Damage To Vital Organs Research Articles

Umbilical cord blood as a hematopoietic stem cell source in transplantation for pediatric sickle cell disease: current challenges and strategies

Allogeneic hematopoietic stem cell transplant (HSCT) is the only established cure for sickle cell disease (SCD), a hemolytic disorder that arises due to a point mutation in the hemoglobin A gene. The result is an abnormal sickle hemoglobin (HbS) replacing hemoglobin A. Of the spectrum of sickle hemoglobinoapthies, homozygous (HbSS) and HbSβ0 thalassemia manifest severe forms of disease characterized by chronic endothelial injury/vasculopathy, ischemic pain, and vital organ damage that commence in childhood and escalate with age resulting in impaired quality of life, increased healthcare burden, and early mortality. HSCT has demonstrated durable disease control and regression of symptoms. Human leukocyte antigen (HLA) matched sibling donor (MSD) transplantation can achieve disease-free survival of > 90%. However, < 18% of SCD patients in the United States have a MSD. Familial mismatched and unrelated donors from registries provide alternate stem cell sources. Umbilical cord blood (UCB) from family or cord blood banks expand donor sources and are attractive due to donor-independent ease of use and availability. These naïve cells tolerate greater degrees of HLA-mismatch. The primary challenge with UCB is optimizing cell dose toward successful engraftment and timely immune reconstitution while minimizing graft-versus-host disease (GVHD). This review summarizes evidence that UCB remains a promising stem cell source where modern methods of graft expansion, conditioning, GVHD prophylaxis, and infection control can overcome these challenges and retain the value of this intervention.

Folic acid-modified disulfiram/Zn-IRMOF3 nanoparticles for oral cancer therapy by inhibiting ALDH1A1+ cancer stem cells

The repurposing of old drugs can reduce the cost of drug development and speed up the availability of drugs for clinical use. Disulfiram (DSF) is an approved drug for alcohol abuse. In recent years, it has been established that DSF exerts an antitumor effect via targeted inhibition of ALDH1+ cancer stem cells (CSCs). However, due to its metal ion dependence, easy hydrolysis and low availability, the clinical application of DSF is limited. Previous studies have also shown that Zn2+ can inhibit CSCs. Accordingly, we developed a novel metal organic framework (IRMOF3)-Zn2+, and DSF was incorporated in the IRMOF3. Folic acid (FA) was subsequently loaded on the surface yielding IRMOF3 (IRMOF3-DSF-FA) for targeted therapy of tumors. The nanoscale IRMOF3-DSF-FA exhibited a high loading capacity, good biocompatibility and strong cell uptake capacity, which could provide metal ions, target tumor tissues and inhibit ALDH1+ CSCs. In vivo experiments showed that IRMOF3-DSF-FA could significantly inhibit the growth of CSCs and tumors, with no significant vital organ damage during treatment. Accordingly, IRMOF3-DSF-FA has great prospects for application as a DSF carrier, opening new horizons for targeted therapy of oral cancer.

Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.

BackgroundDysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response.MethodsWe analysed inhibition of C-reactive protein (CRP) – a biomarker for IL-6 activity – in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases.ResultsIL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity.ConclusionIn clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production.FundingEUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.

CLINICAL SPECTRUM OF HYPERTENSIVE EMERGENCIES WITH SPECIAL REFERENCE TO FASTING LIPID PROFILE

Background: Hypertensive emergencies are severe clinical condition in which sudden increase in arterial blood pressure can lead to acute vascular damage of vital organs. Hypertension and dyslipidemia often co-exist. Dyslipidemia worsens the prognosis in hypertensive emergency patients. So this study aimed to study the clinical profile and spectrum of target organ involved in patients with hypertensive emergencies with special reference to fasting lipid profile. Materials and method: This study is a hospital based cross sectional study carried in 60 patients admitted in medicine ward of JMCH fulfilling the eligible criteria. All patients are subjected to clinical workout with detailed history, examination and also lipid profile value. Lipid profile of study group are compared with lipid profile of 60 normotensive patients Results: The most common presenting complaint in the study is weakness of limbs (75%) followed by headache (46.66%), vomiting, dyspnoea. The most common spectrum of neurological end organ damage is ICH (46.66%) followed by cerebral infarct (23.33%), least common is SAH. Triglyceride, cholesterol, LDL and VLDL level in hypertensive emergencies are significantly higher (p&lt;0.05) than in normotensive patients. Conclusion: The commonest clinical presentation in hypertensive emergency is neurological deficit. Fasting lipid profile is significantly deranged in hypertensive emergencies.

