Development of Hemagglutinin-Neuraminidase Homologous Peptides as Novel Promising Therapeutic Agents Against Peste des Petits Ruminants Virus.

The lack of specific antiviral therapy and complications associated with the existing peste des petits ruminants (PPR) vaccines accentuates the search of novel antiviral blocking agents in order to curtail the PPR infection at initial level. The synthetic hemagglutinin-neuraminidase (HN) homologous peptides may compete with the natural HN protein of PPR virus for binding to signaling lymphocytic activation molecule (SLAM) receptor, consequently, may disrupt peste des petits ruminants virus (PPRV) at entry level. Therefore, insilico analysis, synthesis, purification and subsequent characterization of HN homologous peptides were conducted in this study. The HN homologous peptides were synthesized by means of solid phase chemistry and were purified by reversed-phase-high performance liquid chromatography. The mass as well as sequence of HN homologous peptides were assessed by mass spectroscopy while its secondary structure was elucidated by circular dichroism spectroscopy. The binding (interaction) efficacy of HN homologous peptides with PPRV antibodies was assessed via indirect enzyme linked immunosorbent assay, visual detection test (red wine to purple), bathochromic shift under UV-Vis spectrophotometry and lateral flow immunochromatographic strip test. The antiviral properties and cytotoxicity of these peptides were also assessed in B95a cell line with changes in cytopathic effect and titer of PPRV (Sungri/96). The presence of green fluorescein isothiocyanate over the B95a cell surface pointed towards the binding of HN homologous peptides with surface SLAM receptor. Moreover, the intact beta sheet configuration in water and lower cytotoxicity [cytotoxic concentration 50 (CC50) > 1000 µg/ml] of these peptides signifies its in vivo use. Among HN homologous peptides, the binding efficacy and antiviral properties of pep A was relatively high in comparison to pep B and Pep ppr peptides. The prerequisite concentration of HN homologous peptides (pep A = 12.5 µg/ml; pep B = 25 µg/ml; pep ppr = 25 µg/ml) to exemplify its antiviral effect was much lower than its CC50 level. Hence, this study signifies the therapeutic potential of synthetic HN homologous peptides.

Ulva fasciata, a green alga, attenuates the kidney and liver dysfunctions in rats induced by acetaminophen.

Acetaminophen (AAP) is an analgesic-antipyretic drug which is considered safe at recommended dose, but its overuse may induce renal and hepatic injuries. Marine macro algae have great potential against drug-induced renal and hepatic dysfunctions. The present study described the reno-protective and hepato-protective effects of the ethanol extract of an edible green alga Ulva fasciata and its fractions (n-hexane, chloroform and methanol) against AAP toxicity. In the 1st set of experiment, rats were divided into five groups. Of which two were treatment groups beside three controls, the first treatment group was given ethanol extract of U. fasciata alone and the second group was given the same extract with AAP. In the 2nd set of experiment, rats were divided into nine groups, of which three treatment groups administered n-hexane, chloroform and methanol fractions of ethanol extract of U. fasciata respectively while other three treatment groups received the same fractions individually with AAP. On the 11th day, rats were decapitated after 12 h of fasting from both sets, blood samples were collected for assessment of biochemical parameters and kidney tissues were used for determination of oxidants and antioxidants. Histopathological assessment was also done in kidney tissues. A single dose of AAP (600 mg/kg) affected kidney markers including creatinine, urea and blood urea nitrogen (BUN) and hepatic enzymes. Ethanolic extract of U. fasciata normalized kidney and liver markers in AAP intoxicated rats. AAP also reduced glutathione (GSH) in kidney tissues and altered kidney architecture, which were improved by ethanolic extract and chloroform soluble fraction of U. fasciata. A total of 14 polyunsaturated fatty acids were identified from chloroform soluble fraction of U. fasciata by GC-MS and assumed these may be involved in protective activities of U. fasciata.

