Significance of Estrogen/Progesterone Receptor Expression in Metaplastic Breast Carcinoma.

Introduction: Metaplastic breast carcinoma (MBC) is a rare subgroup of breast neoplasms associated with adverse outcomes because of its aggressive nature. Typically, MBCs show triple-negative hormone receptor (HR) status. Determining the HR status of breast cancer is an integral part because it is an important prognostic factor and helps in the treatment course of the disease. This study aimed to determine the HR status of MBC, its significance, and its association with various clinicopathological parameters. Methods: This was a retrospective study conducted at the Department of Histopathology, Liaquat National Hospital. A total of 140 biopsy-proven cases of MBC were enrolled in the study. Clinical and pathological data were retrieved from the institutes' archives. Immunohistochemical studies were conducted to determine the estrogen receptor (ER) and progesterone receptor (PR) status. Results: The mean age of MBC in our population was found to be 52.18 ± 12.19 years. The HR positivity rate in our population was found to be 32.9%. A significant association was found between HR status and tumor laterality, tumor size, tumor grade, tumor stage, and recurrence. ER/PR-negative MBCs were most probably associated with higher grade and higher tumor stage and were larger in size (6.62 ± 3.43 cm) than ER/PR-positive MBCs (4.20 ± 1.88 cm). Moreover, ER/PR-positive MBCs showed a higher recurrence rate than ER/PR-negative MBCs (43.5% vs. 25.5%, respectively). No statistically significant relationship was found between HR status and patient age, histological subtype, or survival rate. Conclusion: MBC is a rare breast neoplasm. MBC was found to be triple negative in most cases, but a significant percentage were HR (ER/PR) positive. Moreover, we found an association between HR status and various clinicopathological features, indicating that HR status is a significant predictor of MBC prognosis.

Diagnostic accuracy of intraoperative frozen section for margin evaluation of oral cavity squamous cell carcinoma.

OBJECTIVES: Intraoperative frozen-section evaluation is a valuable technique for detecting positive margins intraoperatively for oral squamous cell carcinoma. We conducted this study to determine the diagnostic accuracy of frozen section in detecting margin status and the effect of tumor grade and stage on diagnostic accuracy. RESULTS: A total of 251 biopsy-proven cases of oral squamous cell carcinoma were included in this study. The tissue specimen resected during surgery was sent to the laboratory for frozen section evaluation. The frozen section results were then compared with the permanent section results to determine the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy. The mean age of the patients included in the study was 51.65 ± 10.03 years, with male predominance (55.4%). The overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of frozen section were 88.81%, 94.84%, 95.20%, 88.10%, and 91.63%, respectively. We conclude that frozen section is a useful technique in determining the margin status intraoperatively in oral cancers, with high diagnostic accuracy. Moreover, certain clinical parameters such as age, gender, disease duration, and tumor stage and grade appear to affect the diagnostic accuracy of frozen section.

Single nucleotide polymorphism within chromosome 8q24 is associated with prostate cancer development in Saudi Arabia.

Objective: Genome-wide association studies have demonstrated that single nucleotide polymorphisms (SNPs) are important risk factors for the development of prostate cancer (PCa). Preliminary studies have suggested that the incidence of PCa in Saudi males is low but is probably familial or genetically related. Methods: To identify any possible association of SNP with PCa development in Saudi patients, we investigated a group of SNPs in Saudi PCa patients (n=85) and compared the outcomes to healthy normal controls (n=115) and nodular hyperplasia patients (n=120). DNA was extracted from paraffin-embedded formalin fixed tissue or whole blood from both patients' groups and healthy control group. A total of thirteen SNPs were genotyped using TaqMan® minor groove binder polymerase chain reaction assay. Results: The rs16901979A, s629242T and rs1447295A alleles were found at significantly higher frequency in PCa patients than controls (p<0.05). The rs16901979 CA genotype was found at significantly greater frequency in PCa patients than in healthy controls (43% vs. 14%, odds ratio=4.6, p=0.0001) and benign hyperplasia group (43% vs. 25%, odds ratio=2.2, p=0.009). Conclusion: Our study has highlighted the association of rs16901979 SNP with PCa in Saudi males. Such findings have important implications in the PCa diagnosis and in screening unaffected family members of Saudi patients.

