MicroRNA-155, a double-blade sword regulator of innate tuberculosis immunity.

Tuberculosis (TB) is a chronic, life-threatening disease caused by unusual facultative intracellular bacteria, Mycobacterium tuberculosis. This bacterium has unique resistance to many antimicrobial agents and has become a major global health concern due to emerging multidrug-resistant strains. Additionally, it has developed multiple schemes to exploit host immune signaling and establish long-term survival within host tissues. Thus, understanding the pathways that govern the crosstalk between the bacterium and the immune system could provide a new avenue for therapeutic interventions. MicroRNAs (miRs) are short, noncoding, and regulator RNA molecules that control the expression of cellular genes by targeting their mRNAs post-transcriptionally. MiR-155 is one of the most crucial miR in shaping the host immune defenses against M. tuberculosis. MiR-155 is remarkably downregulated in patients with clear clinical TB symptoms in comparison with latently infected patients and/or healthy individuals, thereby implicating its role in controlling M. tuberculosis infection. However, functional probing of miR-155 suggests dual effects in regulating the host's innate defenses in response to mycobacterial infection. This review provides comprehensive knowledge and future perspectives regarding complex signaling pathways that mediated miR-155 expression during M. tuberculosis infections. Moreover, miR-155-targeting signaling orchestrates inflammatory mediators' production, apoptosis, and autophagy.

Of mitochondrion and COVID-19.

COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19's signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19.

The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs' cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism.

Gingerenone A Attenuates Monocyte-Endothelial Adhesion via Suppression of I Kappa B Kinase Phosphorylation.

During the early stages of atherosclerosis, monocytes bind and migrate into the endothelial layer, promoting inflammation within the aorta. In order to prevent the development of atherosclerosis, it is critical to inhibit such inflammation. The therapeutic effects of ginger have been investigated in several models of cardiovascular disease. However, although a number of previous studies have focused on specific compounds, the mechanisms of action responsible remain unclear. Here, we investigated five major compounds present in ginger, and observed that gingerenone A exhibited the strongest inhibitory effects against tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) induced monocyte-endothelial adhesion. Furthermore, gingerenone A significantly suppressed the expression of TNF-α and LPS-induced vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 2 (CCL2), key mediators of the interaction between monocytes, and endothelial cells. Transactivation of nuclear factor-κB (NF-κB), which is a key transcription factor of VCAM-1 and CCL2, was induced by TNF-α and LPS, and inhibited by treatment of gingerenone A. Gingerenone A also inhibited the phosphorylation of NF-κB inhibitor (IκB) α and IκB Kinase. Taken together, these results demonstrate that gingerenone A attenuates TNF-α and LPS-induced monocyte adhesion and the expression of adhesion factors in endothelial cells via the suppression of NF-κB signaling. J. Cell. Biochem. 119: 260-268, 2018. © 2017 Wiley Periodicals, Inc.

Synthetic strigolactone analogues reveal anti-cancer activities on hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) remains one of the leading causes of death worldwide. The complex etiology is attributed to many factors like heredity, cirrhosis, hepatitis infections or the dysregulation of the different molecular pathways. Nevertheless, the current treatment regimens have either severe side effects or tumors gradually acquire resistance upon prolonged use. Thus, developing a new selective treatment for HCC is the need of the hour. Many anticancer agents derived from plants have been evaluated for their cytotoxicity towards many human cancer cell lines. Strigolactones (SLs)-a newly discovered class of phytohormones, play a crucial role in the development of plant-root and shoot. Recently, many synthetic analogues of SLs have demonstrated pro-apoptotic effects on different cancer cell lines like prostate, breast, colon and lung. In this study, we tested synthetic SLs analogues on HCC cell line-HepG2 and evaluated their capability to induce cell proliferation inhibition and apoptosis. Primary WST-1 assays, followed by annexin-V/7AAD staining, demonstrated the anti-proliferative effects. The SLs analogues TIT3 and TIT7 were found to significantly reduce HepG2 cell viability in a dose- and time-dependent manner and induce apoptosis. Interestingly, though TIT3 and TIT7 strongly affected cancer cell proliferation, both compounds showed moderate anti-proliferative effect on normal cells. Further, migration of cancer cells was suppressed upon treatment with TIT3 and TIT7 in a wound healing assay. In summary, these findings suggest that two SLs analogues TIT3 and TIT7 exert selective inhibitory effects on cancer cells most likely through targeting microtubules. SLs analogues could be used in future as potential anti-cancer candidates in chemotherapy.

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial.

BACKGROUND & AIMS: Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. METHODS: We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naïve and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6-12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29 of 33; 95% confidence interval, 72%-97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28 of 30; 95% CI, 78%-99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%-100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%-100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis. ClinicalTrials.gov ID: NCT02378961.

Chemical screening and development of novel gibberellin mimics.

Gibberellin (GA) plays versatile roles in the regulation of plant growth and development and therefore is widely used as a regulator in agriculture. We performed a chemical library screening and identified a chemical, named 67D, as a stimulator of seed germination that was suppressed by paclobutrazol (PAC), a GA biosynthesis inhibitor. In vitro binding assays indicated that 67D binds to the GID1 receptor. Further studies on the structure-activity relationship identified a chemical, named chemical 6, that strongly promoted seed germination suppressed by PAC. Chemical 6 was further confirmed to promote the degradation of RGA (for repressor of ga1-3), a DELLA protein, and suppress the expression levels of GA3ox1 in the same manner as GA does. 67D and its analogs are supposed to be agonists of GID1 and are expected to be utilized in agriculture and basic research as an alternative to GA.

Urinary biomarkers of exposure to 57 xenobiotics and its association with oxidative stress in a population in Jeddah, Saudi Arabia.

Oxidative stress arises from excessive free radicals in the body and is a trigger for numerous diseases, such as cancer and atherosclerosis. Elevated exposure to environmental chemicals can contribute to oxidative stress. The association between exposure to xenobiotics and oxidative stress, however, has rarely been studied. In this study, urinary concentrations of 57 xenobiotics (antimicrobials, parabens, bisphenols, benzophenones, and phthalates metabolites) were determined in a population from Jeddah, Saudi Arabia, to delineate association with the oxidative stress biomarker, 8-hydroxy-2'-deoxyguanosine (8OHDG). We collected 130 urine samples and analyzed for 57 xenobiotics using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. The association between unadjusted and creatinine- or specific gravity-adjusted concentrations of xenobiotics and 8OHDG was examined by Pearson correlations and multiple regression analysis. High concentrations of mCPP (a metabolite of di-n-octyl phthalate; DnOP) and mCMHP (a metabolite of diethylhexyl phthalate; DEHP) were found in urine. In addition, the concentrations of bisphenol S (BPS) were higher than those of bisphenol A (BPA). The concentrations of metabolites of DEHP, phthalic acid, BPA, BPS, and methyl-protocatechuic acid were significantly associated with 8OHDG. This is the first biomonitoring study to report exposure of the Saudi population to a wide range of environmental chemicals and provides evidence that environmental chemical exposures contribute to oxidative stress.

Oculo-ectodermal syndrome: A case report and further delineation of the syndrome.

Oculo-ectodermal syndrome (OES - OMIM 600628), also known as Toriello Lacassie Droste syndrome, is a very rare condition, first described by Toriello et al., in 1993. OES has been proposed to be a mild variant of encephalocraniocutaneous lipomatosis (ECCL). It is characterized by aplasia cutis congenita (ACC), epibulbar dermoids, coarctation of the aorta, arachnoid cysts in the brain, seizure disorder, hyperpigmented nevi, non-ossifying fibromas and a predisposition to develop giant cell tumors of the jaw. There are few reported cases of OES worldwide but with no definite diagnostic criteria yet. We present a case in a child with unilateral hyperpigmented nevi and ACC on the scalp, ocular lesions (lipodermoid cysts and coloboma), temporal arachnoid cyst, spinal lipomatosis and aortic coarctation with the aim of enhancing the foundation to establish diagnostic criteria for this condition. It additionally serves as a teaching point to emphasize the importance of pursuing a definite diagnosis when faced with such a multisystem illness, to counsel patients and their parents regarding long term morbidity and overall prognosis.

Pulse Pressure: A Predictor of Intervention in Blunt Abdominal Trauma.

BACKGROUND: Patients with life-threatening hemorrhages due to blunt torso trauma are at a particularly high risk of being underdiagnosed. The pulse pressure (PP) starts narrowing down before the traditional parameters start changing, making it a useful tool for assessing and planning early intervention. OBJECTIVE: To assess the utility of low PP in predicting massive transfusion (MT) or operative intervention in patients with isolated blunt abdominal trauma. MATERIAL AND METHODS: A total of 186 patients were included. The PP and mean arterial pressure (MAP) were calculated. Vitals, PP, and MAP were monitored every 15 min during the first 6 h, then every 30 min during the next 6 h, and afterward, every 4 h until discharge. A Chi-square test and an independent t-test (as appropriate) were applied to compare variables with PP at the time of presentation. Differences were considered statistically significant at p-value ≤ 0.05. RESULTS: A total of 55.9% of these patients had injuries due to road traffic accidents (RTA). Emergency operative intervention was provided to 26.3% of the patients. Death was 4.3%. MT was required by 26.3% of the patients. There was a statistically significant association between low PP and sex, length of stay, repeat extended focused assessment with sonography in trauma (eFAST), emergency operational intervention, outcome, MT, number of crystalloids consumed within the first four hours after presentation, injury severity score, systolic blood pressure (SBP), and pulse rate. CONCLUSION: The PP <30 mmHg was observed as a useful predictor for increased blood loss requiring blood transfusion or operative intervention.

The interleukin-10 family: Major regulators of the immune response against Plasmodium falciparum infections.

Malaria caused by the Plasmodium falciparum strain is more severe because of this protozoan's ability to disrupt the physiology of host cells during the blood stages of development by initiating the production of the interleukin-10 (IL-10) family of cytokines. P. falciparum feeds on hemoglobin and causes host cells to adhere to the walls of blood vessels by remodeling their composition. IL-10 is produced by CD4+ T cells that inhibits antigen-presenting cells' activity to prevent inflammation. This cytokine and its family members are crucial in promoting malarial infection by inhibiting the host's protective immune response, thus initiating Plasmodium parasitemia. IL-10 is also responsible for preventing severe pathology during Plasmodium infection and initiates several signaling pathways to alter the physiology of host cells during malarial infection. This review summarizes the critical aspects of P. falciparum infection, including its role in signaling pathways for cytokine exudation, its effect on microRNA, the human immune response in malaria, and the role played by the liver hormone hepcidin. Moreover, future aspects of vaccine development and therapeutic strategies to combat P. falciparum infections are also discussed in detail.

Triple therapy with boceprevir for HCV genotype 1 infection: phase III results in relapsers and nonresponders.

This is an excellent time for patients with hepatitis C virus infection who have failed past treatment with standard of care (SOC) peginterferon (PEG-IFN) and ribavirin (RBV). New treatments have been shown to increase sustained virological response (SVR) rates. Previous relapsers and those with some responsiveness to interferon will clearly benefit from protease inhibitor-based therapy. Patients with little interferon response may not be suited for these regimens, but can be treated by careful selection on a case-by-case basis. Resistance needs to be carefully monitored as these newer and more potent drugs are added to IFN and RBV backbone drugs. Adverse events will be more frequent and will require special attention.

Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.

Bibliometric Analysis of Publications on the Omicron Variant from 2020 to 2022 in the Scopus Database Using R and VOSviewer.

Human respiratory infections caused by coronaviruses can range from mild to deadly. Although there are numerous studies on coronavirus disease 2019 (COVID-19), few have been published on its Omicron variant. In order to remedy this deficiency, this study undertook a bibliometric analysis of the publishing patterns of studies on the Omicron variant and identified hotspots. Automated transportation, environmental protection, improved healthcare, innovation in banking, and smart homes are just a few areas where machine learning has found use in tackling complicated problems. The sophisticated Scopus database was queried for papers with the term "Omicron" in the title published between January 2020 and June 2022. Microsoft Excel 365, VOSviewer, Bibliometrix, and Biblioshiny from R were used for a statistical analysis of the publications. Over the study period, 1917 relevant publications were found in the Scopus database. Viruses was the most popular in publications for Omicron variant research, with 150 papers published, while Cell was the most cited source. The bibliometric analysis determined the most productive nations, with USA leading the list with the highest number of publications (344) and the highest level of international collaboration on the Omicron variant. This study highlights scientific advances and scholarly collaboration trends and serves as a model for demonstrating global trends in Omicron variant research. It can aid policymakers and medical researchers to fully grasp the current status of research on the Omicron variant. It also provides normative data on the Omicron variant for visualization, study, and application.

Role of pH in Regulating Cancer Pyrimidine Synthesis.

Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase. This means that six billion nucleic acids must be synthesized in each cycle. Tumor growth, proliferation, and mutations all depend on this synthesis. Cancer cells require a constant supply of nucleotides and other macromolecules. For this reason, they must stimulate de novo nucleotide synthesis to support nucleic acid provision. When deregulated, de novo nucleic acid synthesis is controlled by oncogenes and tumor suppressor genes that enable increased synthesis and cell proliferation. Furthermore, cell duplication must be achieved swiftly (in a few hours) and in the midst of a nutrient-depleted and hypoxic environment. This also means that the enzymes participating in nucleic acid synthesis must work efficiently. pH is a critical factor in enzymatic efficiency and speed. This review will show that the enzymatic machinery working in nucleic acid synthesis requires a pH on the alkaline side in most cases. This coincides with many other pro-tumoral factors, such as the glycolytic phenotype, benefiting from an increased intracellular pH. An increased intracellular pH is a perfect milieu for high de novo nucleic acid production through optimal enzymatic performance.