Ameliorative Effect of Marine Macroalgae on Carbon Tetrachloride-Induced Hepatic Fibrosis and Associated Complications in Rats

Objectives: Liver fibrosis is one of the serious health concern around the globe. Persistent exposure to drugs, toxicants, and pathogens may induce liver fibrosis. Marine macroalgae are globally consumed because of nutritive and medicinal value. This study was conducted to evaluate the protective role of two seaweeds Padina pavonia and Caulerpa racemosa in carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Materials and Methods: Animal model of hepatic fibrosis was developed by injecting 40% CCl4 dissolved in olive oil [2 mL/kg, body weight (b.w.), i.p.] on alternate days for 30 days. Water extracts (WE) [200 mg/kg b.w., p.o.] of P. pavonia and C. racemosa were given to rats daily for 30 days. On day 31, rats were sacrificed after 12 h fasting. Serum was used for biochemical estimation. 10% neutral buffered formalin was used to preserve the liver sample for histopathological examination, while the other portion was used for the preparation of tissue homogenate to estimate antioxidant enzymes and malondialdehyde levels. Results: WEs of both marine macro-algae significantly abrogate the elevated serum concentrations of aminotransferases (alanine aminotransferase and aspartate aminotransferases), alkaline phosphatase and lactate dehydrogenase along with a substantial (p<0.05) reduction in serum bilirubin levels. They also showed positive effects on oxidative stress, evident by improvement in reduced glutathione, catalase, and glutathione peroxidase activities and down regulation of lipid peroxidation level, with stabilizing the destructive cellular morphology of liver induced by repeated CCl4 injection. Both algal extracts also improved kidney function (urea and creatinine) along with lipid metabolism (triglycerides and cholesterol). Conclusion: Water extract of C. racemosa has shown great potential in attenuating liver fibrosis induced by CCl4.

Association of Obesity with COVID-19 Severity and Mortality: A Systemic Review and Meta-Regression

ObjectiveTo estimate the association of obesity with severity (defined as use of invasive mechanical ventilation or intensive care unit admission) and all-cause mortality in coronavirus disease 2019 (COVID-19) patients. Patients and MethodsA systematic search was conducted from inception of COVID-19 pandemic through January 31st, 2021 for full-length articles focusing on the association of increased BMI/ Obesity and outcome in COVID-19 patients with help of various databases including Medline (PubMed), Embase, Science Web, and Cochrane Central Controlled Trials Registry. Preprint servers such as BioRxiv, MedRxiv, ChemRxiv, and SSRN were also scanned. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used for study selection and data extraction. The severity in hospitalized COVID-19 patients, such as requirement of invasive mechanical ventilation and intensive care unit admission with high BMI/ Obesity was the chief outcome. While all-cause mortality in COVID-19 hospitalized patients with high BMI/ Obesity was the secondary outcome. ResultsA total of 576,784 patients from 100 studies were included in this meta-analysis. Being obese was associated with increased risk of severe disease (RR=1.46, 95% CI 1.34-1.60, p<0.001, I2 = 92 %). Similarly, high mortality was observed in obese patients with COVID-19 disease (RR=1.12, 95% CI 1.06-1.19, p<0.001, I2 = 88%). In a multivariate meta-regression on severity outcome, the covariate of female gender, pulmonary disease, diabetes, older age, cardiovascular diseases, and hypertension was found to be significant and explained R2= 50% of the between-study heterogeneity for severity. Similarly, for mortality outcome, covariate of female gender, proportion of pulmonary disease, diabetes, hypertension, and cardiovascular diseases were significant, these covariates collectively explained R2=53% of the between-study variability for mortality. ConclusionsOur findings suggest that obesity is significantly associated with increased severity and higher mortality among COVID-19 patients. Therefore, the inclusion of obesity or its surrogate body mass index in prognostic scores and streamlining the management strategy and treatment guidelines to account for the impact of obesity in patient care management is recommended.

A Meta-analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation and Adverse Effects with Ivermectin Use in COVID-19 Patients

