Research in Pharmaceutical Sciences
Volume:18 Issue: 3, Jun 2023

 Although many recent studies have analyzed the validation of integrin subunit alpha 4 (ITGA4) biomarker for cancer detection in patients with various malignancies, the diagnostic value of ITGA4 methylation for malignant tumors remains uncertain. We performed a systematic review and meta-analysis to unravel the relationship between ITGA4 promoter methylation status and malignant tumors.

Experimental approach:

 A meta-analysis was performed using the metaphor package in R 3.5 and Meta-Disc 1.4 software. Data were derived from a search of main electronic databases up to January 2022. SROC analysis was used to evaluate the status of ITGA4 promoter methylation in colorectal cancer (CRC) and other cancers. A total of 1232 tumor samples and 649 non-tumor samples from 13 studies were analyzed.

 The pooled results including all types of cancer provided evidence that ITGA4 hypermethylation was more frequent in tumor samples than non-tumor samples (OR 13.32, 95% CI 7.96-22.29). Methylation of ITGA4 has a pooled sensitivity of 0.95 (95% CI: 0.94-0.97), a pooled specificity of 0.57 (95% CI: 0.54-0.60), and an area under the curve (AUC) of 0.94. When the analysis was performed independently for CRC, it revealed a higher association (OR = 20.77, 95% CI: 9.15-47.15). The assessment of ITGA4 methylation of tissue samples resulted in a pooled sensitivity of 0.99 (95% CI: 0.97-1.00) and a pooled specificity of 0.90 (95% CI: 0.86-0.93), and AUC of 0.94 for the diagnosis of CRC.

Conclusion and implications:

 ITGA4 methylation analysis is a reliable method for CRC screening in tissue samples.

Crinum asiaticum L. has long been used in Thai traditional medicine to treat osteoarthritis and inflammation by placing it on painful areas without further formulation design which is suboptimal for therapeutic use. Thus, this research aims to formulate a topical hydrogel patch containing C. asiaticum L. extracts (CAE) for anti-inflammatory effects.

Experimental approach: 

The hydrogel patches are made from carrageenan, locust bean gum, with glycerin as a plasticizer and contain CAE formulated by using response surface methodology based on Box-Behnken design for design, determination of the effect of independent factors on the tensile strength, and optimization of the hydrogel patch formulation. In vitro release and skin permeation studies using a modified Franz diffusion cell and anti-inflammatory activity were evaluated.

The optimized CAE hydrogel patch showed a good correlation between predicted and observed tensile strength values and exerted its maximum cumulative lycorine release and permeation at 69.38 ± 2.78% and 48.51 ± 0.45%, respectively which were fit to Higuchi's kinetic model. The release rates were found to decrease with an increase in the polymer proportion of carrageenan and locust bean gum. In addition, the patch exerted potent in vitro anti-inflammatory activity with an IC50 value of 21.36 ± 0.78 μg/mL.

Conclusion and implication: 

The optimized CAE hydrogel patch application was successfully formulated with excellent mechanical properties, cumulative release, permeation, and anti-inflammatory effects. Thus, it has the potential to be further developed as a herbal application to relieve pain and inflammation. The in vivo anti-inflammatory effect of this delivery system should be further investigated.

Renal ischemia/reperfusion (IR) injury is a pathologic phenomenon that caused to increase risk of mortality. The main objective of this study was to investigate the effect of sodium hydrogen sulfide (NaHS) on renal IR injury in male and female rats. 

Experimental approach:

 Fifty-eight male and female rats were randomized into 4 groups of control, sham, IR, and IR + NaHS. The IR was performed by 45 min of ischemia by vessel clamping followed by 24 h reperfusion. The NaHS (100 μmol/kg) treatment was applied 10 min prior to IR. Finally, after 24 h of reperfusion, the measurements were performed.

The serum levels of blood urea nitrogen, creatinine, tissue level of malondialdehyde, and kidney tissue damage score (KTDS) were increased by IR. Urine volume, creatinine, and urea clearances decreased by IR. NaHS administration improved some parameters in males but exacerbated KTDS and serum markers related to renal function. 

Conclusions and implications:

 Our data demonstrated that NaHS didn’t protect female rats against renal IR injury. In males, it has null effects or just a few protective effects via antioxidant activity.

Increasing evidence indicates that oxidative stress is an important factor in the pathogenesis and progression of Alzheimer’s disease (AD). Betaine is trimethylglycine with antioxidant and neuroprotective properties. The present study aimed to evaluate the possible beneficial effects of betaine on oxidative stress and memory deficits induced by intrahippocampal injection of amyloid beta (Aß) in an AD model. 

Experimental approach:

 Forty adult male Wistar rats were divided into 5 equal groups: the control and Aß groups which received oral gavage of saline (1 mL daily) for 14 days. The other 3 groups (betaine + Aß) received betaine (5, 10, and 15 mg/kg, orally) for 14 consecutive days. On the 15th day, all of the groups were injected bilaterallyintrahippocampal of Aß (5 μg/μL), except controls that were injected with normal saline as a vehicle. Seven days after the Aß injection, memory was assessed in a passive avoidance test. Changes in catalase activities and glutathione peroxidase, glutathione, and malondialdehyde concentrations were investigated to determine the antioxidant activity in the rat hippocampus.

