Neuroprotective effects of Bhilawanol and Anacardic acid during glutamate-induced neurotoxicity.

Bhilawanol (Bh) and anacardic acid (AA) are two lipid-soluble compounds mostly found in the nut of Semecarpus anacardium (SA). This herb has many medicinal properties including enhancing learning and memory, yet its active compounds have not been studied for neuroprotective effects. We investigated the neuroprotective effects of Bh and AA against glutamate induced cell death in the adrenal pheochromocytoma cell line of rats (PC12 cells). Cell viability, toxicity and calcium influx were determined by MTT assay, LDH release assay and Fluo-3 imaging while apoptosis was assayed by caspase-3 and Bcl-2 gene expression. Our results showed that Bh and AA treatments significantly increased cell viability, reduced cell toxicity and calcium influx in PC12 cells in addition to suppressing the reactive oxygen species. Furthermore, AA treatment decreased caspase-3 expression level whereas both Bh and AA enhanced the expression of anti-apoptotic gene Bcl-2 in PC12 cells. Both compounds potently inhibited acetylcholinesterase enzyme (AChE) in a dose and time dependent manner. These findings suggest that the traditional use of SA may be explained on the basis of both Bh and AA showing neuroprotective potential due to their effects on enhancing cell viability, reducing cell toxicity most probably by reducing excessive calcium influx and suppression of ROS as well as by decreasing the expression of proapoptotic caspase 3 gene and increasing the expression of antiapoptotic gene Bcl2. Traditional use in enhancing learning and memory was justified in part by inhibition of AChE.

From cytokines to chemokines: Understanding inflammatory signaling in bacterial meningitis.

Bacterial meningitis is a serious central nervous system (CNS) infection, claiming millions of human lives annually around the globe. The deadly infection involves severe inflammation of the protective sheath of the brain, i.e., meninges, and sometimes also consists of the brain tissue, called meningoencephalitis. Several inflammatory pathways involved in the pathogenesis of meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, Mycobacterium tuberculosis, Streptococcus suis, etc. are mentioned in the scientific literature. Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways including Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs), Nucleotide oligomerization domain (NOD)-like receptor-mediated signaling, pneumolysin related signaling, NF-κB signaling and many other pathways that lead to pro-inflammatory cascade and subsequent cytokine release including interleukine (IL)-1ß, tumor necrosis factor(TNF)-α, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) along with other mediators, leading to neuroinflammation. The activation of another protein complex, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, also takes place resulting in the maturation and release of IL-1ß and IL-18, hence potentiating neuroinflammation. This review aims to outline the inflammatory signaling pathways associated with the pathogenesis of bacterial meningitis leading to extensive pathological changes in neurons, astrocytes, oligodendrocytes, and other central nervous system cells.

Quest for malaria management using natural remedies.

Malaria, transmitted through the bite of a Plasmodium-infected Anopheles mosquito, remains a significant global health concern. This review examines the complex life cycle of Plasmodium, emphasizing the role of humans and mosquitoes in its transmission and proliferation. Malarial parasites are transmitted as sporozoites to the human body by biting an infected female Anopheles mosquito. These sporozoites then invade liver cells, multiply, and release merozoites, which infect red blood cells, perpetuating the cycle. As this cycle continues, the affected person starts experiencing the clinical symptoms of the disease. The current treatments for malaria, including chloroquine, artemisinin-based combination therapy, and quinine, are discussed alongside the challenges of drug resistance and misdiagnosis. Although efforts have been made to develop a malarial vaccine, they have so far been unsuccessful. Additionally, the review explores the potential of medicinal plants as remedies for malaria, highlighting the efficacy of compounds derived from Artemisia annua, Cinchona species, and Helianthus annuus L., as well as exploration of plants and phytocompounds like cryptolepine, and isoliquiritigenin against drug-resistant Plasmodium species. Moreover, studies from Pakistan further highlight the diverse vegetal resources utilized in malaria treatment, emphasizing the need for further research into natural remedies. Despite the advantages of herbal medicines, including cost-effectiveness, and fewer side effects; their limitations must be taken into account, including variations in potency and potential drug interactions. The review concludes by advocating for a balanced approach to malaria treatment and prevention, emphasizing the importance of early detection, accurate diagnosis, and integrated efforts to combat the disease in the endemic regions.

