Nitric oxide-inhibited chloride transport in cortical thick ascending limbs is reversed by 8-iso-prostaglandin-F2α

Background: Salt reabsorption in the cortical thick ascending limb (cTAL) is regulated by opposing effects. Thus, while nitric oxide (NO) inhibits sodium chloride (NaCl) reabsorption, 8-iso-prostaglandin-F2α (8-iso-PGF2α) stimulates it. Their interaction, however, has not been evaluated in the cTAL. Because 8-iso-PGF2α has considerable stability while NO is a free radical with a short half-life, we hypothesized that, in the cTAL, the inhibition of NaCl absorption will be reversed by 8-iso-PGF2α. Methods: Chloride absorption (JCl) was measured in isolated perfused cTALs. We also evaluated whether activation of protein kinase A (PKA) is required for this interaction. Since cyclic adenosine monophosphate (cAMP) is a major messenger for the 8-iso-PGF2α signaling cascade, and NO inhibits JCl by decreasing cAMP bioavailability, we measured 8-iso-PGF2α-stimulated cAMP in the presence of sodium nitroprusside (SNP). Results: Basal JCl was 274 ± 85 pmol/min/mm. The NO donor, SNP (10-6 M), decreased JCl by 41% (333.5 ± 35.2 pmol/min/mm vs. 195.9 ± 26.1 pmol/min/mm), while 8-iso-PGF2α (100 μM) increased JCl to 315 ± 46 pmol/min/mm (p \u3c 0.01), reversing the effects of the NO donor. While SNP inhibited JCl, 8-iso-PGF2α failed to increase JCl in the presence of H89. Basal cAMP was 56.3 ± 13.1 fmol/min/mm, that in the presence of the NO donor was 57.8 ± 6.1 fmol/min/mm, and that with 8-iso-PGF2α increased it to 92.1 ± 2.9 fmol/min/mm (n = 10, p \u3c 0.04). Conclusion: We concluded that 1) NO-induced inhibition of JCl in the cTAL can be reversed by 8-iso-PGF2α, 2) 8-iso-PGF2α and NO interaction requires PKA to control JCl in this nephron segment, and 3) in the presence of NO, 8-iso-PGF2α continues to stimulate JCl because NO cannot reverse 8-iso-PGF2α-stimulated cAMP level

Liver mitochondrial membrane permeability modulation in insulin-resistant, uninephrectomised male rats by Clerodendrum volubile P. Beauv and Manihot esculenta Crantz

Background: Non-alcoholic fatty liver disease, which occurs in people who are not alcohol drinkers, describes some of the pathogenic conditions that may be in the least characterized by simple steatosis or can be as serious as non-alcoholic steatohepatitis and cirrhosis. Its mechanistic pathogenesis has been said to arise from insulin resistance and oxidative stress, which may be compounded by obesity. An experimental model showing, systemic insulin resistance, obesity and accumulated hepatic fatty acids was created in adult male rats using high-fat diet manipulation and surgical removal of the left kidney (uninephrectomy). This study sought to identify the impact of these multiple burdens on the liver mitochondrial membrane permeability transition pore opening, and the possible in vitro effects of the extracts of Clerodendrum volubile and Manihot esculenta leaves on the membrane permeabilization. Results: The results indicated that the methanolic extract of Clerodendrum volubile leaf inhibited mitochondrial membrane pore opening in the insulin resistance condition or when it is followed by uni-nephrectomy, while the ethanolic extract of Manihot esculenta leaf does the same in the insulin resistance condition both prior to and following uni-nephrectomy. Conclusion: Since the vegetable extracts were able to abrogate mitochondrial pore opening at low concentrations, the structural integrity of the mitochondria can possibly be restored over time if treated by the vegetable extracts. Research efforts should, therefore, be made to harness the drugability of the bioactives of these vegetables for use in the treatment of non-alcoholic fatty liver disease arising from insulin resistance and renal failure.Fil: Ajayi, Ebenezer Idowu O. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Osun State University; Nigeria. National Institute of Pharmaceutical Education and Research; IndiaFil: Molehin, Olorunfemi R.. Ekiti State University; NigeriaFil: Oloyede, Omotade I.. Ekiti State University; NigeriaFil: Kumar, Vinodu. National Institute of Pharmaceutical Education and Research; IndiaFil: Amara, Venkateswara R.. National Institute of Pharmaceutical Education and Research; IndiaFil: Kaur, Jasmine. National Institute of Pharmaceutical Education and Research; IndiaFil: Karpe, Pinakin. National Institute of Pharmaceutical Education and Research; IndiaFil: Tikoo, Kulbhushan B.. National Institute of Pharmaceutical Education and Research; Indi