Knowledge, acceptance, motivators and barriers of booster dose of COVID-19 vaccination among dental patients: A cross-sectional study.

Given the lingering threat of COVID infection, questions are being raised if coronavirus disease 2019 (COVID-19) vaccine needs annual or regular boosters to maintain high levels of immunity against both the original virus and variants. This study was designed to evaluate the knowledge, acceptance, motivators and barriers of the booster dose of COVID-19 vaccine among the dental patients of District Lucknow, India. A total of 297 respondents were selected by a convenience sampling method in this cross-sectional study from various dental clinics. An anonymous, self-administered, closed-ended questionnaire was used. Overall 37.7% respondents reported to have taken all 3 doses and 57.9% had taken single/double doses. Correct information about booster doses shows a significant association with the number of doses taken. The majority had information about the availability of the Pfizer booster vaccine (69.0%). About 58% of participants had information about the technology used in booster doses. The hesitancy for booster doses and the development of natural immunity by infection show significant associations with the number of doses taken. Only 18.2% patients had hesitation about the booster dose and most of them 78.8% recommended others to take the booster vaccine as soon as possible. The majority assumed that previous COVID-19 vaccines can help them get immune (21.5%) followed by not much research has been done on the booster vaccines (15.5%) and their chronic diseases warn them against the booster dose administration (12.5%). Nearly 18.2% of respondents had hesitation about booster dose and less than one third of the respondents trusted a government source for information about booster dose of COVID vaccine. Nearly 36 % did not know that the booster dose of COVID vaccine is available at health centers. Dental health professionals and policymakers should implement and support strategies to ensure people are vaccinated for COVID-19 booster doses.

Anti-Helicobacter pylori Activity of Six Major Compounds Isolated from Rumex acetosa.

Gastric problems are often caused by the well-known Helicobacter pylori (H. pylori) bacterium. One of the biggest obstacles to the treatment of H. pylori infections is increasing the antibiotic resistance. During our search for naturally derived anti-H. pylori compounds, six major compounds were isolated from the methylene chloride (CH2Cl2) and ethyl acetate (EtOAc) fractions of Rumex acetosa that showed anti-H. pylori activity. Three anthraquinones and three anthraquinone glucosides were identified as the major chemical constituents of the CH2Cl2 and EtOAc fractions, respectively. The chemical structures were identified to be emodin (1), chrysophanol (2), physcion (3), emodin-8-O-ß-d-glucoside (4), chrysophanol-8-O-ß-d-glucoside (5), and physcion-8-O-ß-d-glucoside (6) by UV, 1H NMR, 13C NMR, and mass spectrometry. Anti-H. pylori activity, including the minimum inhibitory concentration (MIC) value of each compound, was evaluated against two H. pylori strains. All isolates exhibited anti-H. pylori activity with different potencies, with an MIC value ranging between 3.13 and 25 µM. However, some variations were found between the two strains. While compound 5 displayed the most potent antibacterial activity with an MIC50 value of 8.60 µM and an MIC90 value of 15.7 µM against H. pylori strain 51, compound 1 exhibited the most potent inhibitory activity against H. pylori strain 43504. The two compounds also showed moderate urease inhibitory activity, with compound 1 demonstrating activity higher than that of compound 5. Furthermore, a molecular docking study revealed the high binding ability of compounds 1 and 5 to the active site of H. pylori urease. The present study suggests that the six anthraquinones isolated from R. acetosa with the whole parts of this plant may be natural candidates for the treatment of H. pylori infection. Further studies are required to determine the exact mechanism of action and to evaluate safety issues in the human body.

Preparation, Characterization, and Evaluation of Physcion Nanoparticles for Enhanced Oral Bioavailability: An Attempt to Improve Its Antioxidant and Anticancer Potential.

