Showing papers in "Exploration of medicine in 2022"

Hyperuricemia—a serious complication among patients with chronic kidney disease: a systematic review and meta-analysis

Abstract: Aim: Hyperuricemia as a putative risk factor for chronic kidney disease (CKD) progression remains controversial and debatable. This systematic review aims to explore the prevalence of hyperuricemia among CKD patients worldwide. Methods: This study was conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines by using the existing literature from online databases such as MEDLINE/PubMed, ScienceDirect, Google Scholar, Cochrane library and grey literature. The effect size with corresponding 95% confidence interval (CI) was calculated to assess the pooled prevalence of hyperuricemia in chronic kidney patients. The subgroup analysis based on gender and geography was also carried out by utilizing comprehensive meta-analysis, version 2.0. Results: Twenty-three studies containing 212,740 participants were eligible for quantitative synthesis. The pooled prevalence of 43.6% (35.2–52.4%) hyperuricemia was reported in patients with CKD globally. In India, 38.4% of prevalence was observed. The gender specific prevalence (9 studies) was reported as 67.4% (60.9–73.3%) in case of male patients and 32.6% (26.7–39.1%) in female patients with 95% CI. Conclusions: The prevalence of hyperuricemia was reported to be reasonably high among CKD patients worldwide. During the management of CKD, this high prevalence demands more prudent attention for this clinical complication which possibly can lead to positive renal outcomes.

Reactive oxygen species in cancer progression and its role in therapeutics

Abstract: The redox status in pathogenesis is critically regulated by careful balance between the generation of reactive oxygen species (ROS) and their elimination. Increased ROS level above the cellular tolerability threshold results in apoptotic or necrotic cell death. ROS belongs to a group of highly reactive compounds that have evolved to play key roles in cellular signaling pathways. It’s widely assumed that a reasonable amount of ROS is essential for a variety of biological processes. Elevated levels of ROS are known to cause various pathologic conditions like neurological disorders, cardiovascular conditions, inflammation, autoimmunity, and cancer. ROS is well known to initiate and assist in progression of tumor by promoting proliferation and survival of cancer cells and thus facilitates pro-tumorigenic signaling in tumor microenvironment. As cancer cells become more resilient to the effects of ROS manipulating drugs, increased antioxidant capacity attenuates their susceptibility to cancer treatment. Excessive environmental stress, on the other hand, can cause cancer cells to die. This review summarizes various molecular mechanisms including the role of checkpoint inhibitors that can be harnessed to develop effective therapeutic strategies for targeting ROS related signaling in cancer.

Oxidative stress in obesity and insulin resistance

Abstract: Since obesity is one of the main factors in the development of insulin resistance (IR) and is also associated with increased oxidative stress (OxS) rate, this study aims to review the published literature to collate and provide a comprehensive summary of the studies related to the status of the OxS in the pathogenesis of obesity and related IR. OxS represents an imbalance between the production of reactive oxygen and nitrogen species (RONS) and the capacity of the antioxidant defense system (AOS) to neutralize RONS. A steady-state of RONS level is maintained through endogenous enzymatic and non-enzymatic AOS components. Three crucial enzymes, which suppress the formation of free radicals, are superoxide dismutases, catalases, and glutathione peroxidases. The second line of AOS includes non-enzymatic components such as vitamins C and E, coenzyme Q, and glutathione which neutralizes free radicals by donating electrons to RONS. Emerging evidence suggests that high RONS levels contribute to the progression of OxS in obesity by activating inflammatory pathways and thus leading to the development of pathological states, including IR. In addition, decreased level of AOS components in obesity increases the susceptibility to oxidative tissue damage and further progression of its comorbidities. Increased OxS in accumulated adipose tissue should be an imperative target for developing new therapies in obesity-related IR.

