis.