Peroxisome proliferator-activated receptor alpha is essential factor in enhanced macrophage immune function induced by angiotensin converting enzyme.

An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant Staphylococcus aureus (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans.

Classical and nonclassical effects of angiotensin-converting enzyme: How increased ACE enhances myeloid immune function.

As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic cardiovascular function, inflammation, and cellular proliferation. Less well known is that macrophages and neutrophils make ACE in response to immune activation which has marked effects on myeloid cell function independent of angiotensin II. Here, we discuss both classical (angiotensin) and nonclassical functions of ACE and highlight mice called ACE 10/10 in which genetic manipulation increases ACE expression by macrophages and makes these mice much more resistant to models of tumors, infection, atherosclerosis, and Alzheimer's disease. In another model called NeuACE mice, neutrophils make increased ACE and these mice are much more resistant to infection. In contrast, ACE inhibitors reduce neutrophil killing of bacteria in mice and humans. Increased expression of ACE induces a marked increase in macrophage oxidative metabolism, particularly mitochondrial oxidation of lipids, secondary to increased peroxisome proliferator-activated receptor α expression, and results in increased myeloid cell ATP. ACE present in sperm has a similar metabolic effect, and the lack of ACE activity in these cells reduces both sperm motility and fertilization capacity. These nonclassical effects of ACE are not due to the actions of angiotensin II but to an unknown molecule, probably a peptide, that triggers a profound change in myeloid cell metabolism and function. Purifying and characterizing this peptide could offer a new treatment for several diseases and prove potentially lucrative.

Morphomolecular characterization of invasive fruit borer infesting apple.

Apple, a vital fruit crop worldwide and a major crop grown in northern parts of India, acts as a backbone for the survival and livelihood of the farming community. However, it is prone to severe damage from insect pests and diseases. In the past few years, due to erratic weather patterns, there has been an alarmingly increased infestation of different insect pests, both invasive and non-invasive, resulting in substantial economic losses to this industry. One similar case was seen in the Himalayan region of India, where the apple crop in Karewas was heavily damaged by some invasive fruit borer, feeding on pulp and making galleries to reach the seed locules, thereby destroying the seed material. To ascertain the true identity of this pest, a study based on morpho-molecular characterization of this pest was carried out in the Faculty of Agriculture, Wadura, SKUAST Kashmir, India, during the years 2021 and 2022. The invasive fruit samples were collected from apple orchards at different locations (experimental sites) in North India by installing delta sticky traps @ 5 traps/ha for moth collection. The fruit-boring larvae and pupa were also collected and reared in confined chambers of the laboratory with controlled temperature and humidity. All the laboratory investigations were conducted at the Division of Entomology, FoA, Wadura, SKUAST Kashmir. During the investigation, it was confirmed that the invasive borer is a codling moth (Cydia pomonella L.), a member of the family Tortricidae, order Lepidoptera, which was earlier having quarantine importance in India, as it was only present in the Ladakh region of India. From the phylogenetic analysis of sample sequences, the species of codling moth present at all experimental sites was more identical to the codling moth sequence from Leh (the northernmost arid region), India. Further, the study of life cycle and voltinism revealed that codling moth completes three generations per year in Kashmir, with a single cycle lasting up to 2.5 months. However, the timing of various generations varies, depending on prevailing weather conditions at specific locations and times. The number of generations completed by codling moth in Kashmir conditions during apple growing season was three full and a half overwintering generations. The study of the life cycle of this important pest was necessary to know the weak link for its effective management and to prevent the economic loss in apple fruit.

Knowledge, attitudes, and practices of vaccinators about expanded programs on immunization: a cross-sectional study.