Recent advances of gut microbiota in chronic kidney disease patients

Abstract: Chronic kidney disease (CKD) is a worldwide public health issue and has ultimately progressed to an end-stage renal disease that requires life-long dialysis or renal transplantation. However, the underlying molecular mechanism of these pathological development and progression remains to be fully understood. The human gut microbiota is made up of approximately 100 trillion microbial cells including anaerobic and aerobic species. In recent years, more and more evidence has indicated a clear association between dysbiosis of gut microbiota and CKD including immunoglobulin A (IgA) nephropathy, diabetic kidney disease, membranous nephropathy, chronic renal failure and end-stage renal disease. The current review describes gut microbial dysbiosis and metabolites in patients with CKD thus helping to understand human disease. Treatment with prebiotics, probiotics and natural products can attenuate CKD through improving dysbiosis of gut microbiota, indicating a novel intervention strategy in patients with CKD. This review also discusses therapeutic options, such as prebiotics, probiotics and natural products, for targeting dysbiosis of gut microbiota in patients to provide more specific concept-driven therapy strategy for CKD treatment.

Placental CD4+ T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia

Abstract: Aim: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4+ T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4+ T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4+ T cells from normal pregnant (NP) women. However, the role of PE CD4+ T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4+ T cells stimulate AT1-AA in pregnant nude-athymic rats. Methods: CD4+ T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4+ T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4+ T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained. Results: MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4+ T cells compared to NP nude + NP CD4+ T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4+ T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4+ T cells. Conclusions: These results show that placental CD4+ T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy.

The gut microbiome and the immune system

Abstract: The human body contains trillions of microbes which generally live in symbiosis with the host. The interaction of the gut microbiome with elements of the host immune system has far-reaching effects in the development of normal gut and systemic immune responses. Disturbances to this intricate relationship may be responsible for a multitude of gastrointestinal and systemic immune mediated diseases. This review describes the development of the gut microbiome and its interaction with host immune cells in both health and disease states.

Development of systolic dysfunction unrelated to myocardial infarction in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study

Abstract: Aim: While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion. Methods: We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF < 50%. Results: During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P < 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P < 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P < 0.0001). Conclusions: In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).

Incident atrial fibrillation and heart failure in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study

Abstract: Aim: The present study investigated the appearance and severity of atrial fibrillation (AF) and heart failure (HF) in 8,702 hypertensive patients with left ventricular hypertrophy (LVH) receiving antihypertensive treatment in a prospective trial. Methods: Patients who had a history of AF or HF were not included, and the participants had sinus rhythm when they were randomly allocated to blinded study medication. Endpoints were adjudicated. Results: Incident AF occurred in 679 patients (7.8%) and HF in 246 patients (2.8%) during 4.7 ± 1.1 years mean follow-up. Incident AF was associated with a > 4-fold increased risk of developing subsequent HF [hazards ratios (HRs) = 4.7; 95% confidence intervals (CIs), 3.1–7.0; P < 0.001] in multivariable Cox analyses adjusting for age, sex, race, randomized treatment, standard cardiovascular risk factors and incident myocardial infarction. The development of HF as a time-dependent variable was associated with a multivariable-adjusted 3-fold increase of the primary study endpoint (HRs = 3.11; 95% CIs, 1.52–6.39; P < 0.001) which was a composite of myocardial infarction, stroke or cardiovascular death. Incident HF was associated with a > 3-fold increased risk of developing subsequent AF (HRs = 3.3; 95% CIs, 2.3–4.9; P < 0.001). This development of AF was associated with a > 2-fold increase of the composite primary study endpoint in multivariable Cox analysis (HRs = 2.26; 95% CIs, 1.09–4.67; P = 0.028). Conclusions: Incident atrial fibrillation and heart failure are associated with increased risk of the other in treated hypertensive patients with left ventricular hypertrophy. Such high-risk hypertensive patients who subsequently develop both atrial fibrillation and heart failure have particular high risk of composite myocardial infarction, stroke or cardiovascular death (ClinicalTrials.gov identifier: NCT00338260).

Signaling pathways and targets of natural products in psoriasis treatment

Abstract: Aim: Psoriasis is a common chronic inflammatory skin disorder, which has adverse effects on patients’ quality of life. Natural products exhibit significant therapeutic capacities with small side effects and might be preferable alternative treatments for patients with psoriasis. This study summarizes the signaling pathways with the potential targets of natural products and their efficacy for psoriasis treatment. Methods: The literature for this article was acquired from PubMed and Web of Science, from January 2010 to December 2020. The keywords for searching included “psoriasis” and “natural product”, “herbal medicine”, “herbal therapy”, “medicinal plant”, “medicinal herb” or “pharmaceutical plant”. Results: Herbal extracts, natural compounds, and herbal prescriptions could regulate the signaling pathways to alleviate psoriasis symptoms, such as T helper 17 (Th17) differentiation, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), nuclear factor-kappa B (NF-κB), mitogen‑activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and other signaling pathways, which are involved in the inflammatory response and keratinocyte hyperproliferation. The anti-psoriatic effect of natural products in clinical trials was summarized. Conclusions: Natural products exerted the anti-psoriatic effect by targeting multiple signaling pathways, providing evidence for the investigation of novel drugs. Further experimental research should be performed to screen and characterize the therapeutic targets of natural products for application in psoriasis treatment.

Time-varying serum uric acid predicts new-onset atrial fibrillation in treated hypertensive patients. The LIFE Study

Abstract: Aim: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based treatment. Because losartan reduces serum uric acid (SUA) levels, the aim of the present study was to investigate relations of SUA with new-onset AF in the study. Methods: Hypertensive patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) and no prior AF (n = 8,243) were treated for 5.0 ± 0.4 years with losartan- or atenolol-based therapy. Associations of SUA with new-onset AF documented by Minnesota coding were assessed by Cox models using SUA and systolic blood pressure as time-varying covariates to take into account changes of SUA related to losartan or diuretic treatment, changes in renal function, and aging. Results: Time-varying SUA was associated with new AF defined by Minnesota code [hazard ratio (HR) = 1.19 per 16.8 μmol/L (1 mg/dL), (95% confidence intervals (CIs), 1.12–1.26), P < 0.0001], independent of losartan treatment [HR = 0.75 (95% CIs, 0.61–0.93), P = 0.007], older age [HR = 1.95 per 7.0 years (95% CIs, 1.73–2.20), P < 0.0001], male sex [HR = 1.46 (95% CIs, 1.09–1.94), P = 0.010] and higher Cornell voltage-duration product [HR = 1.10 per 1,023 ms·mm (95% CIs, 1.01–1.21), P = 0.034]. Similar results were obtained in Cox models with SUA levels partitioned according to baseline quartiles and in which AF was defined by physician reports or by both Minnesota coding and physician reports. Conclusions: In-treatment SUA is a strong predictor for new-onset AF in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and ECG-LVH. Further research is needed to clarify how uric acid may provoke AF (ClinicalTrials.gov identifier: NCT00338260).

Nano-immunotherapeutics: targeting approach as strategic regulation at tumor microenvironment for cancer treatment

Abstract: Cancer is the leading cause of mortality worldwide, which necessitates our consideration related to novel treatment approach. Tumor cells at the tumor microenvironment (TME), regulate a plethora of key mechanistic signaling pathways that obstruct antitumor immune responses by immune suppression, immune resistance or acquired immune tolerance. The present therapeutic regimes are provided independently or in combination, or as immunotherapies for cancer immune targeting. Immunotherapy has altered the arena of oncology and patient care. By using the host immune system, the immunostimulatory molecules can exert a robust, personalized response against the patient’s own tumors. Alternatively, tumors may exploit these strategies to escape immune recognition, and accordingly, such mechanisms represent chances for immunotherapy intervention. Nonetheless, despite promising outcomes from immunotherapies in recurrent and metastatic cancers, immune-therapeutics in clinics has been limited owing to unpredictability in the produced immune response and reported instances of immune-related adverse effects. The unrealized potential of immunotherapies in cancer management maybe due to the obstacles such as heterogeneous nature, multiple targets, patients’ immune response, specificity for cancer or variability in response generation in toxicity levels, delivery and cost related to therapeutics etc. Further revolutionary trends related to immunotherapies are noticeable with slower progress for cancer management. Recent advances in nanomedicine strategize to ameliorate the lacuna of immunotherapy as it relies on the inherent biophysical characteristics of nanocarriers: size, shape, surface charge and multifunctionality and exploiting them as first line therapy for delivery of biomolecules, single checkpoint inhibitors and for imaging of TME. Therefore, nano-assisted immunotherapies can boost the immunotherapeutic approach, overcoming factors that are with imminent potential risks related to it, thereby significantly improving the survival rate associated with it in cancer patients. Nanotechnology is anticipated to overcome the confines of existing cancer immunotherapy and to successfully combine various cancer treatment modes.

