Innate immune responses to SARS-CoV-2.

This chapter provides an overview of the innate immune response to SARS-CoV-2, focusing on the recognition, activation, and evasion strategies employed by the virus. The innate immune system plays a crucial role in the early defense against viral infections, and understanding its response to SARS-CoV-2 is essential for developing effective therapeutic approaches. The chapter begins by explaining the basics of the innate immune system, including its components and salient features. It discusses the various pattern recognition receptors involved in recognizing SARS-CoV-2, such as toll-like receptors, RIG-I-like receptors, NOD-like receptors, and other cytosolic sensors. The binding and entry of the virus into host cells and subsequent activation of innate immune cells, including neutrophils, monocytes, macrophages, dendritic cells, NK cells, and ILCs, are explored. Furthermore, the secretion of key cytokines and chemokines, including type I interferons, IL-6, IL-17, and TNF-alpha, is discussed as part of the innate immune response. The concept of PANoptosis, involving programmed cell death mechanisms, is introduced as a significant aspect of the response to SARS-CoV-2. The chapter also addresses the innate immune evasion strategies employed by SARS-CoV-2, which allow the virus to evade or subvert the host immune response, contributing to viral persistence. Understanding these strategies is crucial for developing targeted therapies against the virus.

A signature of five 7-methylguanosine-related genes is a prognostic marker for lung squamous cell carcinoma.

Background: N7-methylguanosine (m7G) is an important posttranscriptional modification affecting mRNA and tRNA functions and stability. The genes regulating the m7G process have been previously found involved in the carcinogenesis process. We aimed to analyze the role of m7G-related genes as potential prognostic markers for lung squamous cell carcinoma (LSCC). Methods: Twenty-nine m7G-related genes were selected for the analysis in the LSCC cohort of the Cancer Genome Atlas (TCGA). Univariate, multivariate, and Kaplan-Meier analyses were used to evaluate the predictive value of risk model developed with m7G signature for overall survival (OS).. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of differentially expressed genes (DEGs) were performed for high- and low-risk LSCC groups. Results: We identified 17 differentially expressed m7G methylation-related genes in LSCC versus normal tissues. The expression of five m7G-related genes (EIF3D, LSM1, NCBP2, NUDT10, and NUDT11) was identified as an independent prognostic marker for OS in LSCC patients. A risk model with these five m7G-related genes predicted 2-, and 3-year survival rates of 0.623 and 0.626, respectively. The risk score significantly correlated with OS: LSCC patients with a higher risk score had shorter OS (P<0.01) and it was associated with lower immune response (P<0.01). Conclusions: We developed a novel m7G-related gene signature that can be of great utility to predict the prognosis for patients with LSCC.

Effects of Ketogenic Diet on Reproductive Hormones in Women With Polycystic Ovary Syndrome.

Context: Ketogenic diet has recently made a comeback as a part of lifestyle and dietary modifications in patients with polycystic ovary syndrome (PCOS). Despite studies suggesting its beneficial effects in reversing hormonal imbalance in women with PCOS, evidence has been patchy and derived from small populations under varying conditions. Objective: To pool evidence from clinical trials to study the effects of ketogenic diet on reproductive hormones (LH/FSH ratio, free testosterone, serum progesterone) and observe evidence of weight change. Methods: PubMed, ScienceDirect, Scopus, and Web of Science core collection were searched for clinical trials evaluating the effects of ketogenic diet in established PCOS women consistent with the Rotterdam classification. Single- or double-arm studies that included an outcome of interest were included. Two investigators worked independently to screen potential articles and a designated investigator extracted data on study characteristics and evaluated the outcomes. Data were pooled using a random-effects model. The quality of selected studies was assessed using the Cochrane Risk of Bias Tool. Results: Following ≥45 days of intervention with ketogenic diet among women with PCOS, significant improvement was observed in reproductive hormone levels, with reduced LH/FSH ratio (d -0.851; 95% CI -1.015, -0.686; P < .001), reduced serum free testosterone (d -0.223; 95% CI -0.328, -0.119; P  < .001), and an increased in serum sex hormone binding globulin (SHBG) (d 9.086; 95% CI 3.379, 14.792; P = .002). Significant weight loss was unanimously observed in all included studies (d -11.56; 95% CI -14.97, -8.15; P < .001). Conclusion: Short-term ketogenic diet potentially improved hormonal imbalances commonly associated with PCOS.

