Calotropis procera: A double edged sword against glioblastoma, inhibiting glioblastoma cell line growth by targeting histone deacetylases (HDAC) and angiogenesis.

Despite substantial investments in anti-glioblastoma (GBM) drug discovery over the last decade, progress is limited to preclinical stages, with clinical studies frequently encountering obstacles. Angiogenic and histone deacetylase inhibitors (HDACi) have shown profound results in pre-clinical studies. Investigating a multicomponent anti-cancer remedy that disrupts the tumor angiogenic blood vessels and simultaneously disrupts HDACs, while inducing minimal side effects, is critically needed. The crude extracts derived from medicinal plants serve as a renewable reservoir of anti-tumor drugs, exhibiting reduced toxicity compared to chemically synthesized formulations. Calotropis procera is a traditional medicinal plant, and its anticancer potential against many cancer cell lines has been reported, however its antiangiogenic and HDAC inhibitory action is largely unknown. The anticancer activity of methanol leaf extract of C. procera was tested in three types of human glioblastoma cell lines. Wild-type and transgenic zebrafish embryos were used to evaluate developmental toxicity and angiogenic activity. A human angiogenic antibody array was used to profile angiogenic proteins in the U251 GM cell line. A real-time reverse transcriptase polymerase chain reaction (RT PCR) assay was used to detect the differential expression of eleven HDAC genes in U251 cells treated with C. procera extract. The extract significantly reduced the proliferation of all three types of GBM cell lines and the cytotoxicity was found to be more pronounced in U251 GM cells, with an IC50 value of 2.63 ± 0.23 µg/ml, possibly by arresting the cell cycle at the G2/M transition. The extract did not exhibit toxic effects in zebrafish embryos, even at concentrations as high as 1000 µg/ml. The extract also inhibited angiogenic blood vessel formation in the transgenic zebrafish model in a dose-dependent manner. The results from the angiogenic antibody array have suggested novel angiogenesis targets that can be utilized to treat GBM. Real-time RT PCR analysis has shown that C. procrea extract caused an upregulation of HDAC5, 7, and 10, while the mRNA of HDAC1, 2, 3 and 8 (Class I HDACs), and HDAC4, 6, and 9 (Class II) were downregulated in U251 GM cells. The cytotoxicity of the C. procera extract on GBM cell lines could be due to its dual action by regulation of both tumor angiogenesis and histone deacetylases enzymes. Through this study, the C. procera leaf extract has been suggested as an effective remedy to treat GBM with minimal toxicity. In addition, various novel angiogenic and HDAC targets has been identified which could be helpful in designing better therapeutic strategies to manage glioblastoma multiforme in human patients.

Nicotinic acid modulates microglial TREM-2 gene in Phytohaemagglutinin-Induced in vitro model of Alzheimer's disease like pathology.

Alzheimer's disease (AD) is a multifactorial,neurodegenerative disorder linked withextracellular amyloid beta (Aß) plaques deposition and formation of intracellular neurofibrillary tangles (NFTs). Currently, no effective therapies are available to cure AD. Neuroinflammation isa well-known hallmark in the onset and advancement of AD and triggering receptor expressed on myeloid cells-2 (TREM-2), a microglial gene, is responsible for regulating inflammatory responses and clearance of cellular debris. Loss of TREM-2functionincreases neuroinflammation associated expression of pro-inflammatory markersthus resultingin reduced clearance of Aß that further aid in disease progression.Therefore, targeting neuroinflammation is a good therapeutic approach for AD. This study aimed to determine the neuroprotective effect of nicotinic acid (NA) in vitro model of AD-like pathology induced in F-98 cell line using Phytohemagglutinin (PHA). MTT assay was employed for checking the cell viability as well as the proliferation of the cells following treatment with NA. PHA at the concentration of 10 µg/mL produces maximum plaques. The neuroprotective effect of NA was next evaluated against PHA-induced plaques and it was observed that NA reverses the damages induced by PHA i.e., by inhibiting the clustering of the cells and replacing the damaged cells with the new ones. Further, NA also increased the expression of TREM-2/DAP-12 with parallel decreased in the expression of IL-1ß, TNF-α and iNOS. It also successfully altered disease associated ADAM-10 and BACE-1 compared to PHA control. These findings suggest that NA might be considered as a good therapeutic candidate for the treatment of neurodegenerative disorders like AD.