Multi-faced roles of reactive oxygen species in anti-tumor T cell immune responses and combination immunotherapy

Abstract: T cells play a central role in anti-tumor immunity, and reactive oxygen species (ROS) lie at the crossroad on the anti-tumor T cell responses. To activate efficient T cell immunity, a moderate level of ROS is needed, however, excessive ROS would cause toxicity to the T cells, because the improper level leads to the formation and maintenance of an immunosuppressive tumor microenvironment. Up to date, strategies that modulate ROS, either increasing or decreasing, have been widely investigated. Some of them are utilized in anti-tumor therapies, showing inevitable impacts on the anti-tumor T cell immunity with both obverse and reverse sides. Herein, the impacts of ROS-increasing and ROS-decreasing treatments on the T cell responses in the tumor microenvironment are reviewed and discussed. At the same time, outcomes of combination immunotherapies are introduced to put forward inspirations to unleash the potential of immunotherapies.

High salt induced augmentation of angiotensin II mediated hypertension is associated with differential expression of tumor necrosis factor-alpha receptors in the kidney

Abstract: Aim: Chronic high salt (HS) intake causes minimal changes in blood pressure (BP) but it induces augmented hypertensive response to angiotensin II (AngII) administration in rodents. The mechanism of this augmentation is not clearly understood. As tumor necrosis factor-alpha (TNF-α) induces natriuresis by activating TNF-α receptor type 1 (TNFR1) but not type 2 (TNFR2), we hypothesize that TNFR1 activity is reduced when HS is given in combination of AngII that leads to enhanced sodium retention and thus, causing augmented hypertension. The aim of this study is to examine the responses to chronic HS intake and AngII administration on the renal tissue protein expressions of TNFR1 and TNFR2 in mice. Methods: Different groups of mice (n = 6–7 in each group) chronically treated with or without AngII (25 ng/min; implanted minipump) for 4 weeks which were fed either normal salt (NS; 0.4% NaCl) or high salt (HS; 4% NaCl) diets. Systemic BP was measured by tail-cuff plethysmography. At the end of treatment period, kidneys were harvested after sacrificing the mice with euthanasia. Immuno-histochemical analysis of TNFR1 and TNFR2 proteins in renal tissues was performed by measuring the staining area and the intensity of receptors’ immunoreactivities using NIS-Elements software. The results were expressed in percent area of positive staining and the relative intensity. Results: HS intake alone did not alter mean BP (HS; 77 ± 1 vs. NS; 76 ± 3 vs. mmHg; tail-cuff plethysmography) but AngII induced increases in BP were augmented in HS group (104 ± 2 vs. 95 ± 2 mmHg; P < 0.05). The area of TNFR1 staining was higher in HS than NS group (6.0 ± 0.9% vs. 3.2 ± 0.7%; P < 0.05) but it was lower in AngII + HS than in AngII + NS group (5.0 ± 0.7% vs. 6.3 ± 0.7%; P = 0.068). TNFR2 immunoreactivity was minimal in NS and HS groups but it was high in AngII + NS and even higher in AngII + HS group. Conclusions: These data suggest that the HS induced increased TNFR1 activity that facilitates enhanced sodium excretion is compromised in elevated AngII condition leading to salt retention and augmented hypertension.

The potential anti-cancer effects of melatonin on breast cancer

Abstract: Melatonin is the primary hormone of the pineal gland that is secreted at night. It regulates many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. The precise functions of melatonin are mediated by guanosine triphosphate (GTP)-binding protein (G-protein) coupled melatonin receptor 1 (MT1) and MT2 receptors. However, nuclear receptors are also associated with melatonin activity. Circadian rhythm disruption, shift work, and light exposure at night hamper melatonin production. Impaired melatonin level promotes various pathophysiological changes, including cancer. In our modern society, breast cancer is a serious problem throughout the world. Several studies have been indicated the link between low levels of melatonin and breast cancer development. Melatonin has oncostatic properties in breast cancer cells. This indolamine advances apoptosis, which arrests the cell cycle and regulates metabolic activity. Moreover, melatonin increases the treatment efficacy of cancer and can be used as an adjuvant with chemotherapeutic agents.

