Curcumin Nanoemulsion: Unveiling Cardioprotective Effects via ACE Inhibition and Antioxidant Properties in Hypertensive Rats.

Background and Objectives: Curcumin, derived from Curcuma longa, is a well-known traditional medicinal compound recognized for its therapeutic attributes. Nevertheless, its efficacy is hampered by limited bioavailability, prompting researchers to explore the application of nanoemulsion as a potential alternative. Materials and Methods: This study delves into the antihypertensive effects of curcumin nanoemulsion (SNEC) by targeting the renin-angiotensin-aldosterone system (RAAS) and oxidative stress in deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats. To gauge the cardio-protective impact of SNEC in DOCA salt-induced hypertension, molecular docking was undertaken, uncovering curcumin's high affinity and adept binding capabilities to the active site of angiotensin-converting enzyme (ACE). Additionally, the investigation employed uninephrectomized rats to assess hemodynamic parameters via an AD instrument. Serum ACE, angiotensin II, blood urea nitrogen (BUN), and creatinine levels were quantified using ELISA kits, while antioxidant parameters were evaluated through chemical assays. Result: The outcomes of the molecular docking analysis revealed robust binding of curcumin to the ACE active site. Furthermore, oral administration of SNEC significantly mitigated systolic, diastolic, and mean arterial blood pressure in contrast to the DOCA-induced hypertensive group. SNEC administration also led to a reduction in left ventricular end-diastolic pressure (LVEDP) and an elevation in the maximum rate of left ventricular pressure rise (LV (dP/dt) max). Moreover, SNEC administration distinctly lowered serum levels of ACE and angiotensin II compared to the hypertensive DOCA group. Renal markers, including serum creatinine and BUN, displayed a shift toward normalized levels with SNEC treatment. Additionally, SNEC showcased potent antioxidant characteristics by elevating reduced glutathione, catalase, and superoxide dismutase levels, while decreasing the concentration of thiobarbituric acid reactive substances. Conclusions: Collectively, these findings underscore that curcumin nanoemulsion exerts noteworthy cardio-protective effects through ACE activity inhibition and remarkable antioxidant properties.

Neuroprotective effects of trigonelline in kainic acid-induced epilepsy: Behavioral, biochemical, and functional insights.

Trigonelline, an alkaloid found in the seeds of Trigonella foenum-graecum L. (fenugreek), has been recognized for its potential in treating various diseases. Notably, trigonelline has demonstrated a neuroprotective impact by reducing intrasynaptosomal calcium levels, inhibiting the production of reactive oxygen species (ROS), and regulating cytokines. Kainic acid, an agonist of kainic acid receptors, is utilized for inducing temporal lobe epilepsy and is a common choice for establishing kainic acid-induced status epilepticus, a widely used epileptic model. The neuroprotective effect of trigonelline in the context of kainic acid-induced epilepsy remains unexplored. This study aimed to induce epilepsy by administering kainic acid (10 mg/kg, single subcutaneous dose) and subsequently evaluate the potential anti-epileptic effect of trigonelline (100 mg/kg, intraperitoneal administration for 14 days). Ethosuccimide (ETX) (187.5 mg/kg) served as the standard drug for comparison. The anti-epileptic effect of trigonelline over a 14-day administration period was examined. Behavioral assessments, such as the Novel Object Recognition (NOR) test, Open Field Test (OFT), and Plus Maze tests, were conducted 2 h after kainic acid administration to investigate spatial and non-spatial acquisition abilities in rats. Additionally, biochemical analysis encompassing intrasynaptosomal calcium levels, LDH activity, serotonin levels, oxidative indicators, and inflammatory cytokines associated with inflammation were evaluated. Trigonelline exhibited significant behavioral improvements by reducing anxiety in open field and plus maze tests, along with an amelioration of memory impairment. Notably, trigonelline substantially lowered intrasynaptosomal calcium levels and LDH activity, indicating its neuroprotective effect by mitigating cytotoxicity and neuronal injury within the hippocampus tissue. Moreover, trigonelline demonstrated a remarkable reduction in inflammatory cytokines and oxidative stress indicators. In summary, this study underscores the potential of trigonelline as an anti-epileptic agent in the context of kainic acid-induced epilepsy. The compound exhibited beneficial effects on behavior, neuroprotection, and inflammation, shedding light on its therapeutic promise for epilepsy management.

