Glioblastoma Multiforme: Probing Solutions to Systemic Toxicity towards High-Dose Chemotherapy and Inflammatory Influence in Resistance against Temozolomide.

Temozolomide (TMZ), the first-line chemotherapeutic drug against glioblastoma multiforme (GBM), often fails to provide the desired clinical outcomes due to inflammation-induced resistance amid inefficient drug delivery across the blood-brain barrier (BBB). The current study utilized solid lipid nanoparticles (SLNPs) for targeted delivery of TMZ against GBM. After successful formulation and characterization of SLNPs and conjugation with TMZ (SLNP-TMZ), their in-vitro anti-cancer efficacy and effect on the migratory potential of cancer cells were evaluated using temozolomide-sensitive (U87-S) as well as TMZ-resistant (U87-R) glioma cell lines. Elevated cytotoxicity and reduction in cell migration in both cell lines were observed with SLNP-TMZ as compared to the free drug (p < 0.05). Similar results were obtained in-vivo using an orthotopic xenograft mouse model (XM-S and XM-R), where a reduction in tumor size was observed with SLNP-TMZ treatment compared to TMZ. Concomitantly, higher concentrations of the drug were found in brain tissue resections of mice treated with SLNP-TMZ as compared to other vital organs than mice treated with free TMZ. Expression of inflammatory markers (Interleukin-1ß, Interleukin-6 and Tumor Necrosis factor-α) in a resistant cell line (U87-R) and its respective mouse model (XM-R) were also found to be significantly elevated as compared to the sensitive U87-S cell line and its respective mouse model (XM-S). Thus, the in-vitro and in-vivo results of the study strongly support the potential application of SLNP-TMZ for TMZ-sensitive and resistant GBM therapy, indicatively through inflammatory mechanisms, and thus merit further detailed insights.

Therapeutic effect of Thymoquinone on behavioural response to UCMS and neuroinflammation in hippocampus and amygdala in BALB/c mice model.

RATIONALE: Major depressive disorder is the leading cause of disability worldwide. The corticolimbic system plays a critical role in the emotional and cognitive aspects of major depressive disorder. Owing to the unsatisfactory efficacy of conventional antidepressants, there is a need to explore novel therapies. OBJECTIVES: The current study aimed to explore the antidepressant potential of thymoquinone, a natural compound with anti-inflammatory activity, and propose its underlying mechanism of action in the unpredictable chronic mild stress (UCMS) mouse model. METHODS: Coat state, forced swim test, elevated plus maze test, novelty suppressed feeding test and social interaction test were performed to quantify the behavioural shift induced by UCMS and the effect of thymoquinone and fluoxetine treatment. In addition, messenger RNA (mRNA) expression levels of inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and BDNF and NeuN were analysed by a quantitative real-time polymerase chain reaction in the hippocampus and amygdala of experimental and control groups. RESULTS: UCMS significantly deteriorated coat state. Thymoquinone reinstated the resignation behaviour and latency to feed affected by UCMS. UCMS induced an increase in inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in the hippocampus and amygdala, which was decreased by thymoquinone. UCMS caused an increase in BDNF and NeuN mRNA levels in the amygdala while a decrease in the hippocampus. This opposite effect on BDNF was also compensated by thymoquinone; however, thymoquinone did not significantly change Ki67 and NeuN mRNA levels in the hippocampus. CONCLUSIONS: Thymoquinone restored the behavioural changes induced by UCMS. In addition, the antidepressant effect of thymoquinone is in line with changes in inflammatory parameters and changes in BDNF in the hippocampus and amygdala.

Impaired renal functions in Pakistani cohort of rheumatoid arthritis.

OBJECTIVE: To determine the frequency of impaired renal functions and hypertension in rheumatoid arthritis. METHODS: This study was conducted between May 1st 2018 to February 1st 2019 at Rheumatology Division, Department of Medicine Central Park Medical College Lahore, total 260 study participants were selected, demographic detail were asked in detail, disease duration of RA and hypertension, DMARD's, self-use NSAID's,/hakeem medications, smoking were asked in detail, BMI and blood pressure were measured,5 ml of blood was taken by trained phlebotomist, and sent for the estimation of serum urea and creatinine on (COBAS-III) machine, after availability of results each individuals eGFR (creatinine clearance) was calculated by Cockroft Gualt(CG) and Modification in diet in renal disease method (MDRD). RESULTS: In this study the mean age of study participants was 42.4 (± 9.5) years with disease duration of 7.7(±4.8) years, prevalence of Impaired renal functions of 14.6% (n=38) and hypertension in 53.5% (n=139).Regression analysis shows there is significant association between hypertension, smoking and self/hakeem medications with impaired renal functions (p-0.5). Kappa analysis shows both (MDRD & CG methods) had uniformity in picking up cases of impaired renal functions 75.6% (p-0.05). CONCLUSION: In RA decline in renal functions is seen with self-use NSAID's/hakeem medications along with other modifiable factors like smoking and hypertension, while conventional DMARD's don't show association with decline. There is very high prevalence of hypertension in rheumatoid arthritis.

Modifiable cardiovascular risk factors in Rheumatoid Arthritis.

OBJECTIVE: To determine the frequency of modifiable cardiovascular risk factors in Rheumatoid Arthritis patients at tertiary care hospital. METHODS: During this study 246 patients of Rheumatoid Arthritis were enrolled from outpatients department of Medicine of Central Park Medical College Hospital, Lahore from July 1, 2016 to January 31, 2017. Demographic data and questions related to study were noted. After 14 hours of fasting 5ml of venous blood was drawn for Cholesterol, triglycerides, HDL and blood sugar level. Blood tests were performed on COBAS c III (ROCHE), Framingham 10 year Risk score was calculated for every individual. RESULTS: The mean age of male population was (50.2 ±7.5) and females (48.4±7.6) and female gender was common. Seventy eight (78%) of study population has one modifiable risk factor. Most frequent risk factor found in this study was BMI>30 in 48.4% (n=119), High LDL 43.5% (n=107), moderate to high FRS score 40.2% (n=99), Hypertension 37.4% (n=92), Diabetes Mellitus was present in 22.8% (n=56), while smoking was least frequent risk factors with frequency of 15.9% (n=39). Framingham cardiovascular risk score was significantly different, males were having higher mean 10 year risk score (19.7%) and females (8.7%) with (p-<0.01). Regression analysis revealed that older patients of Rheumatoid Arthritis with disease duration of more than seven years are four times more likely to have High Framingham risk score, moderate to high LDL and diabetes mellitus with significant high Odds ratio (p-value <0.05). CONCLUSION: Rheumatoid Arthritis patients are having increased chances of developing cardiovascular risk factors leading to cardiovascular events with male sex, increasing age and disease duration.