Abstract 2826: Rewiring CAR T-cells for absolute solid tumor specificity and safety

Abstract Translation of the unprecedented efficacy of chimeric antigen receptor (CAR) T-cell technology into solid tumors requires a solution to the problem of on-target damage of vital organs. We have developed an inhibitory CAR platform (iCAR) that imposes self-regulation in CAR T-cells to restrict inappropriate activation against normal cells without compromising tumor efficacy. The system consists of an iCAR that is co-expressed with a conventional activating CAR (aCAR) designed to activate T-cells. The iCAR and aCAR scFvs bind distinct cell-surface antigens that are ubiquitously expressed across all solid tumor histologies and normal tissues. The iCAR is allele-specific whereas the aCAR is pan-allelic. The iCAR technology was validated in functional assays and NSG models with cancer cell lines that mimic loss-of-heterozygosity (LOH) which is common in most human cancers due to increased chromosomal instability. In this context, loss of iCAR target expression due to LOH generates irreversible target specificity. Tumor-specific overexpression of aCAR and iCAR targets, a common barrier to the clinical translation of potent agents targeting the cell-surface proteins is not required. We have shown using in vitro and in vivo models that CAR T-cell activation and target killing are fully inhibited by dual iCAR + aCAR antigen engagement. This outcome validates the concept of iCAR-mediated protection of normal cells in vital organs. In contrast, tumors that mimic iCAR target LOH through CRISPR editing were fully eradicated with aCAR engagement alone. T-cell activation, proliferation, and cytotoxic activity after exposure to target cells lacking iCAR target antigen was found to be quantitatively indistinguishable from the results obtained with single input aCAR CAR T-cells. These results suggest that iCAR technology can enable treatment of cancer patients with solid tumors using CAR T-cells that maximize potency and efficacy by mitigating on-target CRS, neurotoxicity, and inevitable organ damage. The restriction of CAR T activation to the local tumor environment by iCAR-mediated self-regulation directly addresses a fundamental technology gap that cannot be solved by CAR T dosing or aCAR modification alone. Citation Format: Michael R. Weist, Adi Sharbi-Yunger, Jason Yi, Caitlin Schnair, David Bassan, Tanya Kim, Sarit Tabak, Yael Lopesco, Leehee Weinberger, Nir Bujanover, Neta Chaim, Kristina Vucci, Orit Foord, Frank J. Calzone, Rick Kendall, Gregor B. Adams. Rewiring CAR T-cells for absolute solid tumor specificity and safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2826.

Transdermal Delivery of High Molecular Weight Antibiotics to Deep Tissue Infections via Droplette Micromist Technology Device (DMTD).

Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked to life-threatening vital organ damage. Currently there are no effective topical application strategies to deliver these high molecular weight antibiotics across the stratum corneum. To overcome this difficulty, we tested if high molecular weight antibiotics delivered by Droplette micromist technology device (DMTD), a transdermal delivery device that generates a micromist capable of packaging large molecules, could attenuate deep skin tissue infections. Using green fluorescent protein-tagged E. coli and live tissue imaging, we show that (1) the extent of attenuation of deep-skin E. coli infection was similar when treated with topical DMTD- or systemic IP (intraperitoneal)-delivered CMS; (2) DMTD-delivered micromist did not spread the infection deeper; (3) topical DMTD delivery and IP delivery resulted in similar levels of vancomycin in the skin after a 2 h washout period; and (4) IP-delivered vancomycin was about 1000-fold higher in kidney and plasma than DMTD-delivered vancomycin indicating systemic toxicity. Thus, topical DMTD delivery of these antibiotics is a safe treatment for the difficult-to-treat deep skin tissue infections by MDR bacteria.