ImportanceRepurposing Ivermectin, a known anti-parasitic agent, for treating COVID-19 has demonstrated positive results in several studies. We aim to evaluate the benefit and risk of Ivermectin in COVID-19. MethodsWe conducted a systematic search for full-text manuscripts published from February 1, 2020, to August 15th, 2021 focusing on Ivermectin therapy against COVID-19. The primary outcomes were mortality, need for intensive care unit (ICU) admission; secondary outcomes were - adverse effects, need for mechanical ventilation, viral clearance, time to viral clearance, need for hospitalization, and length of hospital stay. Random-effects models were used for all analyses. ResultsWe included a total of 52 studies (n=17561) in the qualitative analysis, out of these, 44 studies (n=14019) were included in the meta-analysis. In the mortality meta-analysis (N=29), odds of death were lower in the Ivermectin-arm compared to control (OR 0.54, p=0.009). Although lower odds of mortality were observed in various subgroup analyses of RCTs, they did not reach statistical significance: therapeutic RCTs: mild-moderate COVID-19 (OR 0.31, p=0.06), therapeutic RCTs: severe/critical COVID-19 (OR 0.86, p=0.56), inpatient RCTs: mild-moderate COVID-19 (OR 0.18, p=0.08), inpatient RCTs: severe/critical COVID-19 (OR 0.86, p=0.56). Ivermectin, mostly as adjuvant therapy, was associated with higher odds of viral clearance (N=22) (OR 3.52, p=0.0002), shorter duration to achieve viral clearance (N=8) (MD - 4.12, p=0.02), reduced need for hospitalization (N=6) (OR 0.34, p=008). ConclusionOur meta-analysis suggests that the mortality benefit of Ivermectin in COVID-19 is uncertain. But as adjuvant therapy, Ivermectin may improve viral clearance and reduce the need for hospitalization. HighlightsO_ST_ABSWhat We Already Know about This TopicC_ST_ABSO_LICOVID-19 is an ongoing global pandemic, for which Ivermectin has been tried on a therapeutic and prophylactic basis. C_LIO_LIResults from several clinical trials and observational studies suggest that Ivermectin may improve survival and clinical outcomes with a good safety profile when compared with other treatments; however, the current evidence is limited.. C_LI What This Article Tells Us That Is NewO_LIThis systematic review and meta-analysis provide a summary of the latest literature on the efficacy and safety of Ivermectin use for COVID-19. C_LIO_LIBased on our analysis of the latest evidence, we found that Ivermectins benefit in reducing mortality cannot be concluded with confidence. However, as an adjuvant therapy it may help reduce the need for hospitalization, duration for viral clearance while increasing the likelihood of achieving viral clearance. C_LIO_LIWe need more high-quality data for conclusive evidence regarding the benefit of Ivermectin in reducing the need for ICU admissions, mechanical ventilation and duration of hospital stay in COVID-19 patients. C_LI

Mortality and Severity in COVID-19 Patients on ACEIs & ARBs - A Meta-Regression Analysis

PurposeThe primary objective of this review is to examine studies reporting association of mortality in COVID-19 patients with whether they were on Angiotensin-converting-enzyme inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs). A secondary objective is to similarly access associations with higher severity of the disease in COVID-19 patients. Materials and MethodsWe searched multiple COVID-19 databases (WHO, CDC, LIT-COVID) for randomized trials and longitudinal studies from all over the world reporting mortality and severity published before January 18th, 2021. Meta-analyses were performed using 53 studies for mortality outcome and 43 for the severity outcome. Mantel-Haenszel odds ratios were generated to describe overall effect size using random effect models. To account for between study results variations, multivariate meta-Regression was performed with preselected covariates using maximum likelihood method for both the mortality and severity models. ResultOur findings showed that the use of ACEIs/ARBs did not significantly influence either mortality (OR=1.16 95% CI 0.94 to 1.44, p= 0.15, I2 = 93.2%) or severity (OR=1.18, 95% CI 0.94 to 1.48 p= 0.15, I2 = 91.1%) in comparison to not being on ACEIs/ARBs in COVID-19 positive patients. Multivariate meta-regression for the mortality model demonstrated that 36% of between study variations could be explained by differences in age, gender, and proportion of heart diseases in the study samples. Multivariate meta-regression for the severity model demonstrated that 8% of between study variations could be explained by differences in age, proportion of diabetes, heart disease and study country in the study samples. ConclusionWe found no association of mortality or severity in COVID-19 patients taking ACEIs/ARBs.

Nephroprotective effect of ethanol extract and fractions of a sea lettuce, Ulva fasciata against cisplatin-induced kidney injury in rats.