Introduction: The periodic evaluation of knowledge, attitudes, and practices (KAP) of healthcare workers, including vaccinators, concerning expanded programs on immunization (EPI) is very crucial for a better healthcare system. This study was carried out to assess the KAP of vaccinators about the EPI, including cold storage of vaccines and their practices related to vaccine cold chain management. Method: A cross-sectional study was conducted from January 2022 to June 2022 among registered vaccinators in the twin cities (Islamabad and Rawalpindi) of Pakistan. A structured self-administered questionnaire (English and Urdu) was developed as per the Pakistan national EPI policy and strategic guidelines 2022 and World Health Organization (WHO) guidelines, as well as from earlier studies (Cronbach's alpha value of 0.734). The final questionnaire consisted of closed-ended questions in four sections, including sociodemographic information, knowledge (with dichotomous variables of yes/no), attitudes (with a 5-point Likert scale ranging from strongly agree to strongly disagree), and handling of vaccines and cold chain management. Completed questionnaires were entered into Microsoft Excel and then imported into SPSS version 25 for statistical analysis. Results: A total of 186 vaccinators completely filled out their questionnaires, with a 97.9% response rate. More than half of the participants (57.5%) had no training related to EPI. Most of the respondents had a moderate to poor level of knowledge regarding EPI. The overall attitude was positive, and 57% of the participants strongly agreed that the national immunization programs can significantly contribute to the decrease in morbidity and mortality rates among children. In the current study, participants showed good practices toward EPI, vaccine storage, and cold chain management. The majority (93.5%) of the participants checked the expiry of vaccines at regular intervals to maintain the first expiry first out (FEFO) in their healthcare setting. Discussion: In conclusion, most of the vaccinators had moderate to poor knowledge, a positive attitude, and good practices toward EPI, vaccine cold storage, and cold chain management. Lack of training among vaccinators on EPI was also observed. These findings have suggested that continuous training, education, and regular supervision of vaccinators in EPI are important for maximum immunization effectiveness and coverage.

Formulation of Functional Liquid Diets Under IDDSI Levels 0 to 2 for Dysphagia Patients: Physico-Chemical, Sensory, Antioxidant and Electromyographic Oral Processing Analyses.

Dysphagia is a significant health concern especially amongst the old age population. It is an ailment brought on by the weakening of the swallowing muscles. To reduce the risk of choking in dysphagia patients, the food is usually diluted to suit their swallowing ability. But dilution results in reducing the nutritional density of the foods thus causing undernutrition and malnutrition in patients. In this study, functional liquid diets were formulated under International Dysphagia Diet Standardization Initiative (IDDSI) levels 0-2. The developed diets were analysed for their proximate composition, colour, antioxidant and sensory properties. Antioxidant activities were determined using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and total phenolic content (TPC) methods. The highest ABTS+ value was observed in pumpkin puree (level-2) i.e. 98.59%. Black carrot juice (level-1) showed the highest DPPH free radical scavenging activity and FRAP value viz. 88.43% and 689.33 µM TE/g, respectively. Electromyography (EMG) is an upcoming technique of food texture evaluation which provides real-time information about food oral processing. In this study, an EMG was conducted to measure the myoelectrical activity of human suprahyoid and masseter muscles by placing electrodes on the skin's surface during the oral processing of liquid. The EMG parameters correlated significantly with viscosity, ease of swallowing and IDDSI levels of the formulated diets. Hence EMG can be used as a tool for design and development of textured-modified diets for dysphagia patients. The sensory scores of formulated diets in this study were high indicating that these liquid diets may be incorporated into the diet plans of dysphagia patients.

Relationship Between Cardiometabolic Index in Early Pregnancy and Hypertensive Disorder Complicating Pregnancy.

Background This study aimed to examine the cardiometabolic index during early pregnancy in individuals with hypertension-complicating pregnancy, especially preeclampsia. Additionally, this study sought to determine the relationship between cardiometabolic index and the incidence of varying degrees of preeclampsia. Methodology This study included 289 pregnant women diagnosed with preeclampsia who were registered and delivered at our hospital. These women were assigned to the preeclampsia group. Additionally, a group of 289 healthy pregnant women of identical gestational ages within the same time frame was included for comparison. Clinical data on pregnancy, including body mass index (BMI), blood pressure, waistline, triglyceride levels, and cardiometabolic index, were compared between the two groups. An analysis was conducted to examine the association between early pregnancy cardiometabolic index and the occurrence of preeclampsia. Results There was a significant association between the quartile of cardiometabolic index and the proportion of preeclampsia patients (p < 0.001). Furthermore, after controlling for age and BMI, the risk of preeclampsia remained significantly elevated and was associated with the cardiometabolic index. Conclusions A positive correlation was observed between cardiometabolic index during early pregnancy and the occurrence of preeclampsia.