This study aims to enhance the dissolution rate of a poorly water-soluble drug physcion by producing its nanoparticles (NPs) using an antisolvent precipitation with a syringe pump (APSP) method and to assess its antioxidant and cytotoxic potential. The NPs were prepared using a simple and cost-effective APSP method and subsequently characterized by different analytical techniques including dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray powder diffractometry (XRD). They were also subjected to solubility and dissolution studies, and different parameters such as dissolution efficiency (DE), mean dissolution time (MDT), and difference (f1) and similarity factors (f2) were determined. Furthermore, physcion and its NPs were investigated for antioxidant and cytotoxic effects using various in vitro assays. SEM and DLS analysis indicated that the average size of physcion NPs was 110 and 195 ± 5.6 nm, respectively. The average ζ-potential and polydispersibility index (PDI) of the prepared NPs were -22.5 mV and 0.18, respectively, showing excellent dispersibility. XRD confirmed the amorphous nature of physcion NPs. The solubility and dissolution rates of NPs were significantly higher than those of the original powder. The antioxidant potential studied by the (DPPH), FRAP, and H2O2 assays was greater for physcion NPs than that for the raw powder. The IC50 values of physcion NPs against the aforementioned models were 57.56, 22.30, and 22.68 µg/mL, respectively. Likewise, the cytotoxic potential investigated through the MTT assay showed that physcion NPs were more cytotoxic to cancer cell lines A549 (IC50 4.12 µg/mL), HepG2 (IC50 2.84 µg/mL), and MDA-MB-231 (IC50 2.97 µg/mL), while it had less effect on HPAEpiC (IC50 8.68 µg/mL) and HRPTEpiC (IC50 10.71 µg/mL) normal human epithelial cells. These findings have proved that the APSP method successfully produced physcion NPs with enhanced solubility, dissolution rate, and antioxidant and cytotoxic activities.

Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A Comprehensive Multidisciplinary Update.

Background and Objectives: The uterine smooth muscle tumors of uncertain malignant potential (STUMP) are tumors with pathological characteristics similar to leiomyosarcoma, but that do not satisfy histological criteria for leiomyoma. These are problematic lesions with intermediate morphologic features; thus, diagnosis and treatment are difficult. This narrative review aims to review data in the literature about STUMPs, particularly focusing on management and therapeutic options and strategies for women who desire to preserve fertility. Material and Methods: authors searched for "uterine smooth muscle tumor of uncertain malignant potential" in PubMed and Scopus databases, from 2000 to March 2023. Pertinent articles were obtained in full-text format and screened for additional references. Only articles in English language were included. Studies including full case description of patients with histopathological diagnosis of STUMP in accordance with Stanford criteria were included. Results: The median age was 43 years old. Symptoms are similar to those of leiomyomas, with a mean diameter of 8.0 cm. Total hysterectomy with or without bilateral salpingo-oophorectomy is the standard care for women if fertility desire is satisfied. Myomectomy alone can be considered for young patients. Although these tumors have not a high malignant potential, several studies described recurrence and metastases. Conclusions: STUMPs are complex uterine smooth muscle tumors, with a rare but reasoned clinical-diagnostic management. Considering the high clinical and histological complexity of these tumors, high level of expertise is mandatory.

Parasite Diversity in a Freshwater Ecosystem.

Parasites are a significant component of biodiversity. They negatively affect fish appearance, growth, and reproduction. In this study, the prevalence of infection, diversity, and mean intensity of parasites were examined in 9 freshwater fish species (45 samples per fish species). Ecto-parasites were examined on the skin, gills, and fins with a hand lens. Wet mounts were prepared using mucosal scrapings from all the external and internal organs of the sampled fish. Microscopy, muscle compression, and the pepsin-HCL artificial digestion technique were also performed. In this study, 26 species of parasites were identified including three taxa belonging to 9 species of protozoan parasites, 11 treamtodes, and 6 monogenean parasites. The identified protozoan parasites were Entamoeba histolitica, Chilodonella sp., Coccidia sp., Costia sp., Cryptobia sp., Ichthyopthiris-multifilis, Microsporidia, Piscinoodinium sp., and Ichthyobodo necator. The identified trematode parasites were Fasciola gigantica, Echinostoma revolutum, Fasciola hepatica, Haplorchis pumilio, Brachylaima cribbi, Echinostoma cinetorchis, Neascus sp., Deropegus sp., Trematode Soldier, Centrocestus formosanus, and Clinostomum marginatum. The identified monogenean parasites were Dactylogyrus limipopoensis, Dactylogyrus anchoratus, Dactylogyrus myersi, Dactylogyrus vastator, Gyrodactylus salaris, and Ancyrocephalus. The diversity of parasites was maximum at the Okara site. The host's organs that were targeted for parasitic infection included the intestine, liver, gills, fins, skin, and kidneys. The majority of the parasites were identified in Labeo rohita followed by Hypophthalmichthys molitrix, Ctenopharyngodon idella, Oreochromis niloticus, Cyprinus carpio, and Wallagu attu. Two species appeared to be resistant species because none of the parasites were observed in Notopterus notopterus or Sperata seenghala. This study also concluded that the prevalence of parasites increased with increasing length, size, and age of fish.