Feed your microbiome and improve sleep, stress resilience, and cognition

Abstract: The brain and gut are connected both physically and biochemically. The gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, the enteric nervous system and vagus nerve, and the gut microbiome. It can influence brain function and even behavior, suggesting that dietary interventions may help enhance and protect mental health and cognitive performance. This review focuses on the role of the microbiome and its metabolites in sleep regulation, neurodegenerative disorders, mechanisms of stress, and mood. It also provides examples of nutritional interventions which can restore healthy gut microbiota and aid with risk reduction and management of many disorders related to mental and cognitive health. Evidence suggests a shift in the gut microbiota towards a balanced composition could be a target to maintain brain health, reduce stress and improve quality of life.

Adenine-rich diet: a potential mechanism for renal fibrosis progression

Abstract: Chronic kidney disease (CKD) is a major health problem but there are many modalities to prevent and manage CKD progression. Diet is one of these factors, which needs to be evaluated more. Adenine is a water-soluble nucleoprotein that exists in both vegetables and animal foods, which triggers and aggravates fibrosis process besides other metabolic derangements such as diabetes mellitus affection that accelerates glomerular filtration rate decline rapidly.

Early taurine administration as a means for halting the cytokine storm progression in COVID-19 patients

Abstract: Around the world, more than 6.2 million individuals have died as a result of coronavirus disease 2019 (COVID-19). According to a recent survey conducted among immunologists, epidemiologists, and virologists, this disease is expected to become endemic. This implies that the disease could have a continuous presence and/or normal frequency in the population. Pharmacological interventions to prevent infection, as well as to treat the patients at an early phase of illness to avoid hospitalization are essential additions to the vaccines. Taurine is known to inhibit the generation of all inflammatory mediators linked to the cytokine storm. It can also protect against lung injury by suppressing increased oxidants production and promoting the resolution of the inflammatory process. Neutrophil lactoferrin degranulation stimulated by taurine may have antiviral effects against SARS-CoV-2, limiting viral replication. It is hypothesized that if taurine is administered early in the onset of COVID-19 disease, it may stop the cytokine storm from progressing, lowering morbidity and mortality.

Elimination of hepatitis C virus infection in Europe: targeting the obstacles

Abstract: *Correspondence: Dante Romagnoli, Gastroenterology Unit, Polyclinic, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy. dromagno@unimore.it; romagnoli.dante@aou.mo.it Academic Editor: Lindsay A. Farrer, Boston University School of Medicine, USA; Amedeo Lonardo, Azienda Ospedaliero-Universitaria di Modena, Italy Received: November 23, 2021 Accepted: December 29, 2021 Published: February 24, 2022

Incident left bundle branch block predicts cardiovascular events and death in hypertensive patients with left ventricular hypertrophy. The LIFE Study

Abstract: Aim: Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH. Methods: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up. Results: Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P < 0.05), older age, higher Cornell voltage (both P < 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 0.001). Conclusions: These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).

Incursions by severe acute respiratory syndrome coronavirus-2 on the host anti-viral immunity during mild, moderate, and severe coronavirus disease 2019 disease

Abstract: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the human host can lead to various clinical manifestations, from symptomless carriers to mild to moderate to severe/critical illness. Therefore, the clinical classification of SARS-CoV-2 disease, based on severity, is a reliable way to predict disease states in SARS-CoV-2 infection. Recent studies on genomics, transcriptomics, epigenomics, and immunogenomics, along with spatial analysis of immune cells have delineated and defined the categorization of these disease groups using these high throughout technologies. These technologies hold the promise of providing not only a detailed but a holistic view of SARS-CoV-2-led pathogenesis. The main genomic, cellular, and immunologic features of each disease category, and what separates them spatially and molecularly are discussed in this brief review to provide a foundational spatial understanding of SARS-CoV-2 immunopathogenesis.

Semaglutide: a game changer for metabolic diseases?