Astaxanthin, a carotenoid antioxidant, pretreatment alleviates cognitive deficits in aircraft noised mice by attenuating inflammatory and oxidative damage to the gut, heart and hippocampus

BackgroundWe first explore whether aircraft noise (AN) induces cognitive deficit via inducing oxidative damage in multiple vital organs including intestines, hearts and hippocampus tissues. Second, we explore whether the AN-induced cognitive deficits and inflammatory and oxidative damage to multiple organs can be alleviated by Astaxanthin (AX) pretreatment. MethodsCognitive deficits were induced by subjecting the mice to AN 2 h daily for 7 consecutive days. An intragastrical dose of AX emulsifier (at the dose of daily feed intake [6 g] of a mouse three times weekly) was given to mice for consecutive 8 weeks prior to the start of AN. Cognitive functions were evaluated by using passive avoidance apparatus, Y-maze, Morris water maze and novel recognition test. Intestinal permeability was determined by measuring the intestinal clearance of fluorescein-isothiocyante. Evans Blue extravasation assay was used to measure the permeability of blood-brain-barrier. Inflammatory and oxidative damage to multiple organs were determined by measuring several pro-inflammatory cytokines and oxidative stress indicators in intestines; hearts and hippocampus. ResultsMice treated with AN displayed exacerbated stress reactions, cognitive deficits, gut barrier hyperpermeability, increased upload of lipopolysaccharide translocation, systemic pro-inflammatory cytokines overproduction, blood-brain-barrier hyperpermeability, hippocampal neuroinflammation and increased levels of oxidative stress indicators in intestine, heart and hippocampus. All of the above-mentioned disorders caused by AN were significantly (P < 0.05) reversed by AX. ConclusionsOur data indicate that AX pretreatment alleviates cognitive deficits in aircraft noised mice by attenuating inflammatory and oxidative damage to intestines, hearts and hippocampal tissues.

Effect of Formaldehyde Exposure on Oxidative Stress Markers, Liver and Kidneys of Medical Students during Dissection in Gross Anatomy Laboratory

Background: Medical students are routinely exposed to formaldehyde during their dissecting practical classes and human exposure to formaldehyde is associated with multiple adverse effects. Chronic exposures may cause oxidative stress and may result in some vital organ damage. Materials/Methods: The study included the total class population of the 2017 set of medical students (56 male students) from College of Medicine, Chukwuemeka Odumegwu Ojukwu University, Uli. These students were recruited immediately after first year, that is, before the commencement of dissection. Baseline samples were collected before exposure to formaldehyde. Subsequent samples were collected at one month, three and six-month intervals. All samples were collected immediately after dissection at the required period. The dissection periods are two times per week each lasting for 3 hours (1-4 pm). Eight millilitres (8 ml) of fasting blood samples were collected from all subjects by sterile disposable syringes into a sterile plain container and allowed to clot, retracted and centrifuge at 3000 rpm for 10 minutes. Thereafter, serum was separated into two aliquots. One part of the samples were stored at -20 ˚C for analysis of oxidative stress markers (GPx, SOD and MDA) within two weeks of collection, while the remaining aliquot was stored at -20 ˚C and used for the analysis of liver and kidney markers. Data obtained was analyzed using SPSS version 2021. Results: Glutathione peroxidase and superoxide dismutase (SOD) activities were significantly reduced after one and three-month periodic exposures when compared with the baseline study. Malondialdehyde (MDA) level was significantly lower when the baseline study was compared with the one month and three-month exposure but does not differ significantly from that of six-month exposures. The activity of ALT was significantly higher after one and three-month periodic exposures when compared with the baseline study. However, when the baseline study was compared with six-month exposures, it was not significant. When the activities of AST, ALP and other liver markers which include albumin, AFP, total protein, conjugated and unconjugated bilirubin of baseline study were compared with the one, three and six-month periodic exposures, it was not statistically significant across all groups. When the concentrations of the serum electrolytes of the baseline study were compared with one, three and six-month periodic exposures, it was not statistically significant. However, the concentration of urea was found to be significant when one-month periodic exposures were compared with the baseline study.