New therapies for hepatitis C virus infection.

An estimated 170 million people in the world are infected with hepatitis C virus (HCV). These individuals are at risk for developing complications like cirrhosis and/or hepatocellular carcinoma. Occurrence of HCV has been recorded to be high in certain parts of the world like Africa and Southeast Asia. The prevalence is considerably lower in the United States, with an estimated number of people with positive HCV antibodies around 1.8% of the population and an estimated 3.1 million individuals having active HCV infection. Treatment of hepatitis C has undergone a complete overhaul several times over the past decade and continues to evolve striving for constant improvement. We now are at the cusp of yet another such overhaul with the protease inhibitors about to be introduced into the market.

Management of hepatocellular carcinoma: treatment options and indications for orthotopic liver transplantation.

Hepatocellular carcinoma (HCC) is the most common tumor worldwide and the leading cause of death amongst patients with cirrhosis. There are an estimated 500,000 or more new cases diagnosed each year in the world, with recent data suggesting an increase in incidence in the United State. Since the majority of HCC occurs in the setting of cirrhosis, an effective protocol for treatment needs to be in place addressing both management of underlying cirrhosis and cancer.

Molecular Epidemiology of Extensively-Drug Resistant Acinetobacter baumannii Sequence Type 2 Co-Harboring bla NDM and bla OXA From Clinical Origin.

BACKGROUND: The therapeutic management of carbapenem-resistant Acinetobacter baumannii (CR-AB) represents a serious challenge to the public health sector because these pathogens are resistant to a wide range of antibiotics, resulting in limited treatment options. The present study was planned to investigate the clonal spread of CR-AB in a clinical setting. METHODOLOGY: A total of 174 A. baumannii clinical isolates were collected from a tertiary care hospitals in Lahore, Pakistan. The isolates were confirmed by VITEK 2 compact system and molecular identification of recA and bla OXA-51. Antimicrobial profile and the screening of carbapenem-resistant genes were carried out using VITEK 2 system and PCR, respectively. The molecular typing of the isolates was performed according to the Pasteur scheme. RESULTS: Of the 174 A. baumannii isolates collected, the majority were isolated from sputum samples (46.5%) and in the intensive care unit (ICU, 75%). Among these, 113/174 (64.9%) were identified as CR-AB, and 49.5% and 24.7% harbored bla OXA-23 and bla NDM-1, respectively. A total of 11 (9.7%) isolates co-harbored bla OXA-51, bla NDM-1, and bla OXA-23. Interestingly, 46.9% of the CR-AB belonged to sequence type 2 (ST2; CC1), whereas 15.9% belonged to ST1 (CC1). All of the CR-AB isolates showed extensive resistance to clinically relevant antibiotics, except colistin. CONCLUSION: The study concluded CR-AB ST2 clone harboring bla OXA-23 and bla NDM-1 are widely distributed in Pakistan's clinical settings, which could result in increased mortality. Strict compliance with the National Action Plan on Antimicrobial Resistance is necessary to reduce the impacts of these strains.

Association of IL28 B and IL10 Polymorphism with HCV Infection and Direct Antiviral Treatment.

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in IL28B and IL10 regions are important in predicting the antiviral response in hepatitis C virus (HCV) patients. In this study, the association of IL28B and IL10 genetic polymorphisms and other clinical factors was assessed as a predictive marker for the sustained virological response (SVR) of HCV patients taking direct-acting antivirals (DAAs). METHODS: We processed 384 serum specimens of HCV serology positive cases for qualitative and quantitative polymerase chain reaction (PCR). Patients were followed up for 12 weeks after the start of antiviral therapy, and the viral load was monitored at each time point. IL28B and IL10 polymorphisms (rs8103142 and rs12980275, rs1800872 and rs3021094, respectively) were detected by real-time PCR, followed by melt curve analysis for genotyping. RESULTS: This study's findings indicate an independent association of SVR with high basal viral load (P=0.005) and an HCV genotype other than 3 (P=0.001). Patients with viral load log10 >6.5 IU/mL required more days to reach an undetectable viral RNA load. The results of the genetic analysis showed a significant association of rs8103142 genotype CC (P<0.01) and rs12980275 genotype AA (P=0.01) with non-SVR. Both SNPs showed an independent association in the multivariate analysis. CONCLUSION: High basal viral load, HCV genotype, and host polymorphisms of rs8103142 and rs12980275 have an independent association in predicting the therapeutic response of HCV patients. The preliminary identification of polymorphisms prior to treatment will help in predicting the outcome of therapy.