Assessment of antidiabetic, anti-inflammatory, antioxidant and anticancer activity competence of methonolic extracts of Trianthema ortulacastrum and Andrographis paniculata.

An in-vitro investigation was performed to evaluate and compare the phytochemical, antioxidant, antidiabetic, anti-inflammatory, and anti-lung cancer activities of methanol extracts of aerial parts of Andrographis paniculata and Trianthema portulacastrum. Furthermore studied major functional groups of phytochemicals present in the methanol extracts of these plants through Fourier transform infrared (FTIR) analysis. The results showed that the methanol extract of A. paniculata contain more number of pharmaceutically valuable phytochemicals such as alkaloids, flavonoids, terpenoids, saponin, glycoside, phytosterol, and tannin than T. portulacastrum. Similar way the methanol extract of A. paniculata showed considerable dose dependent antioxidant (DPPH: 63%), antidiabetic (α-amylase: 82.31% and α-glucosidase inhibitions: 72.34%), and anti-inflammatory (albumin-denaturation inhibition: 76.3% and anti-lipoxygenase: 61.2%) activities (at 900 µg mL-1 concentration) than T. portulacastrum. However, the anti-lung cancer activities of these test plants against A549 cells were not considerable. According to FTIR analysis, the A. paniculata methanol extract has a larger number of characteristic peaks attributed to the active functional groups of pharmaceutically valuable bioactive components that belong to different types of phytochemicals. These findings imply that A. paniculata methanol extracts can be used for additional research, such as bioactive compound screening and purification, as well as assessing their potential biomedical uses in various in-vitro and in-research settings.

Interface engineering in ZnO/CdO hybrid nanocomposites to enhanced resistive switching memory for neuromorphic computing.

Resistive random-access memory (RRAMs) has attracted significant interest for their potential applications in embedded storage and neuromorphic computing. Materials based on metal chalcogenides have emerged as promising candidates for the fulfilment of these requirements. Due to its ability to manipulate electronic states and control trap states through controlled compositional dynamics, metal chalcogenide RRAM has excellent non-volatile resistive memory properties. In the present we have synthesized ZnO-CdO hybrid nanocomposite by using hydrothermal method as an active layer. The Ag/C15ZO/Pt hybrid nanocomposite structure memristors showed electrical properties similar to biological synapses. The device exhibited remarkably stable resistive switching properties that have a low SET/RESET (0.41/-0.2) voltage, a high RON/OFF ratio of approximately 105, a high retention stability, excellent endurance reliability up to 104 cycles and multilevel device storage performance by controlling the compliance current. Furthermore, they exhibited an impressive performance in terms of emulating biological synaptic functions, which include long-term potentiation (LTP), long-term depression (LTD), and paired-pulse facilitation (PPF), via the continuous modulation of conductance. The hybrid nanocomposite memristors notably achieved an impressive recognition accuracy of up to 92.6 % for handwritten digit recognition under artificial neural network (ANN). This study shows that hybrid-nanocomposite memristor performance could lead to efficient future neuromorphic architectures.

Phytotoxicity and cytotoxicity attributes of immobilized Bacillus cereus treated and untreated textile effluents on Vigna mungo seeds and Artemia franciscana larvae.

The physicochemical attributes of textile effluents collected from secondary treatment stage was investigated in this study and also assess the biosorption potential of membrane immobilized Bacillus cereus and free form of Bacillus cereus on textile effluent through bioreactor model study to find a sustainable solution to manage the textile effluent as vital need. Furthermore, the phytotoxicity and cytotoxicity nature of treated and untreated textile effluents on Vigna mungo and Artemia franciscana larvae under laboratory conditions as a novel approach. The textile effluent physicochemical parameter analysis results showed that the properties such as colour (Hazen unit), pH, turbidity, As, Biological Oxygen Demand (BOD), Chemical Oxygen Demand (COD), Cd, Cl, Cr, Cu, Hg, Ni, Pb, SO42-, and Zn were beyond the acceptable limits. Bacillus cereus immobilized on a polyethylene membrane eliminated greater amounts of dye (25.0 ± 1.3, 56.5 ± 1.8, 57.18 ± 1.5, and 54.34 ± 1.7 Hazen unit from An1, Ae2, Ve3, and So4 respectively) and pollutants (As: 0.9-2.0, Cd: 6-8, Cr: 300-450, Cu: 5-7, Hg: 0.1-0.7, Ni: 8-14, Pb: 4-5, and Zn: 4-8 mg L-1) from textile effluent in a week of biosorption investigation using a bioreactor model (batch type) compared to a free form of B. cereus on textile effluent. The phytotoxicity and cytotoxicity study results revealed that the membrane immobilized B. cereus treated textile effluent exposure showed reduced phytotoxicity and minimal cytotoxicity (including mortality) percentage compared with free form B. cereus treated and untreated textile effluents. These entire results conclude that the membrane immobilized B. cereus may considerably minimize/detoxify the harmful pollutants from the textile effluents. A large scale level biosorption approach need to be performed to validate the maximum pollutants removing potential of this membrane immobilized bacteria species and optimal conditions for effective remediation.