Modulation of Apoptosis and Autophagy by Melatonin in Juglone-Exposed Bovine Oocytes.

Melatonin, an antioxidant hormone secreted by the pineal gland, has been recognized as a regulator for numerous biological events. The deleterious effects of juglone, a polyphenolic extract of walnut trees, on embryo development has been previously reported. In the current study, we aimed to display the impact of melatonin administrated during in vitro oocyte maturation (IVM) on juglone-treated oocytes. Thus, in vitro matured oocytes were collected after 24 h post incubation with juglone in the presence or absence of melatonin. Reactive oxygen species (ROS), glutathione (GSH) content, mitochondrial distribution, and the relative abundance of mRNA transcription levels were assessed in oocytes, in addition, oocytes were in vitro fertilized to check the competency levels of oocytes to generate embryos. We found that administration of melatonin during the maturation of oocytes under juglone stress significantly improved the cleavage rate, 8-16 cell-stage embryos and day-8 blastocysts when compared to the sole juglone treatment. In addition, the fluorescence intensity of ROS increased, whereas the GSH decreased in juglone-treated oocytes compared to melatonin-juglone co-treated and untreated ones. Additionally, a significant increase in the mitochondrial aberrant pattern, the pattern that was normalized following melatonin supplementation, was observed following juglone administration. The mRNA analysis using RT-qPCR revealed a significant upregulation of autophagy and oxidative-stress-specific markers in the juglone-treated group compared to the co-treatment and control. In conclusion, the study reveals, for the first time, a protective effect of melatonin against the oxidative stress initiated following juglone treatment during the in vitro maturation of oocytes.

Quorum Quenchers from Reynoutria japonica in the Battle against Methicillin-Resistant Staphylococcus aureus (MRSA).

Over the past decade, methicillin-resistant Staphylococcus aureus (MRSA) has become a major source of biofilm formation and a major contributor to antimicrobial resistance. The genes that govern biofilm formation are regulated by a signaling mechanism called the quorum-sensing system. There is a need for new molecules to treat the infections caused by dangerous pathogens like MRSA. The current study focused on an alternative approach using juglone derivatives from Reynoutria japonica as quorum quenchers. Ten bioactive compounds from this plant, i.e., 2-methoxy-6-acetyl-7-methyljuglone, emodin, emodin 8-o-b glucoside, polydatin, resveratrol, physcion, citreorosein, quercetin, hyperoside, and coumarin were taken as ligands and docked with accessory gene regulator proteins A, B, and C and the signal transduction protein TRAP. The best ligand was selected based on docking score, ADMET properties, and the Lipinski rule. Considering all these parameters, resveratrol displayed all required drug-like properties with a docking score of -8.9 against accessory gene regulator protein C. To further assess the effectiveness of resveratrol, it was compared with the commercially available antibiotic drug penicillin. A comparison of all drug-like characteristics showed that resveratrol was superior to penicillin in many aspects. Penicillin showed a binding affinity of -6.7 while resveratrol had a score of -8.9 during docking. This was followed by molecular dynamic simulations wherein inhibitors in complexes with target proteins showed stability inside the active site during the 100 ns simulations. Structural changes due to ligand movement inside the cavity were measured in the protein targets, but they remained static due to hydrogen bonds. The results showed acceptable pharmacokinetic properties for resveratrol as compared to penicillin. Thus, we concluded that resveratrol has protective effects against Staphylococcus aureus infections and that it suppresses the quorum-sensing ability of this bacterium by targeting its infectious proteins.

Downregulation of PI3K/AKT/mTOR Pathway in Juglone-Treated Bovine Oocytes.