Noninvasive central hemodynamic monitoring in the primary care setting: improving prevention and management of cardiovascular diseases.

Background: Although cardiovascular disease (CVD) has markedly declined since the early 1960s due to medical advances and better management, this condition persists as the most critical and preventable cause of death in the US. For that reason, the identification and application of more sensitive, specific, validated, and noninvasive biomarkers of cardiovascular functioning in the primary care setting for the early identification of CVD risk at the subclinical level are warranted. Aim: The goal of the present review is twofold: first, to familiarize the primary care practitioner with noninvasive aortic hemodynamic parameters, including how these could be integrated into primary care services and patient management, and second, to propose a model for earlier detection of CVD based on the noninvasive hemodynamic parameters in the primary care setting. Relevance for Patients: Implementation of noninvasive hemodynamic monitoring in a primary care setting could help in the identification of heart disease risk at the early onset thus preventing the need for expensive treatment or death at later stages.

Introduction to Traditional Medicine and Their Role in Prevention and Treatment of Emerging and Re-Emerging Diseases.

Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt and mutate over time and antibiotic and antiviral resistance ensues. There are many challenges in treating infections such as failure of the microorganisms to respond to the therapeutic agents, which has led to more chronic infections, complications, and preventable loss of life. Thus, a multidisciplinary approach and collaboration is warranted to create more potent, effective, and versatile therapies to prevent and eradicate the old and newly emerging diseases. In the recent past, natural medicine has proven its effectiveness against various illnesses. Most of the pharmaceutical agents currently used can trace their origin to the natural products in one way, shape, or form. The full potential of natural products is yet to be realized, as numerous natural resources have not been explored and analyzed. This merits continuous support in research and analysis of ancient treatment systems to explore their full potential and employ them as an alternative or principal therapy.

Chlorpheniramine, an Old Drug with New Potential Clinical Applications: A Comprehensive Review of the Literature.

Chlorpheniramine Maleate (CPM), also known as chlorphenamine, is a potent alkylamine first-generation H1 antihistamine that has been around since the 1950s. CPM is a widely popular drug commonly used to treat allergic conditions, given its antihistamine properties. Although mainly used in over-the-counter treatment for cough and colds, various studies discuss a wide range of CPM's clinical uses, such as treating asthma, plasma cell gingivitis, chronic urticaria, depression, among others. This antihistamine is usually taken orally; however, intravenous, intramuscular, and subcutaneous routes have been documented. Intranasal routes have recently been explored, especially due to its antiviral properties against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accordingly, given CPM's extensive medical and safety profile, the present review explores this versatile drug's current and potential clinical applications. Although it is widely used mainly for treating common colds and aforementioned allergic conditions, it can be concluded that CPM can be considered to be used for other clinical indications. The repurposing of CPM for other clinical indications such as COVID-19 needs to be further explored through more extensive studies.

Association between hospitalizations for asthma exacerbation and weather conditions in Qingdao: an ecological study.

Background: The hospitalization for asthma exacerbation has varied with seasons, however, the underlying weather reasons have not been fully explored yet. This study is aimed to explore the effect of weather factors on increased number of hospitalization due to worsening of asthma symptoms. This will provide more information to the relevant authorities to allocate appropriate medical resources as per the weather conditions in Qingdao, China. Methods: All adult patients admitted for asthma exacerbation from 1 January, 2017 to 31 December, 2019 were enrolled from 13 main hospitals of Qingdao. The clinical data, including age, sex, smoking history, etc., were collected from the electronic medical record (EMR) systems. The hourly air quality of Qingdao from 2017-2019, including the air quality index (AQI), PM2.5 and PM10, was obtained from the China National Environmental Monitoring Centre. All these parameters during 2017-2019 were compared monthly. For meteorological data, the monthly horizontal wind at 850 hPa and vertical velocity at 500 hPa during 1960-2020 were obtained from National Center for Environmental Prediction (NCEP) and the National Center for Atmospheric Research (NCAR) global reanalysis dataset. The correlation analysis was applied to determine the association between asthma hospitalizations and the environmental factors, including atmospheric pressure, humidity, vertical visibility, and etc., monthly. Results: In all, 10,549 asthmatic inpatients (45.7% males, 54.3% females) were included in the study. The inpatients number for asthma exacerbation had a plateau lasting from March to June of 2019, accompanied with high PM2.5 and PM10, as well as bad air quality from January to March of 2019, potentially governed by the El Niño event in 2018. However, there was no significance correlation between the number of asthma hospitalizations and the average value of all environmental factors. Conclusions: The high rate of hospitalization for asthma exacerbation in Qingdao during the spring of 2019 was associated with the unfavorable weather conditions, which might be linked to the atmospheric circulation in East Asia.