Causes of higher levels of stress among students in higher education who used eLearning platforms during the COVID-19 pandemic.

Background: This work aims to study the levels of stress among students using e-learning platforms during the COVID-19 pandemic in higher education institutions. The major factors of higher-level stress among the student community focused on this study are: Changes in academic environment, family, social, personal, health and cognitive. Objective: the objective of this research the Partial Least Squares Structural Equation Modelling (PLS-SEM) procedure was used to explore the relationship and its impact on various levels of stress. Results: Data were collected by using a total of 1,000 email IDs of students that were made available by teachers from 12 Indian higher education institutions where they were enrolled and by using a random number method. With this procedure, a total of 800 email IDs were selected. The results drawn from this research are that students experienced more stress due to sudden changes in the academic environment, family, and personal factors. The stress levels of cognitive and social were found to be equally distributed among higher education students, but less than academic environment, family and personal. This research intends to fill the gap of short-term individual psychological changes that occur after the outbreak. Conclusion: Policy-makers can take note of the current study's observations in continuing their fight against COVID-19 pandemic by improving the stability for student risk groups.

Cytotoxicity of Newly Synthesized Quinazoline-Sulfonamide Derivatives in Human Leukemia Cell Lines and Their Effect on Hematopoiesis in Zebrafish Embryos.

Many quinazoline derivatives with pharmacological properties, such as anticancer activity, have been synthesized. Fourteen quinazoline derivatives bearing a substituted sulfonamide moiety (4a-n) were previously synthesized and fully characterized. These compounds exerted antiproliferative activity against cell lines derived from solid tumors. Herein, the antileukemic activities of these compounds (4a-n) against two different leukemia cell lines (Jurkat acute T cell and THP-1 acute monocytic) were investigated. Our investigation included examining their activity in vivo in a zebrafish embryo model. Remarkably, compounds 4a and 4d were the most potent in suppressing cell proliferation, with an IC50 value range of 4-6.5 µM. Flow cytometry analysis indicated that both compounds halted cell progression at the G2/M phase and induced apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses also showed that both compounds effectively induced apoptosis by upregulating the expression of proapoptotic factors while downregulating that of antiapoptotic factors. In vivo animal toxicity assays performed in zebrafish embryos indicated that compound 4d was more toxic than compound 4a, with compound 4d inducing multiple levels of teratogenic phenotypes in zebrafish embryos at a sublethal concentration. Moreover, both compounds perturbed the hematopoiesis process in developing zebrafish embryos. Collectively, our data suggest that compounds 4a and 4d have the potential to be used as antileukemic agents.

Ecogenotoxicological studies for an early toxicity screening and monitoring in Epinephalus chlorostigma and Scamberomorus commerson.

The study was planned to investigate DNA fragmentation in fish to screen aquatic toxicity and in Epinephalus chlorostigma and Scamberomorus commerson collected from Red sea near Jizan, Saudi Arabia from three locations "(Corniche North park: "16.92161, 42.54631; Jizan Port: 16.874, 42.54952" N and Jizan Economic City: 17.26589, 42.34738" ")" were used as a case study for the application of comet assay. The study area of the Red Sea is polluted due to anthropogenic activities and the disposal of wastes from multiple sources. Comet and micronucleus assays were used to detect genotoxicity in these fish species harvested from three sites. The concentration of Pb, Cr, Zn, Mn, Cu, Cd, Sn, and Hg was higher in the water samples collected from the polluted site compared to the non-polluted site of the Red sea. Comet assay for S. commerson showed significant (p < 0.05) genetic damage about 44.33 ± 3.03% DNA in comet tail at site S1. It was subsequently reduced to 31.71 ± 3.52% and 22.11 ± 2.52% at sites S2 and S3. E. chlorostigma also showed significant DNA in comet tail as 17.34 ± 2.19%, 11.87 ± 3.01%, and 36.41 ± 3.98% at site S1-S3, respectively. Significant (p < 0.05) DNA damage was observed in the fishes procured from non-polluted locations and upstream locations. The micronucleus induction in E. chlorostigma was recorded as 23.20 ± 4.19 and 2.20 ± 0.58%, respectively, non-polluted and polluted sites. S. commerson exhibited significant differences between polluted and non-polluted sites (44.80 ± 3.73 and 8.20 ± 2.20‰) polluted and upstream (44.80 ± 3.73 and 20.60 ± 4.02‰), respectively. A significant difference was obtained between E. chlorostigma and S. commerson for nuclear abnormalities S. commerson showed higher frequencies for nuclear deformities than E. chlorostigma. S. commerson showed substantial micronucleus induction frequencies collected from an area of low pollution intensity (upstream). This study showed that E. clorostigma and S. commerson could be successfully used as a bioindicator to determine the health of the Red Sea through the most specific assays such as comet and micronucleus tests as an early warning and to devise the monitoring strategies to ensure a safe supply of fish for human consumption.