We have previously reported that juglone, a natural compound found in Juglandaceae with a wide range of biological activities, can reduces the developmental competence of bovine oocytes. In the current study, we investigated the possible mechanisms behind the toxicity of juglone and the relationship with PI3K/AKT/mTOR signaling during the in vitro maturation (IVM) of oocytes. Results show that oocyte exposure to juglone was associated with a significant decrease in filamentous actin (F-actin) accumulation. The RT-qPCR showed downregulation of the meiosis progression indicator GSK-3A, oocyte development marker BMP15, mitochondria fusion controlling MFN1, oxidative stress-related OGG1, and histone methylation-related EZH1, EZH2, SUZ12, G9a, and SUV39H2 genes in juglone-treated oocytes. In addition, glycolysis- (PFK1 and GLUT1), ATP synthesis- (ATPase8 and ATP5F1B), and OXPHOS-specific markers (SDHA and SDHD), as well as the oocyte survival regulators (SOD2, VEGF, and MAPK1) significantly decreased upon juglone treatment. Moreover, lower expression of PI3K, AKT, and mTOR was observed at the transcriptional and/or translational level(s). The autophagy markers LC3B and beclin-1 as well as the DNA damage-specific marker 8-OxoG displayed overexpression in juglone-exposed oocytes. Taken together, our results show that administration of juglone during the IVM can reduce the quality and developmental health of bovine oocytes through downregulation of the PI3K/AKT/mTOR pathway and its downstream signaling cascades.

Improvement in cardio-metabolic health and immune signatures in old individuals using daily chores (Salat) as an intervention: A randomized crossover study in a little-studied population.

Background: Decline in cardio-metabolic health, immunity, and physical activity is associated with old age. Old people also find it difficult to engage in structured exercise programs. Therefore, there is a need to investigate common daily chores as an alternative for exercise that may also help in maintaining cardio-metabolic and immune health. Objective: We aimed to investigate whether Salat, an obligatory Islamic prayer involving various physical movements and closely resembling yoga, enhances the benefits conferred by the current guidelines for physical activity. Methods: A total of 30 overweight adults (mean (SD) age of 53.5 (8.7) years) participated in this study. For a 4-week duration, we compared the effects of Salat before/after meals (Pre-MS/Post-MS) on selected immunological and metabolic parameters in serum samples. We also compared the effects of both Pre-MS/Post-MS regimens in young and old subjects to observe any age-related effects. Results: Most of the baseline metabolic parameters and the count of immune cells were normal. Post-MS resulted in a significant reduction in body weight and percent body fat (%BF). Overall, Post-MS resulted in a clear leukocytosis with a significant increase in granulocytes, monocytes, and lymphocytes. When analyzing the lymphocyte compartment, a clear numerical increase was noted for T, B, and NK cells. The number of CD8+ T cells showed a statistically significant increase. Similarly, Post-MS induced leukocytosis in both young and old individuals, while the increase in granulocytes, monocytes, and lymphocytes was statistically significant in old subjects only. Conclusion: This study demonstrated that the Islamic obligatory and congressional Salat practice is capable of mimicking desirable pro-immune and pro-metabolic health effects. Clinical trial registration: (UMIN000048901).

Antibacterial and Antibiofilm Activity of Juglone Derivatives against Enterococcus faecalis: An In Silico and In Vitro Approach.

Enterococcus faecalis is a Gram-positive bacterium that is normally found in the gastrointestinal tract of humans and animals. E. faecalis is an opportunistic pathogen that causes a number of invasive and noninvasive infections. The emergence of multidrug resistance and biofilm formation by the bacterium have rendered the treatment of E. faecalis infections very difficult. Due its high rate of resistance and biofilm formation, there are very few options of treatment. Therefore, the current study was designed to evaluate the antibacterial and biofilm activities of juglone derivatives such as 2-methoxy-6-acetyl-7-methyljuglone and 2-ethoxy-6-acetyl-7-methyljuglone against multidrug-resistant (MDR) and biofilm-producing strains of E. faecalis. Agar well diffusion and broth microdilution methods were used to determine the antibacterial activities. Biofilm attachment and preformed biofilm inhibition were determined using crystal violet staining assay. Both juglone derivatives displayed promising antibacterial and antibiofilm activities against E. faecalis. Among these compounds, 2-ethoxy-6-acetyl-7-methyljuglone possessed better inhibitory activity with minimum inhibitory concentration (MIC) of 9.7 ± 3 µM as compared to 2-methoxy-6-acetyl-7-methyljuglone (MIC, 19.5 ± 2 µM). Additionally, 2-ethoxy-6-acetyl-7-methyljuglone also showed stronger antibiofilm activity than 2-methoxy-6-acetyl-7-methyljuglone. Furthermore, both the ligand molecules were docked into the binding site of the enterococcal surface protein, and the results revealed that both the molecules are actively binding in the target site. Based on these findings, juglone derivatives may be considered useful for the treatment of E. faecalis infections; however, further studies are required to elucidate the mechanism of action.