Glutamine relieves the hypermetabolic response and reduces organ damage in severe burn patients: A multicenter, randomized controlled clinical trial

BackgroundSevere burns can cause a hypermetabolic response and organ damage. Glutamine is a conditionally essential amino acid with various pharmacological effects. In this study, whether glutamine could alleviate the hypermetabolic response and maintain organ function after burn injury was analyzed. MethodsA multicenter, randomized, single-blind, parallel controlled trial was conducted to evaluate the efficacy of glutamine in decreasing hypermetabolism after burn injury. Physiological and biochemical indexes, such as vital signs, metabolic hormones, metabolic rate, and organ damage, were recorded on the 7th and 14th days after treatment. ResultsIn total, 55 adult burn patients with a total burn surface area (TBSA) of 30–70% were included in this study and randomly divided into the burn control (B, 28 patients) and burn+glutamine (B+G, 27 patients) groups. Except for the glutamine administration, the groups did not differ in the other treatments and nutrition supplements. The levels of diamine oxidase (DAO), lactulose/mannitol (L/M), β2-microglobulin, lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBD) and cardiac troponin l (cTnl) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). The levels of resting energy expenditure (REE), serum catecholamines, glucagon, lactate and Homeostasis model assessment (HOMA) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). No significant difference was found in the length of hospitalization or the mortality rate between the two groups (p > 0.05). ConclusionsGlutamine moderately alleviates the hypermetabolic response and reduces organ damage after severe burns. Therefore, the early application of glutamine, which is effective and safe, should be used as an active intervention as early as possible.

Single institutional experience of management of penetrating trauma chest

Chest trauma is now the second most common non-intentional traumatic injury. Chest trauma is associated with high mortality. Control of blood loss and stabilization of vital organs is of vital importance over diagnostic and therapeutic measures. Bleeding may arise from chest wall, intercostal or internal mammary arteries, great vessels, mediastinum, myocardium, lung parenchyma, diaphragm or abdomen. Modified early warning signs (MEWS) score of &gt;9 on presentation have shown higher rate of mortality. Diagnostic modalities such as extended-focused assessment with sonography in trauma (eFAST) have been effective. The type of surgical approach alters according to the site of injury. We here presented our experience with six such patients. All the six patients involved in this study had penetrating trauma chest with various sharp weapons including dagger, ice pick, flag post. Time of presentation of all these patients were delayed due to ours being a tertiary centre. The patients were explored on the basis of eFAST findings, intercostal drainage, hemodynamics. Out of the six patients two patients succumbed and the patients who died also had high MEWS score. All the patients were approached surgically with respect to the type of injury sustained. Penetrating chest trauma present a challenging clinical situation which warrants early evaluation and intervention. The cases of chest trauma then be it blunt or penetrating should always be treated within the advanced trauma life support (ATLS) guidelines followed by the definitive management. Regardless of any penetrating object, the foreign body should be left in situ and only to be removed under vision. If in case the penetrating object has already been removed the operative intervention is decided on the amount of drainage. With blunt chest trauma, approximately 15% of the deaths result directly from intrathoracic injury, but with penetrating chest trauma, nearly 100% of the deaths result from intrathoracic injury. Hence, the operative exploration of the chest in penetrating chest trauma and should be done on emergent basis as the mechanism of injury, vital organ damage and hemodynamic status all equate to higher rate of mortality.

Nano-engineered tools in the diagnosis, therapeutics, prevention, and mitigation of SARS-CoV-2