A systematic review on COVID-19 pandemic with special emphasis on curative potentials of Nigeria based medicinal plants

Despite the frightening mortality rate associated with COVID-19, there is no known approved drug to effectively combat the pandemic. COVID-19 clinical manifestations include fever, fatigue, cough, shortness of breath, and other complications. At present, there is no known effective treatment or vaccine that can mitigate/inhibit SARS-CoV-2. Available clinical intervention for COVID-19 is only palliative and limited to support. Thus, there is an exigent need for effective and non-invasive treatment. This article evaluates the possible mechanism of actions of SARS-CoV-2 and present Nigeria based medicinal plants which have pharmacological and biological activities that can mitigate the hallmarks of the pathogenesis of COVID-19. SARS-CoV-2 mode of actions includes hyper-inflammation characterized by a severe and fatal hyper-cytokinaemia with multi-organ failure; immunosuppression; reduction of angiotensin-converting enzyme 2 (ACE2) to enhance pulmonary vascular permeability causing damage to the alveoli; and further activated by open reading frame (ORF)3a, ORF3b, and ORF7a via c-Jun N- terminal kinase (JNK) pathway which induces lung damage. These mechanisms of action of SARS-CoV-2 can be mitigated by a combination therapy of medicinal herbs based on their pharmacological activities. Since the clinical manifestations of COVID-19 are multifactorial with co-morbidities, we strongly recommend the use of combined therapy such that two or more herbs with specific therapeutic actions are administered to combat the mediators of the disease.publishedVersionFil: Oladele, Johnson O. Kings University; Nigeria.Fil: Ajayi, Ebenezer Idowu O. Osun State University; Nigeria.Fil: Ajayi, Ebenezer Idowu O. Universidad Nacional de Córdoba. Rectorado; Argentina.Fil: Ajayi, Ebenezer Idowu O. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra.; Argentina.Fil: Oyeleke, Oyedotun M. Kings University; Nigeria.Fil: Oladele, Oluwaseun T. Osun State University; Nigeria.Fil: Olowookere, Boyede D. Kings University; Nigeria.Fil: Adeniyi, Boluwaji M. Benue State University; Nigeria.Fil: Oyewole, Olu I. Osun State University; Nigeria.Fil: Oladiji, Adenike T. University of Ilorin; Nigeria

Eicosapentaenoic acid prevents salt sensitivity in diabetic rats and decreases oxidative stress