Diverse biological functions of the renin-angiotensin system.

The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis.

The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which contributes to disease progression. We previously reported that mice with increased macrophage-specific angiotensin-converting enzyme, termed ACE10/10 mice, resist atherosclerosis in an adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced model. This is due to increased lipid metabolism by macrophages which contributes to plaque resolution. However, the importance of ACE in peripheral blood monocytes, which are the primary precursors of lesional-infiltrating macrophages, is still unknown in atherosclerosis. Here, we show that the ACE-mediated metabolic phenotype is already triggered in peripheral blood circulating monocytes and that this functional modification is directly transferred to differentiated macrophages in ACE10/10 mice. We found that Ly-6Clo monocytes were increased in atherosclerotic ACE10/10 mice. The monocytes isolated from atherosclerotic ACE10/10 mice showed enhanced lipid metabolism, elevated mitochondrial activity, and increased adenosine triphosphate (ATP) levels which implies that ACE overexpression is already altered in atherosclerosis. Furthermore, we observed increased oxygen consumption (VO2), respiratory exchange ratio (RER), and spontaneous physical activity in ACE10/10 mice compared to WT mice in atherosclerotic conditions, indicating enhanced systemic energy consumption. Thus, ACE overexpression in myeloid lineage cells modifies the metabolic function of peripheral blood circulating monocytes which differentiate to macrophages and protect against atherosclerotic lesion progression due to better lipid metabolism.

Cervical cell's nucleus segmentation through an improved UNet architecture.

Precise segmentation of the nucleus is vital for computer-aided diagnosis (CAD) in cervical cytology. Automated delineation of the cervical nucleus has notorious challenges due to clumped cells, color variation, noise, and fuzzy boundaries. Due to its standout performance in medical image analysis, deep learning has gained attention from other techniques. We have proposed a deep learning model, namely C-UNet (Cervical-UNet), to segment cervical nuclei from overlapped, fuzzy, and blurred cervical cell smear images. Cross-scale features integration based on a bi-directional feature pyramid network (BiFPN) and wide context unit are used in the encoder of classic UNet architecture to learn spatial and local features. The decoder of the improved network has two inter-connected decoders that mutually optimize and integrate these features to produce segmentation masks. Each component of the proposed C-UNet is extensively evaluated to judge its effectiveness on a complex cervical cell dataset. Different data augmentation techniques were employed to enhance the proposed model's training. Experimental results have shown that the proposed model outperformed extant models, i.e., CGAN (Conditional Generative Adversarial Network), DeepLabv3, Mask-RCNN (Region-Based Convolutional Neural Network), and FCN (Fully Connected Network), on the employed dataset used in this study and ISBI-2014 (International Symposium on Biomedical Imaging 2014), ISBI-2015 datasets. The C-UNet achieved an object-level accuracy of 93%, pixel-level accuracy of 92.56%, object-level recall of 95.32%, pixel-level recall of 92.27%, Dice coefficient of 93.12%, and F1-score of 94.96% on complex cervical images dataset.

Sustainable Isolation of Bioactive Compounds and Proteins from Plant-Based Food (and Byproducts).

Plant-based food produces significantly less greenhouse gases, and due to its wealth of bioactive components and/or plant-based protein, it becomes an alternative in a sustainable food system. However, the processing and production of products from plant sources creates byproducts, which can be waste or a source of useful substances that can be reused. The waste produced during the production and processing of food is essentially nutrient- and energy-rich, and it is recognized as an excellent source of secondary raw materials that could be repurposed in the process of manufacturing and preparing food, or as feed for livestock. This review offers an overview of the sources and techniques of the sustainable isolation of bioactive substances and proteins from various sources that might represent waste in the preparation or production of food of plant origin. The aim is to uncover novel approaches to use waste and byproducts from the process of making food to provide this waste food an additional benefit, not forgetting the expectations of the end user, the consumer. For the successful isolation of bioactive ingredients and proteins from food of plant origin, it is crucial to develop more eco-friendly and efficient extraction techniques with a low CO2 footprint while considering the economic aspects.