Autophagy in cancer: Recent advances and future directions.

Autophagy is being explored as a potential therapeutic target for enhancing the cytotoxic effects of chemotherapeutic regimens in various malignancies. Autophagy plays a very important role in cancer pathogenesis. Here, we discuss the updates on the modulation of autophagy via dynamic interactions with different organelles and the exploitation of selective autophagy for exploring therapeutic strategies. We further discuss the role of autophagy inhibitors in cancer preclinical and clinical trials, novel autophagy inhibitors, and challenges likely to be faced by clinicians while inducting autophagy modulators in clinical practice.

Targeting malaria and leishmaniasis: Synthesis and pharmacological evaluation of novel pyrazole-1,3,4-oxadiazole hybrids. Part II.

In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3 ±â€¯1.68, 40.1 ±â€¯1.0 and 19.0 ±â€¯1.47 µg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2 ±â€¯2.72, 66.8 ±â€¯2.05 and 73.1 ±â€¯1.69 µg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.

Trigonelline Demonstrated Ameliorative Effects in Dexamethasone Induced Osteoporotic Rats.

AIM: Trigonelline is a potent phytochemical present in fenugreek, which has strong anti-oxidant and phytoestrogenic activities. This study was carried out to investigate this estrogenic activity as a possible mechanisms involved in preventing the symptoms of osteoporosis in dexamethasone induced osteoporosis in rats. MATERIALS AND METHODS: Wistar rats were randomly divided into eight groups, six animals in each group. Osteoporosis was induced using dexamethasone 0.1mg/kg subcutaneously in rats for three times per week for 8 consecutive weeks and treatment with drugs up to 12 weeks as per the treatment schedule described. After 12 weeks, rats were sacrificed; blood samples were collected from each rat and the clear, non hemolysed supernatant sera was used for biochemical examinations. Femurs were used for Bone Mineral Density (BMD), microcomputed tomography (Micro CT), histology and biochemical examinations. RESULTS: BMD, bone micro structure, serum calcium, phosphorus level and serum estradiol levels were decreased while serum PTH levels, SAP and acid phosphatase (ACP) were elevated in dexamethasone treated rats as compared to control (p<0.01). Dexmethasone treated animals showed loss of marrow at multifocal area, cartilage and trabeculae and thinning of trabeculae (bone resorption), zone of cartilage was poorly seen and fat cells in marrow. Trigonelline showed significant improvement and prevent the progression of osteoporosis by enhancing the BMD, restoring bone physiology. CONCLUSION: Our results confirm the estrogenic activity of triogonelline, which is responsible for its effects; still, it needs further evaluation in other animal models to provide a more conclusive view for its therapeutic usefulness in osteoporosis.

Interferon-gamma Low producer genotype +874 overrepresented in Bacillus Calmette-Guerin nonresponding children.