The recent outbreak of SARS-CoV-2 has forever altered mankind resulting in the COVID-19 pandemic. This respiratory virus further manifests into vital organ damage, resulting in severe post COVID-19 complications. Nanotechnology has been moonlighting in the scientific community to combat several severe diseases. This review highlights the triune of the nano-toolbox in the areas of diagnostics, therapeutics, prevention, and mitigation of SARS-CoV-2. Nanogold test kits have already been on the frontline of rapid detection. Breath tests, magnetic nanoparticle-based nucleic acid detectors, and the use of Raman Spectroscopy present myriads of possibilities in developing point of care biosensors, which will ensure sensitive, affordable, and accessiblemass surveillance. Most of the therapeutics are trying to focus on blocking the viral entry into the cell and fighting with cytokine storm, using nano-enabled drug delivery platforms. Nanobodies and mRNA nanotechnology with lipid nanoparticles (LNPs) as vaccines against S and N protein have regained importance. All the vaccines coming with promising phase 3 clinical trials have used nano-delivery systems for delivery of vaccine-cargo, which are currently administered widely in many countries. The use of chemically diverse metal, carbon and polymeric nanoparticles, nanocages and nanobubbles demonstrate opportunities to develop anti-viral nanomedicine. In order to prevent and mitigate the viral spread, high-performance charged nanofiber filters, spray coating of nanomaterials on surfaces, novel materials for PPE kits and facemasks have been developed that accomplish over 90% capture of airborne SARS-CoV-2. Nano polymer-based disinfectants are being tested to make smart-transport for human activities. Despite the promises of this toolbox, challenges in terms of reproducibility, specificity, efficacy and emergence of new SARS-CoV-2 variants are yet to overcome.

Efficient Delivery of Chlorin e6 by Polyglycerol-Coated Iron Oxide Nanoparticles with Conjugated Doxorubicin for Enhanced Photodynamic Therapy of Melanoma.

Chlorin e6 (Ce6) is a promising photosensitizer for tumor photodynamic therapy (PDT). However, the efficacy of Ce6 PDT is limited by Ce6's poor water solubility, rapid blood clearance, and inadequate accumulation in the tumor tissue. This problem is tackled in this work, wherein functionalized superparamagnetic iron oxide nanoparticles (IO-NPs) were used as carriers to deliver Ce6 to melanoma. The IO-NPs were coated with polyglycerol (PG) to afford good aqueous solubility. The chemotherapeutic agent doxorubicin (DOX) was attached to the PG coating via the hydrazone bond to afford affinity to the cell membrane and thereby promote the cell uptake. The hydrophobic nature of DOX also induced the aggregation of IO-NPs to form nanoclusters. Ce6 was then loaded onto the IO nanoclusters through physical adsorption and coordination with surface iron atoms, yielding the final composites IO-PG-DOX-Ce6. In vitro experiments showed that IO-PG-DOX-Ce6 markedly increased Ce6 uptake in mouse melanoma cells, leading to much-enhanced photocytotoxicity characterized by intensified reactive oxygen species production, loss of viability, DNA damage, and stimulation of tumor cell immunogenicity. In vivo experiments corroborated the in vitro findings and demonstrated prolonged blood clearance of IO-PG-DOX-Ce6. Importantly, IO-PG-DOX-Ce6 markedly increased the Ce6 distribution and retention in mouse subcutaneous melanoma grafts and significantly improved the efficacy of Ce6-mediated PDT. No apparent vital organ damage was observed at the same time. In conclusion, the IO-PG-DOX NPs provide a simple and safe delivery platform for efficient tumor enrichment of Ce6, thereby enhancing antimelanoma PDT.

High-Affinity Anti-VISTA Antibody Protects against Sepsis by Inhibition of T Lymphocyte Apoptosis and Suppression of the Inflammatory Response.

Background B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis. Methods Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3+ T cell apoptosis and macrophage activation were determined in vitro. Results VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3+ T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro. Conclusion The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis.

Evaluation of hydroxychloroquine induced retinal toxicity in systemic lupus erythematosus patients

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder, which affects the major organs in the human body. Pathophysiology of SLE is unknown. It mainly affects the joints, and restricts their movement. Hydroxychloroquine (HCQ) an anti-malarial drug is used as the first line of drugs used to treat SLE. The major adverse effect of this drug is irreversible retinopathy. The aim of the study was to evaluate the incidence and prevalence of retinopathy in patients with long-term usage of hydroxychloroquine (for more than 1 year).Methods: In patients with SLE, we recorded a review on HCQ induced toxicity among those taking it for longer period (&gt;1 year). All the patients were above 18 years of age. A total data of 210 patients suffering from SLE and taking HCQ for more than one year was collected. Patients were categorized according to gender and dose pattern. Out of 210 patients, 0 patients were found to be retinal toxic induced by HCQ.Results: Suitable statistical tools were used and data was analysed which showed the incidence and prevalence of HCQ induced toxicity. With the results of our study we can understand that incidence and prevalence rates were very low among the subjects.Conclusions: HCQ is said to reduce the risk of disease remission, improves survival, minimizes the risks of vital organ damage, reduces the frequency of flares and has a protective effect on cardiovascular health. HCQ medication is usually well tolerated. But irreversible retinopathy is the major effect on long term use of HCQ. The present study concludes that in the nominal daily dose of 200mg did not reveal any signs of retinal toxicity in 100% of the population tested within 5 years of HCQ treatment suggesting that the toxicity is rare and can be prevented by reducing the dose of the drug.