An overview of methodological flaws of real-world studies investigating drug safety in the post-marketing setting.

INTRODUCTION: The evaluation of the post-marketing safety profile of drugs is a continuous monitoring process for approved and marketed medicines and it is crucial for detecting new adverse drug reactions. As such, real-world studies are essential to complement pre-marketing evidence with information concerning drug risk-benefit profile and use in wider patient populations and they have a great potential to support post-marketing drug safety evaluations. AREAS COVERED: A detailed description of the main limitations of real-world data sources (i.e. claims databases, electronic healthcare records, drug/disease registers and spontaneous reporting system databases) and of the main methodological challenges of real-world studies in generating real-world evidence is provided. EXPERT OPINION: Real-world evidence biases can be ascribed to both the methodological approach and the specific limitations of the different real-world data sources used to carry out the study. As such, it is crucial to characterize the quality of real-world data, by establishing guidelines and best practices for the assessment of data fitness for purpose. On the other hand, it is important that real-world studies are conducted using a rigorous methodology, aimed at minimizing the risk of bias.

Evaluation of health care professionals' knowledge, attitudes, practices and barriers to pharmacovigilance and adverse drug reaction reporting: A cross-sectional multicentral study.

BACKGROUND: Healthcare professionals' involvement and reporting of adverse drug reactions are essential for the success of a pharmacovigilance program. The aim of this study was to assess healthcare professionals (medical doctors, pharmacists, nurses, dentists, midwives, and paramedics) current knowledge, attitude, practices, and barriers regarding pharmacovigilance and adverse drug reactions reporting in multicentral healthcare settings. METHODS: A cross-sectional face-to-face survey was conducted among currently working healthcare professionals in various hospitals in ten districts of Adana province, Türkiye from March to October 2022. A self-administered, pretested questionnaire (Cronbach's alpha = 0.894 for knowledge, attitudes and practices variables) was used for data collection. The questionnaire's final draft included five sections (sociodemographic/general information, knowledge, attitude, practices, and barriers) with 58 questions. The collected data was analyzed in SPSS (version 25) using descriptive statistics, the chi-square test, and logistic regression. RESULTS: Of the total 435 distributed questionnaires, 412 completed the entire questionnaire, yielding a 94% response rate. The majority of healthcare professionals (60.4%; n = 249) had never received pharmacovigilance training. Among healthcare professionals 51.9% (n = 214), 71.1% (n = 293) and 92.5% (n = 381) had poor knowledge, positive attitudes and poor practices, respectively. Only 32.5% of healthcare professionals kept the record of an adverse drug reaction and only 13.1% reported adverse drug reactions. The profession (medical doctors, pharmacists, nurses, dentists, midwives, and paramedics) of healthcare professionals and a lack of training were predictors of poor adverse drug reaction reporting (p < 0.05). A statistically significant difference in healthcare professionals and knowledge, attitude and practices scores was also observed (p < 0.05). The main barriers which were supposed to discourage adverse drug reactions reporting by the healthcare professionals were higher workload (63.8%) followed by thinking that a single adverse drug reaction report makes no impact (63.6%) and lack of a professional atmosphere (51.9%). CONCLUSION: In the current study, most healthcare professionals had poor knowledge and practice, but they had a positive attitude toward pharmacovigilance and adverse drug reactions reporting. Barriers to under-reporting of adverse drug reactions were also highlighted. Periodic training programs, educational interventions, systematic follow-up of healthcare professionals by local healthcare authorities, interprofessional links between all healthcare professionals, and the implementation of mandatory reporting policies are critical for improving healthcare professionals knowledge, practices, patient safety and pharmacovigilance activities.

Macrophage angiotensin-converting enzyme reduces atherosclerosis by increasing peroxisome proliferator-activated receptor α and fundamentally changing lipid metabolism.