Abstract: Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) molecule approved for the treatment of both type 2 diabetes (T2D) and obesity. Semaglutide has a greater impact on glycated haemoglobin (HbA1c) reduction, compared to other GLP-1 RAs, and is the first molecule of this class available in oral formulation for T2D therapy, representing a useful option for subjects and physicians less prone to start an injective drug. Interestingly, due to its remarkable effects on weight reduction, higher than other GLP-1 RAs and very close to bariatric surgery, semaglutide is designated to change the approach to obesity therapy also in the subject not affected by diabetes. In addition to these favorable features, semaglutide, similarly to other GLP-1 RAs, offers beneficial effects on cardio-vascular (CV), renal, and liver protection, making this molecule an advantageous choice in the therapeutic management of “diabesity” (coexistence of both diabetes and obesity) and its co-morbidity.

A case report: 19-year-old male diagnosed with C1q nephropathy requiring renal replacement therapy

Abstract: C1q nephropathy is a rare glomerular disease. Clinical presentation is diverse and ranges from asymptomatic hematuria or proteinuria to symptoms and signs of nephrotic/nephritic syndrome. On light microscopy, it can be classified into two subtypes: minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) group and immune complex mediated proliferative glomerulonephritis group. A case of a 19-year-old male patient presenting nausea and decreased appetite will be reported. The labs showed severe nephrotic syndrome and a progressive kidney injury over a few months that were never diagnosed. The immune workup came back negative. The patient mentioned that he was taking protein shakes a few months earlier for bettering his physical fitness. A renal biopsy was done and showed a major reduction in renal mass and C1q nephropathy. He received steroids without any improvement. He was started on hemodialysis afterward then got transplanted 8 months later. In front of this rapid deterioration, FSGS might be the underlying etiology rather than MCD. Further studies are warranted to establish a connection between protein supplements, and progression of kidney disease.

A budding concept with certain microbiota, anti-proliferative family proteins, and engram theory for the innovative treatment of colon cancer

Abstract: Inflammatory bowel disease (IBD) is a multifactorial chronic disease. Patients with IBD have an increased risk of developing colorectal cancer which has become a major health concern. IBD might exert a role of engrams for making the condition of specific inflammation in the gut. Dysregulation of immune cells induced by the command of engrams might be crucial in the pathogenesis of damages in gut epithelium. The anti-proliferative (APRO) family of anti-proliferative proteins characterized by immediate early responsive gene-products that might be involved in the machinery of the carcinogenesis in IBD. Herein, it is suggested that some probiotics with specific bacteria could prevent the development and/or progression of the IBD related tumors. In addition, consideration regarding the application of studying APRO family proteins for the comprehension of IBD related tumors has been presented. It is hypothesized that overexpression of Tob1, a member of APRO family proteins, in the epithelium of IBD could suppress the function of adjacent cytotoxic immune cells possibly via the paracrine signaling.

Nutritional prospects of wheatgrass (Triticum aestivum) and its effects in treatment and chemoprevention

Abstract: Nutraceuticals are organic and traditional foods consumed nowadays to maintain a healthy lifestyle and get rid of lifestyle diseases like obesity, cancer, diabetes, hypertension, etc. Globally, herbal products have become increasingly popular in recent years. Wheatgrass (Triticum aestivum) is a nutraceutical proven to be a dietary supplement and beneficial for cancer-suffering patients. Wheatgrass possesses many beneficial antioxidant properties: anti-cancer activity, anti-bacterial activity, anti-fungal activity, and anti-microbial activity. Due to the presence of resistant starch, lignans, phenolic acids, alkylresorcinols, and numerous antioxidant components, including carotenoids and tocopherols, this herbal plant is deserving attention as a source of dietary fiber. Patients consume wheatgrass during cancer treatment as an adjunct to reduce toxicity associated with drugs and chemotherapy and ultimately improve long-term outcomes. Studies have proved that wheatgrass helps treat pancreatic cancer, lung cancer, and breast cancer. So, the multi-targeted herbal drug—wheatgrass—is used as an adjunct therapy alongside conventional medicine to treat cancer and other diseases. A promising therapeutic nutraceutical for avoiding lifestyle disorders is wheatgrass.