Cisplatin is widely used in anticancer therapy, but a substantial percentage of patients who receive the therapeutic dose of cisplatin develop nephrotoxicity. Hepatotoxicity may also develop after a single dose or low repeated doses of cisplatin. Ulva fasciata is an edible seaweed, commonly known as sea lettuces have also been shown various biological activities. In this study, ethanol extract and its solvent fractions (n-hexane and chloroform) of U. fasciata were given (orally) to different groups of rats for 10 days. Injury to the kidney was induced by administrating cisplatin, intraperitoneally (i.p.) to rats at a dose of 7 mg/kg body weight (b.w.) dissolved in 1 mL saline, at 5th day of the experiment. At 10th day rats were sacrificed and kidney parameters (creatinine, urea, and blood urea nitrogen (BUN)) and electrolyte balance (Ca++, Mg++, K+, and Na+) in serum were determined, while oxidative stress markers glutathione (GSH), catalase (CAT) and malondialdehyde (MDA), and inflammatory cytokines, tumor necrosis factor (TNF α), and interleukin (IL-6) were determined in kidney tissues. Histological examination of the kidney was also performed to examine the changes in kidney tissues. Cisplatin caused adverse effects on blood parameters, antioxidants, and inflammatory markers with severe renal tubular injury in kidney tissues. Ethanol extract of U. fasciata and its fractions effectively improved these disorders and diminished the renal dysfunction. However, ethanol extract was found more effective in attenuating the adverse effect of cisplatin than its fractions. n-Hexane-soluble fraction that was subjected to GC-FID and GC-MS analysis revealed the presence of several compounds and some of them are new from this source. It could be concluded that the U. fasciata possesses nephroprotective effect and can attenuate cisplatin-induced renal dysfunction. Since U. fasciata is an edible seaweed, it may be used as a diet supplement.

Hypoglycemic potential of some seaweeds from Karachi coast of Pakistan.

Hypoglycemic activity of ethanol extracts and polysaccharides of seaweeds were studied in Sprague Dawley rats. Based on primary screening of ethanol extracts of 10 seaweeds, three Spatoglossum variabile, Stokeyia indica and Sargassum swartzii were selected for further study and polysaccharides were also extracted from them. Ethanol extracts and polysaccharides were administered to alloxan-induced diabetic rats and glucose level, liver and cardiac enzymes were determined. Antidiabetic activity of ethanol extract of three seaweeds S. swartzii, S. indica and S. variabile caused more than 30% reduction in blood glucose after 6 hours atleast on one dose level (2 mg/200 g and/or 10 mg/200 g body weight) in normal and alloxan diabetic rats. Polysaccharides of these three seaweeds also showed anti-diabetic activity after 6 hours atleast on one dose level (1mg/200 g and/ or 2mg/200g body weight) in normal and alloxan diabetic rats. Seaweed extracts and their polysaccharides caused slight alteration in liver and cardiac enzymes like Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT) and Alkaline Phosphatase (ALP).

Marine macro-algae attenuates nephrotoxicity and hepatotoxicity induced by cisplatin and acetaminophen in rats.

Cisplatin is considered one of the best anticancer medications often used for the treatment of various cancers even with its adverse effects. Acetaminophen (paracetamol) is a widely used analgesic-antipyretic drug that causes hepatotoxicity at higher than the effective doses. The present study assesses the nephroprotective and hepatoprotective effects of two seaweeds against cisplatin and acetaminophen toxicity in rats. Damage to the liver and kidney was induced by administering a single intraperitoneal dose of acetaminophen (600 mg/kg) or cisplatin (7 mg/kg) to groups of rats. The damage to the liver and kidney was assessed by the elevated liver (ALT, AST, ALP, LDH, electrolytes) and kidney (urea, creatinine) biomarkers. The ethanol extract of brown seaweed reversed the elevated levels of kidney and liver biomarkers along with triglycerides, cholesterol, and glucose. Among the two seaweeds, Sargassum ilicifolium showed better nephroprotective and hepatoprotective effects than the standard drug N-Acetyl-cysteine, Halymenia porphyroides showed only limited protection. Findings of this study provide evidence of nephroprotective and hepatoprotective effects of S. ilicifolium. Seaweed could be a beneficial dietary supplement to attenuate nephrotoxicity and hepatotoxicity.

Oxaliplatin-induced posterior reversible encephalopathy syndrome (PRES).