Objectives: Salt sensitivity (SS) is associated with increased cardiovascular risk in patients with Type 2 diabetes mellitus (T2-DM) due to an increase in renal oxidation. ω-3 polyunsaturated fatty acids have shown antioxidant effects, but a typical Western diet contains limited content. In particular, ω-3 polyunsaturated fatty acids are able to activate nuclear factor erythroid 2-related factor 2 (Nrf-2) to prevent diabetes mellitus–related complications by mitigating oxidative stress. Therefore, we hypothesized that eicosapentaenoic acid (EPA; ω-3) modulates SS in rats with T2-DM by decreasing renal oxidative stress via Nrf-2 activation and enhancing the antiinflammatory response via interleukin (IL) 6 modulation. Methods: Three-month-old male rats (n = 40) were fed with a Normal Na-diet (NNaD) and randomly selected into four groups: Healthy Wistar nondiabetic rats (Wi), diabetic controls (eSS), arachidonic acid-treated eSS (AA; ω-6), and EPA-treated eSS (ω-3). After 1 year, rats were placed in metabolic cages for 7 d and fed a NNaD, followed by a 7-d period with a High Na-diet (HNaD). Systolic blood pressure, body weight, serum IL-6 and reactive oxygen species (ROS) levels were determined at the end of each 7-d period. Glycated hemoglobin (HbA1c), triacylglycerol, creatinine, and cholesterol levels were determined. ROS levels and Nrf-2 expression in kidney lysates were also assayed. Histologic changes were evaluated. A t test or analysis of variance was used for the statistical analysis. Results: After a HNaD, systolic blood pressure increased in both the control eSS and AA groups, but not in the EPA and Wi groups. However, HbA1c levels remained unchanged by the treatments, which suggests that the observed beneficial effect was independent of HbA1c levels. The IL-6 levels were higher in the eSS and AA groups, but remained unaltered in EPA and Wi rats after a HNaD diet. Interestingly, EPA protected against serum ROS in rats fed the HNaD, whereas AA did not. In kidney lysates, ROS decreased significantly in the EPA group compared with the eSS group, and Nrf-2 expression was consistently higher compared with the AA and eSS groups. Diabetic rats presented focal segmental sclerosis, adherence to Bowman capsule, and mild-to-moderate interstitial fibrosis. EPA and AA treatment prevented kidney damage. Conclusions: An adequate ω3-to-ω6 ratio prevents SS in diabetic rats by a mechanism that is independent of glucose metabolism but associated with the prevention of renal oxidative stress generation. These data suggest that EPA antioxidant properties may prevent the development of hypertension or kidney damage.Fil: Vara Messler, Marianela. Università di Torino; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mukdsi, Jorge Humberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Osieki, Natalia I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Biología Celular; ArgentinaFil: Benizio, Evangelina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Repossi Marquez, Pablo Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Ajayi, Ebenezer Idowu O. Osun State University; Nigeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Garcia, Nestor Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentin

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa.

The progression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Africa has so far been heterogeneous, and the full impact is not yet well understood. In this study, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations predominantly from Europe, which diminished after the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1, and C.1.1. Although distorted by low sampling numbers and blind spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a source for new variants

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Adaptation of the Wound Healing Questionnaire universal-reporter outcome measure for use in global surgery trials (TALON-1 study): mixed-methods study and Rasch analysis

BackgroundThe Bluebelle Wound Healing Questionnaire (WHQ) is a universal-reporter outcome measure developed in the UK for remote detection of surgical-site infection after abdominal surgery. This study aimed to explore cross-cultural equivalence, acceptability, and content validity of the WHQ for use across low- and middle-income countries, and to make recommendations for its adaptation.MethodsThis was a mixed-methods study within a trial (SWAT) embedded in an international randomized trial, conducted according to best practice guidelines, and co-produced with community and patient partners (TALON-1). Structured interviews and focus groups were used to gather data regarding cross-cultural, cross-contextual equivalence of the individual items and scale, and conduct a translatability assessment. Translation was completed into five languages in accordance with Mapi recommendations. Next, data from a prospective cohort (SWAT) were interpreted using Rasch analysis to explore scaling and measurement properties of the WHQ. Finally, qualitative and quantitative data were triangulated using a modified, exploratory, instrumental design model.ResultsIn the qualitative phase, 10 structured interviews and six focus groups took place with a total of 47 investigators across six countries. Themes related to comprehension, response mapping, retrieval, and judgement were identified with rich cross-cultural insights. In the quantitative phase, an exploratory Rasch model was fitted to data from 537 patients (369 excluding extremes). Owing to the number of extreme (floor) values, the overall level of power was low. The single WHQ scale satisfied tests of unidimensionality, indicating validity of the ordinal total WHQ score. There was significant overall model misfit of five items (5, 9, 14, 15, 16) and local dependency in 11 item pairs. The person separation index was estimated as 0.48 suggesting weak discrimination between classes, whereas Cronbach's α was high at 0.86. Triangulation of qualitative data with the Rasch analysis supported recommendations for cross-cultural adaptation of the WHQ items 1 (redness), 3 (clear fluid), 7 (deep wound opening), 10 (pain), 11 (fever), 15 (antibiotics), 16 (debridement), 18 (drainage), and 19 (reoperation). Changes to three item response categories (1, not at all; 2, a little; 3, a lot) were adopted for symptom items 1 to 10, and two categories (0, no; 1, yes) for item 11 (fever).ConclusionThis study made recommendations for cross-cultural adaptation of the WHQ for use in global surgical research and practice, using co-produced mixed-methods data from three continents. Translations are now available for implementation into remote wound assessment pathways