Angiotensin-converting enzyme 2 gene expression in human male urological tissues: implications for pathogenesis and virus transmission pathways

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs through binding and internalization of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane. Pathological changes are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. The aim of this study was to investigate ACE2 gene expression in the human male urogenital tract using a public database.MethodsA search of transcriptomic datasets from a database to investigate ACE2 gene expression in human urogenital tract tissue.ResultsThe gene expression profile demonstrated that ACE2 gene expression was higher in human kidney cortex and testis than human lung tissue. The gene expression profile demonstrated that ACE2 gene expression in the human bladder and prostate was comparable to human lung tissue.ConclusionsMale urogenital tissues are directly susceptible to SARS-CoV-2 infection through the expression of ACE2. Moreover, the SARS-Cov-2/ACE2 interaction may disturb the male genital and reproductive functions.

Effect of Sub Lethal Doses of Nickel Chloride on CBC and Histology of Cirrhinus Mrigala

This present study aims to investigate the histological and CBC parameters on Cirrhinus marigala after the exposure of Nickel Chloride. The first group of fish was taken as control group and placed in normal water without given any treatment. The second and third groups of fish were administered to two concentrations of sub-lethal doses of 96 hrs (LC50, 3.75ppm) of nickel chloride for 30 days. Results of this study showed that the number of white blood cells, platelets and haemoglobin level were significantly increased where simultaneously the number of red blood cells was significantly decreased due to exposure of nickel chloride. It was also observed that nickel chloride accumulated in organs (Kidneys &lt; Gills &lt; Liver &lt; Heart) of Cirrhinus marigala. Results of histopathology showed the heavy damage of vital organs in fish due to nickel chloride exposure. One-way ANOVA test was performed in SPSS package volume 16 showed that observed data was statistically signi?cant (P &lt; 0.05). This study concluded that nickel chloride effects the CBCs and histopathological parameters of fish Cirrhinus marigala. Keywords: Fish, Toxic effect, Heavy metal, blood parameters

A Systematic Review of Hypertension and Stress - The Silent Killers

Hypertension (HTN) and stress are often referred to as the “silent killers”. The reason the condition is termed as 'silent killer' is because more than 30% of people who have high blood pressure are not even aware of it. Most of the times, there are very minor symptoms or no symptoms at all. Some of the signs you must look out for are difficulty in breathing, chest pain or heaviness, headaches, irregular heartbeat (palpitation), problems in vision, problems in urination. These 'small' indicators may harbor some consequences as damage of arteries and vital organs of the body which may further lead to life-threatening medical emergencies. Therefore, we must not only identify and control hypertension but also promote a healthy lifestyle and preventive strategies to decrease the prevalence of hypertension in the general population. Most of the time, high blood pressure (HBP, or HTN) may show no symptoms and puts the patient at an increased risk for heart disease, heart failure, stroke, etc. Though high blood pressure cannot be cured but it can be managed effectively through lifestyle changes and medication. A primary intent of this article is to educate readers about the risk factors associated with high blood pressure as well as to encourage them to follow a healthy lifestyle in order to reduce the chances of developing hypertension later in their lives. This article is designed to serve as a guide to help readers understand the relationship between high blood pressure and stress as well as to suggest various ways to maintain healthy blood pressure.

Designing S100A9-Targeted Plant Virus Nanoparticles to Target Deep Vein Thrombosis.