Posterior reversible encephalopathy syndrome (PRES), first introduced in 1996, is a neurotoxic state characterised by seizures, headache, vision change, paresis, nausea and altered mental status. Risk factors include hypertension, eclampsia/pre-eclampsia, infection/sepsis and cancer chemotherapy. Although exposure to toxic agents is a common occurrence in patients who develop PRES, oxaliplatin has rarely been associated with it, with only 10 cases reported worldwide. We present the case of an oxaliplatin-induced PRES in a 23-year-old male patient who was started on oxaliplatin/capecitabine as adjuvant chemotherapy for anal canal adenocarcinoma. The patient developed symptoms of headache, slurred speech and left-sided facial weakness on the ninth day after the first dose of oxaliplatin that lasted for 6-8 hours. The patient experienced another episode next day with similar symptoms that lasted for 8 hours. Oxaliplatin was withheld and the patient was discharged on capecitabine only. The patient had no new episodes since discharge on follow-up.

Anaplastic carcinoma of thyroid gland with widespread soft tissue metastasis: an unusual presentation.

Anaplastic thyroid cancer is the rarest tumour of the thyroid gland, representing only 2% of clinically recognised thyroid cancers. The most common metastatic sites are lungs, followed by the intrathoracic and neck lymph nodes. We report the case of a 62-year-old woman who presented to our setting with multiple soft tissue nodules, thyroid mass, head swelling and weight loss. Radiological investigation showed a large thyroid mass with widespread metastasis in subcutaneous tissues of both upper limbs, chest and abdomen. Metastasis was also found in lungs, skull and adrenal glands after which the patient was diagnosed with stage IVc anaplastic thyroid carcinoma (ATC). After careful consideration of patient's clinical condition with multiple poor prognostic factors, medical therapy was withheld and she was discharged on hospice care. The patient expired after 1 month. In ATC, metastasis to subcutaneous tissue is an extremely rare occurrence of which there is hardly any evidence in literature.

Protective role of Sargassum species in liver and kidney dysfunctions and associated disorders in rats intoxicated with carbon tetrachloride and acetaminophen.

Hepatoprotective and reno-potective effect of Sargassum species was investigated in rats against carbon tetrachloride (CCl4) and acetaminophen (AAP) intoxication. The rats were given ethanol extracts of Sargassum ilicifolium, S. lanceolatum and S.swartzii orally at dose of 200mg/kg b.w. (body weight) daily for 14 days. These seaweed treated rats were then intoxicated with single intra-peritoneal dose of CCl4 or AAP on14th day. The administration of CCl4 and AAP caused significant (p<0.05) elevation in liver enzymes; alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and other biochemical parameters, bilirubin, glucose, triglyceride and kidney function markers: urea and creatinine. The pre-treatment with ethanol extracts of S. ilicifolium and S. swartzii protected the liver and kidney significantly (p<0.05) by lowering the elevated level of hepatic enzymes, liver and kidney function markers towards normal range. Sargassum species have also showed positive effect on serum glucose, total cholesterol and triglyceride.

Effect of seaweeds occurring at Karachi coast on mosquito larvae and liver function in rats.

Seaweeds have been consumed as human food from thousands of years. In this study ethanol extract of 16 different seaweeds were tested for mosquito larvicidal activity against 4th instar larvae of Aedes aegyptii. The ethanol extracts of Padina pavonia and Sargassum ilicifolium caused 50% mortality at 1200ppm concentration. However other seaweeds Halimeda tuna, Ulva lactuca (Chlorophyta), Dictyota dichotoma var intricata, Jolyna laminariodes, Sargassum binderi (Phaeophyta), Melanothamnus afaqhusainii and Solieria robusta (Rhodophyta) showed LC50 at ≈1500 ppm concentration. The n-hexane fraction of Padina pavonia was most potent and produced lethality at minimum concentration (LC50 at 250ppm).The effect of ethanol and water extracts of S. binderii was also examined on liver function of healthy rats. The ethanol extract of Sargassum binderi given orally to rats @ 200mg/kg for 14 days slightly increased the concentration of liver enzymes (ALT, AST, ALP and LDH) and urea level as compared with normal control rats, but did not increase bilirubin, glucose, triglycerides, cholesterol and creatinine. Whereas water extract of S. binderi affected ALT while other biochemical parameters were near normal or slightly decreased as compared to normal control.