An Overview on Rumex dentatus L.: Its Functions as a Source of Nutrient and Health-Promoting Plant.

Rumex dentatus L. (Polygonaceae), also known as toothed dock or Aegean dock, is a medicinal plant with a high culinary value in addition to being used as an ethnomedicinal plant. This review focuses on the botanical, nutritional, phytochemical, and pharmacological activities of R. dentatus, as well as the future prospects for systematic investigations into these areas. R. dentatus has been subjected to scientific evaluation, which has confirmed its traditional uses and demonstrated a wide range of biological and pharmacological potentials, including antioxidant, anticancer, antifungal, antibacterial, anti-inflammatory, and other biological properties. Phytochemical analyses showed the presence of anthraquinones, chromones, flavonoids, and essential oils. As a result of this current review, the medicinal significance of R. dentatus has been confirmed, and future research on its unexplored aspects, such as the identification of pharmacologically active chemical constituents and related mechanisms and safety, may be stimulated, with the goal of developing it into a drug.

Assessment of Tocilizumab (Humanized Monoclonal Antibody) for Therapeutic Efficacy and Clinical Safety in Patients with Coronavirus Disease (COVID-19).

Background and objectives: COVID-19 patients exhibit a broad range of manifestations, presenting with a flu-like respiratory tract infection that can advance to a systemic and severe disease characterized by pneumonia, pulmonary edema, severe damage to the airways, and acute respiratory distress syndrome (ARDS, causing fatality in 70% of COVID-19 cases). A 'cytokine storm' profile is found in most severely influenced COVID-19 patients. The treatment protocol of the disease also includes tocilizumab, which is a humanized monoclonal antibody used to treat autoimmune and inflammatory conditions. This study was designed (1) to assess the role of tocilizumab in COVID-19 patients regarding therapeutic efficacy through evaluation of cytokine release syndrome (CRS) resolution and anticoagulant effect, analyzing clinical safety via monitoring of associated adverse effects profile; and (2) to compare the clinical safety and therapeutic efficacy of institutional treatment regimen (alone) versus tocilizumab added to an institutional treatment module in COVID-19 patients. Materials and Methods: In this study, the endpoints parametric assessment of severely diseased patients of COVID-19 was performed (total n = 172, control group (institutional protocol treatment provided), n = 101 and test group (tocilizumab provided), n = 71) at the Khyber Teaching Institution, MTI, Peshawar. The assessments were compared using non-parametric analyses at baseline and after a follow-up of 12−18 days until the patient discharged or expired. Results: Results of the study revealed an insignificant difference among the control vs. test group in resolving inflammatory parameters (C-reactive protein (CRP) 21.30 vs. 50.07; p = 0.470, ferritin 482.9 vs. 211.5; p = 0.612, lactate dehydrogenase (LDH) 29.12 vs.18.8; p = 0.0863, and D-dimer 464 vs.164.4; p = 0.131). However, a statistically significant difference was found between the control group and test group regarding coagulation parameters (international normalized ratio (INR) 0.12 vs. −0.07; p ≤ 0.001; activated partial thromboplastin time (aPTT) 0.42 vs. −1.16; p ≤ 0.001; prothrombin time (PT) 0.31 vs. −0.96; p ≤ 0.001; platelet count −12.34 vs. −1.47; p = 0.012) and clinical survival rate (89.10 vs. 90.14; p < 0.001). Furthermore, there was significantly higher infection rates and raised alanine aminotransferase (ALT) and alkaline phosphatase (ALP) associated with the tocilizumab group as compared to those receiving institutional treatment (bacterial infections: 0.99% vs. 15.49%; p ≤ 0.01, ALT: 3.96% vs. 28.16%; p ≤ 0.01, ALP: 1.98% vs. 22.53%; p ≤ 0.01). Conclusions: From this study, it was concluded that tocilizumab can be a better drug of choice in terms of efficacy, particularly in resolving coagulopathy in severe COVID-19 patients.