Thromboembolic conditions are a leading cause of death worldwide, and deep vein thrombosis (DVT), or occlusive venous clot formation, is a critical and rising problem that contributes to damage of vital organs, long-term complications, and life-threatening conditions such as pulmonary embolism. Early diagnosis and treatment are correlated to better prognosis. However, current technologies in these areas, such as ultrasonography for diagnostics and anticoagulants for treatment, are limited in terms of their accuracy and therapeutic windows. In this work, we investigated targeting myeloid related protein 14 (MRP-14, also known as S100A9) using plant virus-based nanoparticle carriers as a means to achieve tissue specificity aiding prognosis and therapeutic intervention. We used a combinatorial peptide library screen to identify peptide ligands that bind MRP-14. Candidates were selected and formulated as nanoparticles by using cowpea mosaic virus (CPMV) and tobacco mosaic virus (TMV). Intravascular delivery of our MRP-14-targeted nanoparticles in a murine model of DVT resulted in enhanced accumulation in the thrombi and reduced thrombus size, suggesting application of nanoparticles for molecular targeting of MRP-14 could be a promising direction for improving DVT diagnostics, therapeutics, and therefore prognosis.

Destructive effect of iron overload in brain tissue of albino rats: Ameliorative role of silver immobilized organo-modified casein nanocomposite as co-treating agent with Deferasirox

BackgroundIron (Fe) is one of the most essential trace elements in the body that play crucial role in organisms’ survival, however, excess deposition of it puts patients at higher risk of iron overload and tissue injury through production of reactive oxygen species (ROS), elevation of oxidative stress, development of endocrine disorders among which hypogonadism, and increased incidence of cells damage in vital organs. As deferasirox (DFX) is an approved Fe chelator drug, its inability to cross blood brain barrier (BBB) remains a definite obstacle against its use as Fe chelator in the brain. Lately, attention to nanoparticles usage in researches has been widely grown since their role in improving drug therapeutic effects and scavenging free radicals make them good candidates as chelating and antioxidant agents. AimsHerein, after induction of iron overload, organo-modified casein immobilized silver nanocomposite (Ag@Tr-CA) was designed and explored as combined therapy with DFX drug to develop its penetrating efficiency toward BBB and its Fe chelating affinity. Moreover, to distinguish the advanced antioxidant character as well as the beneficial impact of it on lowering brain’s oxidative stress. Meanwhile, its capability in regulating serum pituitary hormones such as follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and testosterone (T), ameliorating DNA damage, and improving brain’s histopathological alterations was also assessed. MethodsThe physicochemical characteristics of Ag@Tr-CA was carried out using X-ray powder diffractometry (XRD), Fourier transform infrared (FTIR), dynamic light scattering (DLS), field emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscope (HR-TEM) analyses. Effect of iron overload and subsequent treatment with DFX + Ag@Tr-CA on brain of adult male albino rats were evaluated using colorimetric methods to determine brain Fe concentration and brain oxidative stress biomarkers. Assessment of serum Fe indices and serum pituitary hormones (FSH, LH, PRL) and T were estimated by ELISA technique. Determination of DNA damage in cerebral cortex cells was accomplished using the alkaline version of comet assay, while detection of brain’s histopathological alterations was performed by examination of H&E sections under light microscope. ResultsThe physicochemical characteristics of Ag@Tr-CA showing the proficiency of Ag nanoparticles (∼35 nm) in creating highly-ordered negatively charged micro-sized casein particles (∼450 μm). After induction of iron overload, DFX + Ag@Tr-CA combination efficiently down brain Fe concentration, brain oxidative stress markers, and DNA damage in cerebral cortex cells linked with improvements in brain histopathological alterations. Comparing DFX therapeutic action alone to its combination to whether Ag@Tr-CA or Tr-CA (organo-modified cross-linked casein nanoparticles) as co-treating agents revealed no significant effect on serum Fe indices, FSH, LH, PRL, and T against iron overload disease. ConclusionThe present results showed that combination of Ag@Tr-CA nanocomposite with DFX makes it a promising co-treating agent against iron overload through improving the physiological, molecular, and histological structure of the brain in iron overloaded rats.

Novel Coronavirus Disease 2019 (COVID-19) and Cytokine Storms for More Effective Treatments from an Inflammatory Pathophysiology.

The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.