Preclinical toxicity test results of a new antiviral–immune-modulator compound consisting of flavonoid molecules (COVID-19 clinical trial preliminary data)

Abstract: Aim: Isolated specific glycone–aglycone conjugated flavonoids which are investigated for their effect of bioavailability and molecular concentrations. The specific formula is then tested via in vitro and in vivo cytotoxicity tests. Methods: Considering the higher affinity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), quercetin, quercetin 3-sambubioside-3’-glucoside, luteolin, apigenin-7-4’alloside, kaempferol-7-O-glucoside, epicatechin-epigallocatechin-3-O-gallate, and hesperetin were selected to investigate the effects of a new combination of the formula. Specific chemical analyses, such as high-performance liquid chromatography (HPLC), liquid chromatography–mass spectrometry (LC–MS), quadrupole time of flight mass spectrometry (QTOF–MS) analysis and ultraviolet–visible (UV–VIS) spectrophotometry, were performed for molecular qualification and quantification. Results: In silico molecular docking analyses have shown that flavonoids can bind strongly to the spike protein and main protease of the SARS-CoV-2 virus. Flavonoids also have anti-inflammatory and immune-modulating activity by inhibiting cytokines. Although flavonoids may be a treatment alternative for coronavirus disease 2019 (COVID-19), an effective flavonoid compound has yet to be developed. The main problem here is that the absorption rate of flavonoids is very low (2–10%) in the intestines, and these compounds are metabolized rapidly. In contrast, according to recent literature, a conjugated flavonoid mixture is better absorbed in the small intestine, and its toxic effects are relatively fewer. Conclusions: It is found that the new formula has no cytotoxic or genotoxic effects. Furthermore, oral administrations of the new compound did not produce any toxicity symptoms or any mortality in male and female rats. The pre-clinical in vitro and in vivo toxicity test results indicated that the new flavonoid formula can be safely used for clinical trials.

Vasopressin: a possible link between hypoxia and hypertension

Abstract: Cardiovascular and respiratory diseases are frequently associated with transient and prolonged hypoxia, whereas hypoxia exerts pro-hypertensive effects, through stimulation of the sympathetic system and release of pressor endocrine factors. This review is focused on the role of arginine vasopressin (AVP) in dysregulation of the cardiovascular system during hypoxia associated with cardiovascular disorders. AVP is synthesized mainly in the neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON), which send axons to the posterior pituitary and various regions of the central nervous system (CNS). Vasopressinergic neurons are innervated by multiple neuronal projections releasing several neurotransmitters and other regulatory molecules. AVP interacts with V1a, V1b and V2 receptors that are present in the brain and peripheral organs, including the heart, vessels, lungs, and kidneys. Release of vasopressin is intensified during hypernatremia, hypovolemia, inflammation, stress, pain, and hypoxia which frequently occur in cardiovascular patients, and blood AVP concentration is markedly elevated in cardiovascular diseases associated with hypoxemia. There is evidence that hypoxia stimulates AVP release through stimulation of chemoreceptors. It is suggested that acting in the carotid bodies, AVP may fine-tune respiratory and hemodynamic responses to hypoxia and that this effect is intensified in hypertension. There is also evidence that during hypoxia, augmentation of pro-hypertensive effects of vasopressin may result from inappropriate interaction of this hormone with other compounds regulating the cardiovascular system (catecholamines, angiotensins, natriuretic peptides, steroids, nitric oxide). In conclusion, current literature indicates that abnormal mutual interactions between hypoxia and vasopressin may significantly contribute to pathogenesis of hypertension.

Treatment opportunities with Fernandoa adenophylla and recent novel approaches for natural medicinal phytochemicals as a drug delivery system

Abstract: Fernandoa adenophylla (FA, Heterophragma adenophyllum) is a plant, cultivated throughout Africa and Southeast Asia. It contains potent phytochemicals such as novel naphthoquinones, their derivatives (peshwaraquinone, dilapachone, adenophyllone, indadone, and lapachol), and triterpenoids [ursolic acid (UA), β-sitosterol (BS), α-amyrin, and oleanolic acid (OA)] that have been assessed and reported to show potential pharmacological activities. The crude extract obtained from the plant has been investigated for certain pharmacological activities such as antibacterial, antifungal, anti-tubercular (TB), antihypertensive, and leishmanicidal activity. A novel drug delivery systems (NDDS) is the latest technique that combines innovative development, formulations, new technology, and methodologies for the safe delivery of pharmaceutical substances in the body. The present study reports the possible treatment opportunities of FA and recent possible novel drug delivery approaches for the natural medicinal phytochemicals.