Role of environmental toxicants in the development of hypertensive and cardiovascular diseases.

The incidence of hypertension with diabetes mellitus (DM) as a co-morbid condition is on the rise worldwide. In 2000, an estimated 972 million adults had hypertension, which is predicted to grow to 1.56 billion by 2025. Hypertension often leads to diabetes mellitus that strongly puts the patients at an increased risk of cardiovascular, kidney, and/or atherosclerotic diseases. Hypertension has been identified as a major risk factor for the development of diabetes; patients with hypertension are at two-to-three-fold higher risk of developing diabetes than patients with normal blood pressure (BP). Causes for the increase in hypertension and diabetes are not well understood, environmental factors (e.g., exposure to environmental toxicants like heavy metals, organic solvents, pesticides, alcohol, and urban lifestyle) have been postulated as one of the reasons contributing to hypertension and cardiovascular diseases (CVD). The mechanism of action(s) of these toxicants in developing hypertension and CVDs is not well defined. Research studies have linked hypertension with the chronic consumption of alcohol and exposure to metals like lead, mercury, and arsenic have also been linked to hypertension and CVD. Workers chronically exposed to styrene have a higher incidence of CVD. Recent studies have demonstrated that exposure to particulate matter (PM) in diesel exhaust and urban air contributes to increased CVD and mortality. In this review, we have imparted the role of environmental toxicants such as heavy metals, organic pollutants, PM, alcohol, and some drugs in hypertension and CVD along with possible mechanisms and limitations in extrapolating animal data to humans.

The nephroprotective effects of Daucus carota and Eclipta prostrata against cisplatin-induced nephrotoxicity in rats.

The overuse of cisplatin (>50 mg/m2) is limited to nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. The objective of this study was to investigate the nephroprotective effects of Daucus carota and Eclipta prostrata extracts on cisplatin-induced nephrotoxicity in Wistar albino rats. The study involved male Wistar albino rats of 8 weeks weighing 220-270 g. A single injection of 5 mg/kg was injected into the rats for nephrotoxicity. Rats were divided into four groups based on dose conentrations. Blood and urine samples of rats were collected on the 0, 7th, 14th, and 21st days for nephrological analysis. The results showed that Cis + DC/Cis + EP (600 mg/kg) significantly (p < 0.001) increased the body weight and reduced the kidney weight of cisplatin-induced nephrotoxicity in rats (p < 0.001) as compared to Cis group. The results showed that 600 mg/kg administration of Cis + DC/Cis +EP successfully (p < 0.005) improved the urine and plasmin creatinine, Na, and K level compared to the Cis group. Histopathological results confirmed that Cis + EP/Cis + DC effectively improved the renal abnormalities. It is concluded that the co-administration of Cis + EP extract showed exceptional nephroprotective effects at a dose rate of 600 mg/kg.

Evolution of Complexity. Molecular Aspects of Preassembly.

An extension of neo-Darwinism, termed preassembly, states that genetic material required for many complex traits, such as echolocation, was present long before emergence of the traits. Assembly of genes and gene segments had occurred over protracted time-periods within large libraries of non-coding genes. Epigenetic factors ultimately promoted transfers from noncoding to coding genes, leading to abrupt formation of the trait via de novo genes. This preassembly model explains many observations that to this present day still puzzle biologists: formation of super-complexity in the absence of multiple fossil precursors, as with bat echolocation and flowering plants; major genetic and physical alterations occurring in just a few thousand years, as with housecat evolution; lack of precursors preceding lush periods of species expansion, as in the Cambrian explosion; and evolution of costly traits that exceed their need during evolutionary times, as with human intelligence. What follows in this paper is a mechanism that is not meant to supplant neo-Darwinism; instead, preassembly aims to supplement current ideas when complexity issues leave them struggling.