AIMS: The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage angiotensin-converting enzyme (ACE) in a mouse model of PCSK9-induced atherosclerosis. METHODS AND RESULTS: Atherosclerosis in mice was induced with AAV-PCSK9 and a high-fat diet. Animals with increased macrophage ACE (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and have a profoundly altered phenotype to process lipids characterized by higher levels of the surface scavenger receptor CD36, increased uptake of lipid, increased capacity to transport long chain fatty acids into mitochondria, higher oxidative metabolism and lipid ß-oxidation as determined using 13C isotope tracing, increased cell ATP, increased capacity for efferocytosis, increased concentrations of the lipid transporters ABCA1 and ABCG1, and increased cholesterol efflux. These effects are mostly independent of angiotensin II. Human THP-1 cells, when modified to express more ACE, increase expression of PPARα, increase cell ATP and acetyl-CoA, and increase cell efferocytosis. CONCLUSION: Increased macrophage ACE expression enhances macrophage lipid metabolism, cholesterol efflux, efferocytosis, and it reduces atherosclerosis. This has implications for the treatment of cardiovascular disease with angiotensin II receptor antagonists vs. ACE inhibitors.

Municipal solid waste treatment for bioenergy and resource production: Potential technologies, techno-economic-environmental aspects and implications of membrane-based recovery.

World estimated municipal solid waste generating at an alarming rate and its disposal is a severe concern of today's world. It is equivalent to 0.79 kg/d per person footprint and causing climate change; health hazards and other environmental issues which need attention on an urgent basis. Waste to energy (WTE) considers as an alternative renewable energy potential to recover energy from waste and reduce the global waste problems. WTE reduced the burden on fossil fuels for energy generation, waste volumes, environmental, and greenhouse gases emissions. This critical review aims to evaluate the source of solid waste generation and the possible routes of waste management such as biological landfill and thermal treatment (Incineration, pyrolysis, and gasification). Moreover, a comparative evaluation of different technologies was reviewed in terms of economic and environmental aspects along with their limitations and advantages. Critical literature revealed that gasification seemed to be the efficient route and environmentally sustainable. In addition, a framework for the gasification process, gasifier types, and selection of gasifiers for MSW was presented. The country-wise solutions recommendation was proposed for solid waste management with the least impact on the environment. Furthermore, key issues and potential perspectives that require urgent attention to facilitate global penetration are highlighted. Finally, practical implications of membrane and comparison membrane-based separation technology with other conventional technologies to recover bioenergy and resources were discussed. It is expected that this study will lead towards practical solution for future advancement in terms of economic and environmental concerns, and also provide economic feasibility and practical implications for global penetration.

The Diagnostic Dilemma of Splenic Non-Hodgkin's Lymphoma and Splenic Abscess: A Narrative Review.

Non-Hodgkin's lymphoma (NHL) is a lymphoproliferative disorder that principally displays lymph node involvement but can also spread to extranodal sites such as the spleen. Primary splenic NHL arises in the spleen and, due to its atypical presentation, can sometimes present similarly to other splenic conditions. This review aims to highlight how primary splenic NHL can be effectively differentiated from other splenic conditions, such as splenic abscesses. PubMed, MEDLINE, Scopus, Google, and Google Scholar were used to identify articles mainly focused on splenic non-Hodgkin's lymphoma and splenic abscess. The search was limited to articles published from January 2005 to November 2022. Of the 229 total articles amassed, only 34 were selected and narratively reviewed. From a thorough review of the current literature, it is evident that splenic NHL displays a similar clinical picture to other splenic conditions, namely splenic abscesses. One cannot easily differentiate between the two conditions, both clinically and via diagnostic imaging. Lymphadenopathy, a hallmark sign of nodal NHL, may or may not be present in splenic NHL. Ultimately, splenectomy with biopsy and immunohistochemical staining (IHC) may be required to confirm the diagnosis. In cases of suspected splenic NHL or splenic abscess with little-to-no symptomatic improvement after medication administration, splenectomy followed by histopathological examination may be required for a definitive diagnosis and proper treatment.