Role of Neuropilin 1 in COVID-19 Patients with Acute Ischemic Stroke.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can trigger the adaptive and innate immune responses, leading to uncontrolled inflammatory reactions and associated local and systematic tissue damage, along with thromboembolic disorders that may increase the risk of acute ischemic stroke (AIS) in COVID-19 patients. The neuropilin (NRP-1) which is a co-receptor for the vascular endothelial growth factor (VEGF), integrins, and plexins, is involved in the pathogenesis of AIS. NRP-1 is also regarded as a co-receptor for the entry of SARS-CoV-2 and facilitates its entry into the brain through the olfactory epithelium. NRP-1 is regarded as a cofactor for binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2), since the absence of ACE2 reduces SARS-CoV-2 infectivity even in presence of NRP-1. Therefore, the aim of the present study was to clarify the potential role of NRP-1 in COVID-19 patients with AIS. SARS-CoV-2 may transmit to the brain through NRP-1 in the olfactory epithelium of the nasal cavity, leading to different neurological disorders, and therefore about 45% of COVID-19 patients had neurological manifestations. NRP-1 has the potential capability to attenuate neuroinflammation, blood-brain barrier (BBB) permeability, cerebral endothelial dysfunction (ED), and neuronal dysfunction that are uncommon in COVID-19 with neurological involvement, including AIS. Similarly, high NRP-1 serum level is linked with ED, oxidative stress, and the risk of pulmonary thrombosis in patients with severe COVID-19, suggesting a compensatory mechanism to overcome immuno-inflammatory disorders. In conclusion, NRP-1 has an important role in the pathogenesis of COVID-19 and AIS, and could be the potential biomarker linking the development of AIS in COVID-19. The present findings cannot provide a final conclusion, and thus in silico, experimental, in vitro, in vivo, preclinical, and clinical studies are recommended to confirm the potential role of NRP-1 in COVID-19, and to elucidate the pharmacological role of NRP-1 receptor agonists and antagonists in COVID-19.

Carveol ameliorates mercury-induced oxidative stress, neuroinflammation, and neurodegeneration in a mouse brain.

BACKGROUND: Mercury compounds are the world's third most hazardous substance. Mercury (II) chloride, also known as mercuric chloride (HgCl2), has been shown to have neurotoxic properties in a variety of forms. In numerous investigations, oxidative stress has been established as a key contributor to HgCl2-induced neurotoxicity. Carveol has been researched as an antioxidant and Nrf2-activator in several studies. This study was conducted to investigate if the carveol could protect mice against HgCl2-induced neuronal damage. METHODS: Mice were exposed to a dose of 0.4 mg/kg of HgCl2 and 20 mg/kg of carveol for 21 days. Animals were then subjected to behavioral evaluation through various methods such as open field test (OFT), elevated plus maze test (EPM), morris-water maze test (MWM), and Y-maze test. RESULTS: Results indicated hippocampal-related behavior anomalies which were improved significantly after carveol treatment. Oxidative stress was accompanied by excessive neuroinflammation, which was demonstrated by elevated levels of inflammatory markers such as TNF-α, p-NFkB, and COX-2, and were measured by Western blot, ELISA, and immunohistochemistry. These elevated levels of inflammatory markers were significantly mitigated upon treatment with carveol. To further investigate the participation of the JNK pathway, we used SP-600125 to inhibit JNK, which enhanced the neuroprotective effects of carveol. Moreover, molecular docking and modeling studies were used to validate these effects. CONCLUSION: Our findings indicate that carveol can inhibit the p-JNK pathway, thereby inhibiting HgCl2-induced apoptosis and downregulating the expression of inflammatory mediators.

Screening of Rhamnus Purpurea (Edgew.) Leaves for Antimicrobial, Antioxidant, and Cytotoxic Potential.