Quality by design based development of nanostructured lipid carrier: a risk based approach

Abstract: The aim of this review is to discuss the development of nanostructured lipid carrier (NLC) by the application of quality by design (QbD). QbD started with the evolution of the quality concept and slow adaptation of quality guidelines, which has now become a regulatory requirement. In this review, brief history and elements of QbD including risk assessment (RA) have been discussed followed by the design of experiments (DoEs) that acts as a tool to analyze the input whose variation can optimize the output with the desired goal. NLC is a versatile delivery system as researchers widely use it to administer therapeutics with different physicochemical properties. The surface of NLC can be modified, making it a suitable delivery system with targeting potential for therapeutics. Implementation of QbD provides a high-quality robust formulation that can consistently meet the patient’s requirement throughout its life cycle without compromising the safety and effectiveness of the drug and delivery system. This review discusses QbD concepts followed by the systematic development of NLC by the application of DoE. Process analytical technology (PAT) and six sigma concepts have also been included which can benefit in the development of optimized NLC.

Paradoxical role of reactive oxygen species in bone remodelling: implications in osteoporosis and possible nanotherapeutic interventions

Abstract: Osteoporosis is a metabolic bone disorder that affects both sexes and is the most common cause of fractures. Osteoporosis therapies primarily inhibit osteoclast activity, and are seldom designed to trigger new bone growth thereby frequently causing severe systemic adverse effects. Physiologically, the intracellular redox state depends on the ratio of pro-oxidants, oxidizing agents (reactive oxygen species, ROS) and antioxidants. ROS is the key contributor to oxidative stress in osteoporosis as changes in redox state are responsible for dynamic bone remodeling and bone regeneration. Imbalances in ROS generation vs. antioxidant systems play a pivotal role in pathogenesis of osteoporosis, stimulating osteoblasts and osteocytes towards osteoclastogenesis. ROS prevents mineralization and osteogenesis, causing increased turnover of bone loss. Alternatively, antioxidants either directly or indirectly, contribute to activation of osteoblasts leading to differentiation and mineralization, thereby reducing osteoclastogenesis. Owing to the unpredictability of immune responsiveness and reported adverse effects, despite promising outcomes from drugs against oxidative stress, treatment in clinics targeting osteoclast has been limited. Nanotechnology-mediated interventions have gained remarkable superiority over other treatment modalities in regenerative medicine. Nanotherapeutic approaches exploit the antioxidant properties of nanoparticles for targeted drug delivery to trigger bone repair, by enhancing their osteogenic and anti-osteoclastogenic potentials to influence the biocompatibility, mechanical properties and osteoinductivity. Therefore, exploiting nanotherapeutics for maintaining the differentiation and proliferation of osteoblasts and osteoclasts is quintessential.

The journey of dostarlimab: a successful weapon for cancer treatment

Abstract: In a number of malignancies, new immuno-oncology therapies that focus on the programmed cell death 1 (PD-1) have improvised the patient condition along with a positive aftereffect. Monoclonal antibodies (mAbs) directed against PD-1 and its ligand (PD-L1), have been widely used to treat a variety of malignancies, including melanoma, renal cancer, and non-small cell lung cancer (NSCLC). Dostarlimab, a therapeutic anti-PD-1 antibody, was authorised by the United States Food and Drug Administration (FDA) in April 2021 under the trade name JEMPERLI. It is a humanised contrary PD-1 immunoglobulin G 4 (IgG4) mAb, which successfully blocks interaction with PD-L1 and PD-L2 by binding tightly to the PD-1 receptor. This article summarizes the different aspects associated with the dostarlimab, including currently available anti-PD-1/PD-L1 antibodies, pharmacokinetics (PK), pharmacodynamics, adverse reaction, and mechanism of action of dostarlimab, as well as various reported clinical trials.