Self-medication practices with conventional and herbal drugs among ear, nose, and throat patients.

OBJECTIVE: This study evaluates the self-practices with conventional and herbal drug use among ear, nose, and throat outpatients. METHODS: A cross-sectional survey-based study was carried out among all ear, nose, and throat outpatients on their first visit to the otorhinolaryngology department at a tertiary care hospital. The survey comprised a total of 14 questions with 4 different sections, including demographic characteristics, self-medication of conventional medicines, herbal medication usage, and perception regarding herbal medicines. RESULTS: Overall, 255 questionnaires were distributed among patients, of which 183 completed the questionnaire (response rate=71.7%). Respondents reported self-medication (44.8%) with conventional drugs before visiting a hospital. The most commonly used medicine was analgesics (31.7%) and antibiotics (21.9%). Nearly half of the patients (49.2%) used at least one herbal drug. The most commonly used herbal medications were Tilia cordata (78.8%), Zingiber officinale (62.2%), and Camellia sinensis (45.5%). According to the International Union for Conservation of Nature Red List, most of the medicinal herbs were considered as data deficient/least concern. About 36.6% of the participants perceived that herbal drugs are effective for ear, nose, and throat problems. Moreover, 22.9% of the patients did not know about herbal-drug interaction with other medications. CONCLUSIONS: This study observed a considerable prevalence of self-based practices with conventional and herbal medications. Strict national regulations on conventional and herbal medication access and long-term actions should be implemented to discourage inappropriate drug use.

miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive disease with poor prognosis, which is mainly due to drug resistance. The biology determining the response to chemo-radiotherapy in HNSCC is poorly understood. Using clinical samples, we found that miR124-3p and miR766-3p are overexpressed in chemo-radiotherapy-resistant (non-responder) HNSCC, as compared to responder tumors. Our study shows that inhibition of miR124-3p and miR766-3p enhances the sensitivity of HNSCC cell lines, CAL27 and FaDu, to 5-fluorouracil and cisplatin (FP) chemotherapy and radiotherapy. In contrast, overexpression of miR766-3p and miR124-3p confers a resistance phenotype in HNSCC cells. The upregulation of miR124-3p and miR766-3p is associated with increased HNSCC cell invasion and migration. In a xenograft mouse model, inhibition of miR124-3p and miR766-3p enhanced the efficacy of chemo-radiotherapy with reduced growth of resistant HNSCC. For the first time, we identified that miR124-3p and miR766-3p attenuate expression of CREBRF and NR3C2, respectively, in HNSCC, which promotes aggressive tumor behavior by inducing the signaling axes CREB3/ATG5 and ß-catenin/c-Myc. Since miR124-3p and miR766-3p affect complementary pathways, combined inhibition of these two miRNAs shows an additive effect on sensitizing cancer cells to chemo-radiotherapy. In conclusion, our study demonstrated a novel miR124-3p- and miR766-3p-based biological mechanism governing treatment-resistant HNSCC, which can be targeted to improve clinical outcomes in HNSCC.

Comparative Upper Respiratory Tract Transcriptomic Profiling Reveals a Potential Role of Early Activation of Interferon Pathway in Severe COVID-19.

Infection with SARS-CoV-2 results in Coronavirus disease 2019 (COVID-19) is known to cause mild to acute respiratory infection and sometimes progress towards respiratory failure and death. The mechanisms driving the progression of the disease and accumulation of high viral load in the lungs without initial symptoms remain elusive. In this study, we evaluated the upper respiratory tract host transcriptional response in COVID-19 patients with mild to severe symptoms and compared it with the control COVID-19 negative group using RNA-sequencing (RNA-Seq). Our results reveal an upregulated early type I interferon response in severe COVID-19 patients as compared to mild or negative COVID-19 patients. Moreover, severely symptomatic patients have pronounced induction of interferon stimulated genes (ISGs), particularly the oligoadenylate synthetase (OAS) family of genes. Our results are in concurrence with other studies depicting the early induction of IFN-I response in severe COVID-19 patients, providing novel insights about the ISGs involved.