Exploring new antimicrobial and cytotoxic drugs has been one of the most active areas of research. Rhamnus purpurea (Edgew.) buckthorn (Rhamnaceae) is a wild shrub traditionally used in Pakistan for the treatment of various ailments including cancer and infectious diseases. The aim of this study is to find novel antimicrobial and cytotoxic agents of plant origin. The crude methanol extract and full range of fractions of R. purpurea leaves were screened for the said activities using in vitro antimicrobial, antioxidant, and cytotoxic models following standard protocols. The antimicrobial activity was evaluated using the agar well diffusion method, while the antioxidant activity was assessed with 1,1-diphenyl-2-picryl hydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. The cytotoxic effect was investigated against the human cancer cell lines i.e. Caco-2 (gut), A549 (lung), HepG2 (liver), and MDA-MB-231 (breast) by MTS assay. In addition, toxicity studies were conducted on renal and alveolar primary epithelial cells (HRPTEpiC and HPAEpiC, respectively). Phytochemical investigation showed the presence of secondary metabolites such as alkaloids, saponins, tannins, glycosides, phenols, carbohydrates, proteins, and flavonoids. The n-hexane and chloroform fractions showed significant activity against Staphylococcus aureus (MIC 0.60 and 0.68 mg/mL, respectively), Salmonella typhi (MIC 0.48 and 0.45 mg/mL, respectively), and Bacillus subtilis (MIC 0.54 and 0.76 mg/mL, respectively). Among fungal strains, crude methanol and chloroform fractions exhibited significant activity against Fusarium solani (MIC 0.53 and 0.44 mg/mL, respectively) and Aspergillus niger (MIC 0.47 and 0.42 mg/mL, respectively). The crude methanol, n-hexane and chloroform fractions revealed the highest antioxidant activity at 1000 µg/mL, compared to that of ascorbic acid. The n-hexane fraction showed a significant cytotoxic effect against Caco-2, A549, and HepG2 cell lines with IC50 values of 5.65 ± 0.88, 5.50 ± 0.90, and 4.95 ± 1.0 µg/mL, respectively. Similarly, the chloroform fraction depicted significant activity against Caco-2, A549, and HepG2 cell lines with IC50 values of 4.55 ± 1.25, 4.65 ± 1.55, and 2.85 ± 0.98 µg/mL, respectively. The crude methanol extract and almost all fractions exhibited the highest selectivity index (>2.0) for Caco-2, A549, and HepG2 cancer cell lines, providing safety data for this study. The results showed that R. purpurea leaves have excellent antimicrobial, antioxidant, and cytotoxic potential and warrant further studies to search for novel compounds for the said activities.

Flavonoid Derivatives as Potential Cholinesterase Inhibitors in Scopolamine-Induced Amnesic Mice: An In Vitro, In Vivo and Integrated Computational Approach.

Flavonoids are one of the most exciting types of phenolic compounds with a wide range of bioactive benefits. A series of flavone derivatives (F1-F5) were previously synthesized from substituted O-hydroxy acetophenone and substituted chloro-benzaldehydes. The titled compounds F1-F5 in the present study were evaluated for their anticholinesterase potential (against AChE and BuChE). The obtained results were then validated through a molecular docking approach. Compound F5 was found to be the most potent inhibitor of AChE (IC50 = 98.42 ± 0.97 µg/mL) followed by compound F4, whereas compound F2 was found to be the most promising inhibitor of BuChE (IC50 = 105.20 ± 1.43 µg/mL) among the tested compounds. The molecular docking analysis revealed a similar trend in the binding affinity of compounds with the targeted enzymes and found them to be capable of forming highly stable complexes with both receptors. The selected compounds were further subjected to in vivo assessment of cognitive function in a scopolamine-induced amnesic animal model, in which almost all compounds F1-F5 significantly attenuated the amnesic effects as evaluated through Y-Maze Paradigm and novel object discrimination (NOD) tasks, findings that were further supported by ex vivo experimental results. Among (F1-F5), F5 showed significant anti-amnesic effects in scopolamine-induced amnesic models and ameliorated the memory loss in behavioral model studies as compared to counterparts. In ex vivo study, noteworthy protection from oxidative stress in the brains of scopolamine-induced amnesic mice was also recorded for F5. These findings also confirmed that there were no significant differences among the in vivo and ex vivo results after administration of F1-F5 (7.5 or 15 mg/kg) or donepezil (2 mg/kg). These synthesized flavonoids could serve as potential candidates for new neuroprotective and nootropic drugs. However, further studies are needed to validate their observed potential in other animal models as well.