The Deleterious Effects of COVID-19 in the Peripartum Period: A Case Report.

While the Coronavirus Disease 2019 (COVID-19) pandemic continues to wreak havoc across the nation and the globe as one of the most significant global health crises of our time, recent attention has been turned to the effects of COVID-19 on pregnancy and the puerperium. Although most cases have been asymptomatic, for some patients, the disease may be accompanied by serious complications such as pneumonia, acute respiratory distress, multi organ failure, and death. Several case studies have noted that patients with co-morbidities are at a significant risk of these complications. In a recent systematic review and meta-analysis, authors conclude that cardiovascular disease was associated with increased composite poor outcome in patients with COVID-19. The following case report highlights the multi-system complications and severity of symptoms that can take place after childbirth in a patient with co-morbid obstetric and prenatal conditions and an initially asymptomatic COVID-19 infection.

Characterization and Applications of Colloidal Systems as Versatile Drug Delivery Carriers for Parenteral Formulations.

Preparing a suitable formulation for parenteral administration is already a difficult task; this, coupled with poor water-soluble new chemical entity (NCE), complicates this situation even further. There are several methodologies available to enhance water solubility, but this alone does not entail successful formulation. Making a micro/nano emulsion with a suitable surfactant not only increases the drug solubility but also the cell membrane permeability. Thus, not only biopharmaceutic classification system (BCS)-II (low solubility compounds) but also BCS-III (low permeability) and BCS-IV drugs (low solubility and low permeability) can be further exploited. Those drug candidates otherwise will not move further in NCE evaluation or clinical trials. This succinct review article delves into various aspects of biphasic micro/nano emulsion systems for parenteral drug delivery including the structure of the biphasic colloidal systems, characterization parameters, stability issues, regulatory considerations, and applications in life sciences.

Onychomycosis: Current Understanding and Strategies for Enhancing Drug Delivery into Human Nail Tissue.

BACKGROUND: Onychomycosis is by far the most common finger or toe nail fungal infectious disease caused by dermatophytes, non-dermatophytic molds or yeast. It accounts for 50% of the total nail disorders, and affects patients physically, socially, and psychologically and can seriously influence their quality of life. OBJECTIVES: Oral antifungals are routinely used to treat the nail fungal disease; however oral therapy is associated with severe side effects and longer treatment times. In recent years, drug delivery directly into the nail or nail bed has gained attention and various topical products have been tested that can cure the disease when applied topically or transungually. Nevertheless, drug penetration into and through the nail is not straightforward and requires chemicals to improve its permeability or by applying physical stress to promote drug penetration into and through the nail. This lucid review presents an overview of various causes of onychomycosis, current therapeutic approaches, and efforts aimed at increasing the permeability of nails through various strategies such as chemical, physical and mechanical methods for permeation enhancement. CONCLUSION: Various strategies have been proposed for the treatment of onychomycosis, however, much research into a more precise and effective therapy is still required.

Analysis of the immunoglobin E molecular sensitization profile in children with allergic asthma and predictive factors for the efficacy of allergy immunotherapy.