BACKGROUND: There are limited reports on the influence of the immune regulatory genotypes on the efficacy of Bacillus Calmette-Guerin (BCG) in man. This study was designed to evaluate the influence of the cytokine genotype interferon (IFN)-gamma +874T/A on T cell in vitro assays in BCG nonresponders (negative to either in vivo or in vitro test with purified protein derivative or both). METHODS: Ninety healthy children who were without any clinical evidence of the disease, 45 with a BCG-scar and the remaining 45 without scar were assessed for in vitro T cell responses. CD4+ and CD8+ cell counts were measured by flow cytometry. r32kDaBCG (Ag85A-BCG) protein was used to stimulate T cells and IFN-gamma cytokine concentration in the cultures were measured by enzyme-linked immunosorbent assay. Polymorphism in IFN-gamma (+874T/A) region was detected by amplification refractory mutation system-polymerase chain reaction. RESULTS: T cell subsets were within the normal range in all subjects. Children with TT genotype showed significantly higher antigen-induced IFN-gamma (P < 0.001) as compared with those with AT/AA genotype. The highest values were observed in children with TT genotype combined with positive antigen-specific peripheral blood mononuclear cells proliferation. Seventy-five percent of the vaccinated children with TT genotype showed high amounts of stimulated IFN-gamma compared with 66% of scar negative and 16% of scar positive but with AA genotype. CONCLUSIONS: IFN-gamma (+874T/A) polymorphism seemed to be a strong and independent predictor for clinical outcome of both scar-positive and scar-negative children. These results may help in planning future vaccination strategies. The ability to mount in vitro lymphoproliferation did not distinguish the success or failure of BCG vaccination nor predict susceptibility to the disease.

DNA damage in leukocytes of mice treated with copper sulfate.

Single stranded DNA breaks induced by copper sulfate (CuSO(4)) in mice has been studied in vivo using Alkaline Single Cell Gel Electrophoresis (Comet assay). Mice were administered orally with doses of 0, 1.25, 2.50, 5.00, 7.50, 10.00 and 12.50 mg/kg body weight (b.wt.) of CuSO4 respectively. The samples of whole blood were collected at 24, 48, 72 h, first week and second week post-treatment and the assay was carried out to determine single strand DNA breaks as represented by comet tail-length. In addition, the sample was used to study the repair efficiency by incubating the samples with RPMI medium for 2 h. Results indicated a significant DNA damage at all the doses after treatment with CuSO4 when compared to controls showing a clear dose-dependent response (p < 0.05). A gradual decrease in the tail-lengths from 48 h post-treatment was observed and by second week, the values returned to control levels at all doses. The study on the repair efficiency indicated that mice treated with all the doses of CuSO4 showed decrease in mean comet tail-length indicating repair efficiency capacity but less when compared to those of controls. The study also reveals that comet assay is a sensitive and rapid method for detecting DNA damage caused by trace metals such as copper (Cu).

Higher events rate in patients with a normal gated myocardial perfusion imaging with dipyridamole than exercise: "Run for reliability".

OBJECTIVE: The aim of this is to evaluate the negative predictive value (NPV) of a normal gated myocardial perfusion imaging (NGMPI) with exercise and dipyridamole in a propensity matched population. MATERIALS AND METHODS: This is a prospective study conducted at Nuclear Cardiology Department of Karachi Institute of Heart Diseases, Karachi from December 2008 until June 2010. A total of 809 patients with a NGMPI with adequate exercise (558/809) or dipyridamole (251/809) stress were included and followed-up for 12-30 months (mean 24 ± 3 months) for fatal or non-fatal myocardial infarctions (MI). RESULTS: Mean ejection fraction (%), end diastolic volume (ml), and end systolic volume (ml) in exercise and dipyridamole cohorts were (72 ± 08, 66 ± 11), (68 ± 13, 81 ± 17), and (19 ± 11, 26 ± 12) respectively. On follow-up, in dipyridamole cohort 2 fatal and 6 non-fatal MIs were reported. While in exercise cohort only 2 non-fatal MIs were reported. The NPV of a NGMPI with exercise was 99.7% (95% confidence interval [CI] 98.93-99.96%) with an event rate of 0.3% (95% CI; 0.03-0.6%) and annualized event rate of 0.15%. The NPV of NGMPI with dipyridamole was 96.80% (95% CI; 2.2-4.3%) with an event rate of 3.2% (95% CI; 1.39-3.83%) and annualized event rate of approximately 1.6%. Event free survival for dipyridamole group was significantly lower than exercise analyzed by Log-rank test (14.509, P < 0.001). CONCLUSION: A NGMPI with dipyridamole stress has higher event rate (low-NPV) as compared with exercise and this raises concern over its credibility to label these patients into low-risk group.