Role of silver nanoparticles in fluorimetric determination of urea in urine samples.

Herein, an economical, analytical and sensitive method was established for the fluorometric determination of urea using freshly prepared silver nanoparticles (Ag-NPs) in real urine samples. The standard addition and second-order derivative methods were selected for the ongoing research work to eliminate the possible effect of interferences in a real environment. In this work, Ag-NPs were prepared by reducing silver nitrate salt in the presence of 1,3-di-(1H-imidazole-1-yl) -2-propanol (DIPO) in an aqueous medium. Urea in the urine samples was successfully determined through the complexation of Ag-NPs with urea molecules. The results revealed high percent recovery with ± RSD of urea in the three different urine samples, where percent recoveries by spectrofluorometric standard addition were 99.77 ± 3.4, 100.24 ± 5.1, 100.93 ± 2.8 and that is by the spectrofluorometric second-order derivative method were 103.57 ± 2.4, 101.8 ± 1.3, 98 ± 3.2, respectively. The successful application of these analytical methods in the spectrofluorometric determination of urea in urine samples can accumulate further addition in the effects and possible role of Ag-NPs in the determination of biological molecules in biological and non-biological samples in the scientific as well as clinical fields.

Mitochondrial sirtuins genetic variations and gastric cancer risk: Evidence from retrospective observational study.

AIMS: The purpose of the present study was to analyze the role of selected polymorphisms of SIRT3 and SIRT5 in gastric carcinogenesis. METHODS: For this study, 500 blood samples of GC patients and 500 blood samples of healthy individuals were collected. Six selected polymorphisms of mitochondrial sirtuins were analyzed for analysis using Tetra-Arms PCR followed by DNA sequencing. RESULTS: Mutant allele frequencies of selected polymorphisms [rs3782116 (p < 0.0001), rs6598072 (p < 0.0001) and rs11246020 (p < 0.0001), rs938222 (p = 0.0136), rs3757261 (p = 0.0005) and rs2841511 (p = 0.0015)] were observed significant higher in GC patients vs controls. Haplotype analysis was performed, and 51 haplotypes were generated using haploview software. Among these haplotypes, eleven haplotypes were found associated with a significantly increased risk of GC. Furthermore, SNP-SNP interaction showed a significant correlation between studied SNPs and GC risk. Kaplan Meier analysis showed that mutant allele frequencies of selected polymorphisms are linked with a significant decrease in survival of GC patients CONCLUSIONS: It can be concluded that selected SNPs may be associated with enhanced risk of GC and hence can be potential prognostic markers for prognosis and predisposition of GC.

Prevalence of hepatitis B & C infections in prospective blood donors deferred due to history of jaundice.