BACKGROUND: As the incidence of allergic asthma in children increases, the immunoglobin E (IgE) molecular sensitization profile of allergic asthma remains underreported while the level of total IgE (tIgE) and sIgE/tIgE have not been studied as predictors of efficacy of allergen immunotherapy (AIT) for allergic asthma, specifically in children. METHODS: Starting from August 2018 to March 2019 in the Respiratory Department of the Children's Hospital of Chongqing Medical University, asthmatic children, with positive skin prick tests to Der p or Der f, were enrolled in this study. Total IgE, allergen serum-specific IgE (sIgE) of Der p, Der f, Blomia tropicalis (Blo t), cat dander, dog dander, egg white, milk, cockroach, shrimp, and crab, along with Der p allergen components, Der p1 and Der p2, were measured by ImmunoCAP™ assay. RESULTS: A total of 142 children with allergic asthma were enrolled, all of whom showed positive IgE for Der p, Der p1, Der p2, and Der f; meanwhile, the positive rates of Blo t, cat dander, dog dander, egg white, milk, cockroach, shrimp, and crab were 91.84%, 10.96%, 7.32%, 9.15%, 11.58%, 17.03%, 18.90%, and 18.28% respectively. A significantly high correlation was found between total IgE and the sIgE of Der f, Der p, Der p 1, and Der p 2. Asthmatic children with a family history of allergy displayed higher total IgE and unknown IgE levels than those patients without a family history of allergy. The ratios of Der f sIgE/tIgE and Der p sIgE/tIgE were higher in the negative family history of allergy group than in the positive family history of allergy group. Furthermore, total IgE and unknown IgE were higher in the polysensitized group than in the in monosensitized group. The ratios of Der f sIgE/tIgE and Der p sIgE/tIgE were higher in the monosensitized group than in the polysensitized group. CONCLUSIONS: From this study, we noticed that dust mites are the main cause of asthma in children investigated. Our findings indicate patients with no family history of allergy and monosensitized patients have a higher ratio of sIgE/tIgE, and those patients may benefit more from AIT.

Formulation and characterization of lornoxicam-loaded cellulosic-microsponge gel for possible applications in arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease associated with severe joint pain. Herein, we report lornoxicam loaded cellulosic microsponge gel formulation with sustained anti-inflammatory effects that are required to manage arthritic pain. The microsponges were formulated using quasi emulsion-solvent diffusion method employing four different surfactant systems, namely polyvinyl alcohol (PVA), Tween80, Gelucire 48/16 and Gelucire 50/13. All the lornoxicam loaded microsponge formulations were extensively characterized with a variety of analytical tools. The optimized microsponge formulation was then converted into gel formulation. The lornoxicam loaded microsponge gel formulation had adequate viscosity and sufficient pharmaceutical properties as confirmed by the texture analysis and the drug release followed Super case II transport. It is noteworthy that we described the preparation of a new cellulosic polymers based microsponge system for delivery of lornoxicam to provide quick as well as lasting (sustained) anti-inflammatory effects in rats using carrageenan induced rat paw edema model. We were able to demonstrate a 72% reduction in inflammation within 4 h using the optimize transdermal gel formulation utilizing Transcutol P as permeation enhancer and with the aid of skin micro-piercing by microneedles, hence, demonstrating the potential of this microsponge gel formulation in arthritis management.

A Pathophysiological Perspective on COVID-19's Lethal Complication: From Viremia to Hypersensitivity Pneumonitis-like Immune Dysregulation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for our recent coronavirus disease 2019 pandemic, is driving a lung immunopathology that strongly resembles a severe form of hypersensitivity pneumonitis (HP). A review of recent Severe acute respiratory syndrome-related coronavirus (SARS-CoV) and SARS-CoV-2 medical reports, as well as described characteristics of HP, lead us to postulate a theory for SARS-CoV-2 severe disease. We propose that the novel SARS-CoV-2 can act as a trigger and substrate of an HP-like severe immune reaction especially in genetically vulnerable individuals in addition to those with immune senescence and dysregulation. Accordingly, the purpose of our letter is to shift the emphasis of concern surrounding immune activity from viral infection to an HP-like severe immune reaction. We review similarities in disease presentation between infection and allergy, relevant immunopathology, and outline phases of SARS-CoV-2 disease with perspectives on therapy and critical care. Altogether, the favored course is to begin treatments that address the disease at the earliest phase before immune dysregulation leading to uncontrolled pulmonary inflammation.

Dose Issues in Cancer Chemotherapy.

In this review, human methotrexate dosing regimens, as well as their relationship to data from in vitro cell culture and in vivo animal and human studies, are discussed. Low-dose, intermediate-dose, and high-dose therapies are covered. Since in vitro and in vivo screenings of potential cancer drugs are commonplace in the development of cancer chemotherapy, comparisons of the three criteria for effectiveness are important.