Association of SLCO1B1 gene variants with angiotensin-converting enzyme inhibitor-induced cough in a Pakistani hypertensive cohort.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) are prescribed for individuals with high cardiovascular (CV) risk; however, persistent cough limits the use of ACEIs in a large number of patients. The current study aimed to identify the genetic variants in the SLCO1B1 gene that might be associated with ACEI-related cough in a Pakistani hypertensive population. Methods: A prospective cohort study was conducted at a tertiary care hospital in Pakistan. A total of 74 patients who had been treated with ACEIs were recruited through a convenient sampling method. The study was approved by the Institutional Review Board & Ethics Committee of the Shifa International Hospital, Islamabad. Patients provided 2 ml of blood for sequencing after signing informed consent. Partial gene sequencing of SLCO1B1 was carried out to find single nucleotide polymorphisms (SNPs) and haplotypes. Results: It was found, through a structured questionnaire, that thirty-eight (38) patients experienced cough within 2 weeks of ACEI administration and were considered as a case group (cough), and thirty-six (36) patients were considered as a control group (no cough). The incidence of cough was 51%. We found six different SNPs and 9 haplotypes in the partial gene sequences of SLCO1B1. Haplotype H4 was associated significantly with cough after adjusting for sex and smoking status. Other SNPs and haplotypes were not significantly associated with ACE-Is-induced cough. Conclusion: These findings emphasize the significance of SLCO1B1 genetic variants, specifically H4, as a potential predictor of ACEI-induced cough. It could be included in clinical practice as a possible risk factor for ACEI-induced cough once confirmed in larger clinical trials with bigger sample sizes. The replication of these findings in larger and more diverse populations is likely to contribute to the therapeutic use of ACEIs by predicting ACEI-induced cough.

Genetic Biomarkers in Association with Depressive Disorder in UAE Residents: A Pilot Case Study.

OBJECTIVES: We sought to explore the expression of genes associated with depressive disorder in patients with depression compared to control patients. A large body of research in the area of genetics has shown familial aggregation for depressive disorders. The purpose of this study was to identify genetic risk factors in developing depression, particularly among the population residing in the UAE. METHODS: We investigated five associated genes (PPARGC1A, CAMKMT, HSD11B1, SLC6A4, and MAOA) previously linked to depression and anxiety in other populations. The study was carried out in Al Ain, although participants were from different nationalities. Blood samples were collected over a period of seven months, and lab work was carried out over a period of two months from September 1, 2018 to May 30, 2019. We screened the prevalence of the PPARGC1A, CAMKMT, HSD11B1, SLC6A4, and MAOA in 29 patients with depressive disorder and 30 controls using the quantitative real-time polymerase chain reaction method. RESULTS: The expression of the PPARGC1A gene, studied for the first time in the UAE population. The independent t-test was used to check the significance of difference between the expression levels of target genes where the control was set at a reference level of 1.0. PPARGC1A gene is lower among the depressed group which showed mean difference: 0.4 and p-value: 0.02, indicating a strong association with depression. No significant difference was found in the genes' expression of CAMKMT with p-value 0.150, MAOA p-value 0.070, SLC6A4 p-value 0.750, and HSD11B1 p-value 0.100 in two groups in comparison with (p < 0.050). CONCLUSIONS: These results open several possibilities for further research to study the role of this gene as a protective factor against developing depression.

Overview of schizophrenia research and treatment in Pakistan.

Mental health is the most neglected health sector in Pakistan, and the majority of citizens have limited or no access to primary and secondary psychiatric services. The incidence of schizophrenia (SCZ) has increased at an alarming rate in Pakistan, relative to that of other psychiatric disorders. While numerous studies have investigated SCZ, few have addressed the issue about the Pakistani population. In the present review, the researchers discuss current data integral to the prevalence, pathophysiology, and molecular genetics of SCZ; treatment approaches to the disease; and patient responses to drugs prescribed for SCZ in Pakistan. Most Pakistani patients exhibit poor responses to antipsychotic drugs. Based on our review, the researchers hypothesize that genetic dissimilarities between Pakistani and Western populations contribute to such poor responses. Consequently, an understanding of such genetic differences and the provision of personalized treatment may simultaneously aid in improving SCZ treatment in Pakistan.