Data showed that betaine pretreatment of Aß-injected rats improved memory in avoidance tasks. In addition, betaine pretreatment attenuated oxidative stress.

Conclusion and implications:

 The current findings showed that oral administration of betaine could prevent Aß-induced impairment of memory possibly through suppression of oxidative stress in the hippocampus area of rats.

The GC-MS analysis reported n-hexadecanoic acid or palmitic acid as a major component of the ethanolic extract of Halymenia durvillei (HDET). This compound shows cytotoxic effects against various human cancer cells. The present study investigated the effect of HDET on the viability and proliferation of MDA-MB-231, a triple-negative breast cancer (TNBC) cell line.

Experimental approach:

 Cell proliferation and cell cycle analysis were determined by flow cytometry and cell cycle regulatory protein expression levels were then determined by Western blotting. The presence of reactive oxygen species (ROS) was evaluated by dichlorofluorescein, followed by analyzing changes in gene expression of antioxidant enzymes using a real-time polymerase chain reaction.

HDET dose-dependently reduced cell viability with the 50% inhibitory concentration (IC50) of 269.4 ± 31.2 μg/mL at 24 h. The cell proliferation assays showed increased succinimidyl ester fluorescent intensity after treatment with > 100 μg/mL of HDET, indicating the inhibition of cell proliferation. Cell cycle analysis using propidium iodide staining showed an increased percentage of cells in the G2/M phase. HDET also decreased the levels of cell cycle regulatory proteins including cyclin D1 and increased the level of p21. HDET promoted oxidative stress by increasing ROS levels along with the reduction of catalase expression. However, HDET did not induce apoptosis and caspase activation in TNBC cells. 

Conclusion and implications:

 These findings suggest that HDET which is rich in palmitic acid may serve as a potential therapeutic agent to target TNBC via arrest cell cycle progression at the G2/M phase.

Properties of Alzheimer's disease, can be caused by several reasons and there is no definite treatment for it. We aimed to study the effect of the hydroalcoholic extract, methanolic and n-hexane fractions of brown algae Sargassum angustifolium on memory impairment in mice and rats. 

Experimental approach:

 Hydroalcoholic extract (25, 50, 100, 200 mg/kg), methanolic (20 and 40 mg/kg) and n-hexane (40 and 60 mg/kg) fractions of S. angustifolium were administered for 21 days intraperitoneally before scopolamine injection (2 mg/kg) on day 21. Rivastigmine was administered for 3 weeks intraperitoneally as well. Then, cognitive function was evaluated by three behavioral tests: passive avoidance, object recognition, and the Morris Water Maze test.

Scopolamine induced memory impairment and rivastigmine significantly reversed the memory dysfunction in all three tests. Hydroalcoholic extract and methanolic fraction significantly reversed scopolamine-induced memory impairment in passive avoidance by 64% and 55% and enhanced the recognition index in the object recognition test. In the Morris water maze test probe trial and training session, on days 3 and 4, the hydroalcoholic extract showed a significant decrease in time spent in the target quadrant and path length, respectively. Also, hydroalcoholic extract and methanolic fraction decreased escape latency time in training sessions on days 3 and 4, by 50% and 31% in comparison to scopolamine. N-hexane fractions had no significant effect on scopolamine-induced cognitive impairment. 

Conclusion and implications:

 Although the n-hexane fraction wasn’t effective, the administration of hydroalcoholic extract and the methanolic fraction of S. angustifolium enhanced scopolamine-induced memory impairment.

Huntington’s disease (HD) is a neurodegenerative disease characterized by neuronal death in the striatum. Asiatic acid is an active component of Shorea robusta (Dipterocarpaceae) plants with neuroprotective activity and is considered an acceptable therapeutic candidate for different neurodegenerative diseases. In the present study, the beneficial pharmacological action of Shorea robusta resin extract (SRRE) was assessed in 3-nitropropionic acid (3-NP)-induced HD in rats.

Experimental approach:

 The neuroprotective effect of SRRE (285.7 and 666.7 mg/kg, p.o., 14 days) was studied in 3-NP (10 mg/kg)-induced rats by measuring body weight, behavioral parameters including neurological scoring, motor coordination, spatial memory, and depression-like behavior, neuro-biochemical parameters (gamma-aminobutyric acid and acetylcholinesterase), and oxidative stress parameter in the brain. Histopathology of the rat’s brain was also studied.

SRRE treatment (285.7 mg/kg and 666.7 mg/kg) substantially restored body weight, motor coordination, and mitochondrial enzyme complex I function and improved memory impairment as compared to 3-NP-treated rats. Furthermore, SRRE treatment significantly restored the antioxidant enzyme activity in brain tissue and ameliorated the histopathological changes induced by 3-NP.