Background & objectives: As per national guidelines, prospective blood donors with a history of jaundice of unknown cause are deferred permanently to prevent the transmission of hepatitis B and C. The validity of this guideline was tested by comparing prevalence rates of hepatitis B and C in prospective blood donors deferred due to a history of jaundice, with that of donors who were found fit. Methods: Blood samples of 212 consecutive donors (male, n=203) deferred due to a history of jaundice were studied for hepatitis B and C by rapid test kits as well as by chemiluminescence (n=115) or ELISA (n=97). Consecutive healthy donors (n=549; male, n=518) were also studied by ELISA (n=266) or chemiluminescence (n=283). Results: The cumulative prevalence detected by rapid test kit and ELISA/chemiluminescence tests of hepatitis B (n=10) and C (n=2) among donors deferred due to a history of jaundice (n=212) was 5.7 per cent [95% confidence interval (CI): 2.9, 9.9]. The prevalence of reactive results among healthy donors (n=549) by ELISA/chemiluminescence tests was 3.3 per cent (95% CI: 1.9, 5.2), which included hepatitis B (n=15) and hepatitis C (n=3) cases. Compared to healthy donors, the odds of seropositivity among jaundice-deferred donors was 1.7 (95% CI: 0.8, 3.6), P=0.15. For rapid test-negative deferred donors, the odds of seropositivity by ELISA/chemiluminescence declined to 0.4 (0.1, 1.5), P=0.19. Interpretation & conclusions: The prevalence rates of hepatitis B and C in prospective blood donors deferred due to a history of jaundice of unknown aetiology did not differ significantly from that in healthy donors. The current practice of permanently deferring such donors depletes valuable donor pool. A strategy of rejecting only those donors who are found reactive on pre-donation testing by rapid test needs further validation.

A Case Series on Enteroviral Meningitis in Pakistan.

Enteroviruses (EVs) are the most common cause of viral meningitis with a peak incidence between late summer and fall. The onset of symptoms is characteristically abrupt and typically includes headache, fever, nausea or vomiting, malaise, photophobia, and meningismus. In addition, diarrhea, upper respiratory symptoms, and a rash may also be present. The clinical presentation and epidemiologic features help in the diagnosis and it is confirmed by the detection of RNA in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR). We present the clinical description, diagnosis, and management of five consecutive cases of viral meningitis secondary to enterovirus that presented to the emergency department at a tertiary care center in Karachi, Pakistan, over a span of five weeks during the monsoon season. These cases or outbreaks have not been reported previously in Pakistan and, hence, this case series is the first of its kind. All of our patients were young males, with ages between 18-35 years, did not have any prior co-morbidities, and resided in different localities of Karachi, Pakistan. The presenting complaints were severe headache in all five patients (100%), fever in all five patients (100%), and diarrhea in two out of five patients (40%). On examination, neck stiffness was present in all patients (100%). After the required workup and detection of RNA in the CSF by PCR, diagnosis of enteroviral meningitis was confirmed. The patients were given symptomatic treatment and discharged home with no neurologic complications. Aseptic meningitis occurring during the summer or fall is most likely to be caused by non-polio EVs (eg. coxsackievirus, echovirus, etc.). It is self-limiting and only requires supportive treatment. However, clinically it cannot be differentiated from other central nervous system infections and significant morbidity has been reported, including hospitalization and impairment of routine activities.

Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish.

Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.

Tuning of ionic mobility to improve the resistive switching behavior of Zn-doped CeO2.

Correlation between the resistive switching characteristics of Au/Zn-doped CeO2/Au devices and ionic mobility of CeO2 altered by the dopant concentration were explored. It was found that the ionic mobility of CeO2 has a profound effect on the operating voltages of the devices. The magnitude of operating voltage was observed to decrease when the doping concentration of Zn was increased up to 14%. After further increasing the doping level to 24%, the device hardly exhibits any resistive switching. At a low doping concentration, only isolated Vo existed in the CeO2 lattice. At an intermediate doping concentration, the association between dopant and Vo formed (Zn, Vo)× defect clusters. Low number density of these defect clusters initially favored the formation of Vo filament and led to a reduction in operating voltage. As the size and number density of (Zn, Vo)× defect clusters increased at a higher doping concentration, the ionic conductivity was limited with the trapping of isolated Vo by these defect clusters, which resulted in the diminishing of resistive switching. This research work provides a strategy for tuning the mobility of Vo to modulate resistive switching characteristics for non-volatile memory applications.

Genomic expression discovery predicts pathways and opposing functions behind phenotypes.

Discovering states of genetic expression that are true to a high degree of certainty is likely to predict gene function behind biological phenotypes. The states of expression (up- or down-regulated) of 19200 cDNAs in 10 meningiomas are compared with normal brain by an algorithm that detects only 1 false measurement per 192000; 364 genes are discovered. The expression data accurately predict activation of signaling pathways and link gene function to specific phenotypes. Meningiomas appear to acquire aberrant phenotypes by disturbing the balanced expression of molecules that promote opposing functions. The findings expose interconnected genes and propose a role of genomic expression discovery in functional genomics of living systems.