Sialuria-Related Intellectual Disability in Children and Adolescent of Pakistan: Tenth Patient Described has a Novel Mutation in the GNE Gene.

BACKGROUND: Sialuria is a rare inborn error of metabolism caused by excessive synthesis of sialic acid due to the mutation in the binding site of the cytidine monophosphate-sialic acid of UDPGlcNAc 2-Epimerase/ManNAc Kinase (GNE/MNK). OBJECTIVE: This is the first study investigating the molecular basis of neuronal disorders exhibiting sialuria in Pakistani children/adolescents. METHODS: The current study genotyped GNE SNPs rs121908621, rs121908622 and rs121908623 by using PCR, RFLP, and DNA sequencing methods. Socioeconomic and clinical histories were also recorded. RESULTS: Our data suggest that clinical symptoms and financial status play a significant role in conferring sialuria related Intellectual Disability (ID). SNP: rs121908623 showed G/A substitution (R263Q) in the GNE gene. CONCLUSION: We have identified one case study in Pakistan, so this makes our research a leap forward towards the identification of the 10th case study worldwide.

Association of Single Nucleotide Polymorphisms in Catechol-O-Methyltransferase and Serine-Threonine Protein Kinase Genes in the Pakistani Schizophrenic Population: A Study with Special Emphasis on Cannabis and Smokeless Tobacco.

Schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to identify SNPs in the genes. The present study shows that COMT Val and COMT Met allelic frequencies for the controls were p=0.52, q=0.48 and for the schizophrenic cases they were p=0.34, q=0.66 respectively. The distribution of polymorphism in COMT Val158Met genotype by Hardy-Weinberg equilibrium (HWE) was P=0.61 for controls and P=0.005 for cases. The data reveal that SNP rs1130214 T allele mutation was found neither in patients nor in controls in the 5' untranslated region (UTR). This proves that no association of AKT1 and positive association of COMT with schizophrenia exist in the population of Pakistan. Moreover, a study based on a single family showed COMT Met allele inheritance in schizophrenic offspring. This suggested that COMT allele alteration influences susceptibility to at least some forms of psychosis in the Pakistani population. Interestingly, according to our socio-economical survey, COMT genotype has no association with cannabis but it is strongly associated with tobacco. The Pakistani population with Val158Met SNP showed more susceptibility towards developing schizophrenia. This study highlights the genetic differences between Pakistani and other Caucasian populations.

Drugs targeting SNPrs35753505 of the NRG1 gene may prevent the association of neurological disorder schizophrenia in a Pakistani population.

The Neuregulin 1 (NRG1) gene has been associated with schizophrenia in several populations, and all four types of NRG1 genes are linked with neurotransmitters activities. In this study for the first time we have demonstrated an association between NRG1 mutation and schizophrenia in Pakistani population. We examined the relationship of three genetic variants SNPs: rs3924999, rs2954041 and rs35753505 of NRG1 gene with the onset of disease. Genomic DNA samples were obtained from the blood of 100 patients and 80 matched controls. All three NRG1 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism method and further confirmed by DNA sequencing. The SNPs frequencies were estimated by Hardy-Weinberg equilibrium and Chi-square tests. Our study established a significant association of rs35753505 with schizophrenia but no association with rs3924999 and rs2954041. The frequency of risk allele C was significantly higher (62.5%) in rs35753505 patients when compared to controls (28.13%). Genotype frequency by Hardy-Weinberg equilibrium for SNPrs3924999 in patients was GG 77.4%, GA 21.12% and AA 1.44% and showed no association with the disease. Similarly, no genotype association was observed in rs2954041: GG 92.98%, GT 6.89%, TT 0.13% of NRG1. However, one unexpected G allele, 100% guanine (G) with no adenine (A) was found to be present in SNP rs35753505 in both patients and controls. This is an interesting finding that both cohorts display only allele G peak but no peak for allele A in the electropherogram for this SNP. Our results suggest that SNP rs35753505 of NRG1 plays an important role in conferring susceptibility to the schizophrenia in a Pakistani population.