Conclusion and implications:

 The neuroprotective effect of SRRE on 3-NP-induced HD in rats was mediated by a reduction in oxidative stress which may favor the usefulness of Shorea robusta in HD.

Background and purpose:

 Salvia abrotanoides is considered a medicinal plant and has a broad distribution in Iran. In Iran's traditional medicine, it is also used to treat leishmaniasis, malaria, atherosclerosis, cardiovascular disease, and as a disinfectant. This research aimed to determine the anti-Candida component from S. abratonoides and anti-Trichomonas natural compounds from the stems of this plant. 

Experimental approach:

 The plant shoots were collected, dried, and after removing the leaves, grounded. Dried plant material was extracted in a maceration tank, concentrated by a Rotavap, degreased, and fractionated by normal column chromatography. Based on anti-fungal screening against Candida species, Fr. 4, with more anti-fungal activity, was selected for phytochemical analysis, by different chromatographic methods on the silica gel column and Sephadex LH-20. Isolated compounds were elucidated by NMR analysis, mass spectrum, and ultraviolet spectroscopy. Anti-fungal effects were investigated using the fungal suspension, incubation, and parasite-counting methods on purified compounds. Antibacterial effects were assessed using the Broth dilution test and reported according to the MIC parameter.

Two diterpenoid compounds named carnosol (compound 1), 11-hydroxy-12-methoxy-20- norabiata-8, 11, 13-trien (compound 2), and a flavonoid: 6,7-dimethoxy-5, 4'-dihydroxyflavone (compound 3) were isolated and identified. Compound 1 had selective anti-fungal effects against C. albicans, C. glabrata, and C. parapsilosis, but weak toxicity against Trichomonas vaginalis with IC50 of 675.8 μg/mL, less than metronidazole with an IC50 of 13.2 μg/mL. 

Conclusion and implications:

Carnosol as the main component was assayed against Candida, Aspergillus, Rhizopus, and Trichomanas species. The results confirmed its effect on Candida compared to standard drugs.

Neonates of pregnant women with epilepsy may compromise normal neurodevelopment and hippocampal morphology. Memory and learning disorders and a decrease in verbal IQ scores are seen in these children later in life. In the previous study, we suggested that the central muscarinic cholinergic receptors had an important role in learning and memory deficits induced by prenatal pentylenetetrazol-kindling in pups born to kindled mothers. This study aimed to investigate the effects of kindling during pregnancy on long-term potentiation (LTP) induction and the role of M1 muscarinic acetylcholine receptors in the hippocampus of male offspring. 

Experimental approach:

Twenty female Wistar rats were divided into two groups on the 13th day of their gestation (kindled and control; n = 10). Animals in the first group were kindled by i.p. injections of 25 mg/kg body weight pentylenetetrazol every 15 min until seizures occurred and the control group received normal saline. The effect of maternal seizures and perfusion of specific M1 muscarinic receptors antagonist (telenzepine at doses of 0.01, 0.1, and 1 nmol) on the LTP induction of 80 pups were tested at 12 weeks of age by field potential recordings.

The results of the electrophysiological study revealed that recurrent seizures during pregnancy impaired field excitatory postsynaptic potentials (fEPSP)-LTP induction and normal development of M1 muscarinic receptors in the hippocampus of male offspring. Also, the results demonstrated that maternal seizure did not significantly affect the paired-pulse indexes and population spike-LTP in the hippocampus of male offspring. 

Conclusion and implications:

 Our study showed that recurrent seizures during pregnancy cause impaired fEPSP-LTP induction and abnormal development of the M1 muscarinic receptor in the hippocampus.

Diabetic nephropathy (DN) is a chronic kidney failure, which may lead to fatality. Mesangial cell proliferation, renal inflammation, stress oxidative, and fibrosis are involved in DN progression. Yacon leaves (Smallanthus sonchifolius (Poepp.) H. Rob.) contains large amounts of phenolic compounds and it has the ability to inhibit oxidative stress, inflammation, and fibrosis. Considering the potential of yacon leaves extract (YLE), it may be used for DN treatment. This research aimed to elucidate YLE’s potential as anti-DN through anti-inflammatory, antioxidant, and antifibrosis mechanisms. 

Experimental approach:

 Mesangial cells were induced by glucose 20 mM for 5 days and treated with YLE concentrations as much as 5, 10, and 50 μg/mL. TGF-β1, TNF-α, and MDA levels were measured using the ELISA method. SMAD2, SMAD3, SMAD4, and SMAD7 gene expressions were analyzed using the qRTPCR method.

YLE at 5, 10, and 50 μg/mL could reduce the levels of TGF-β1, TNF-α, and MDA compared with the DN cells model. YLE could reduce gene expressions of SMAD2, SMAD3, and SMAD4 and increase SMAD7 expression. 

Conclusion and implications:

 YLE potentially mitigated diabetic nephropathy through antifibrosis, antiinflammatory, and antioxidant capacities.