Combination drug therapy by herbal nanomedicine prevent multidrug resistance protein 1: promote apoptosis in Lung Carcinoma.

Given the numerous adverse effects of lung cancer treatment, more research on non-toxic medications is urgently needed. Curcumin (CUR) and berberine (BBR) combat drug resistance by controlling the expression of multidrug resistant pump (MDR1). Fascinatingly, combining these medications increases the effectiveness of preventing lung cancer. Their low solubility and poor stability, however, restrict their therapeutic efficacy. Because of the improved bioavailability and increased encapsulation effectiveness of water-insoluble medicines, surfactant-based nanovesicles have recently received a great deal of attention. The current study sought to elucidate the Combination drug therapy by herbal nanomedicine prevent multidrug resistance protein 1: promote apoptosis in Lung Carcinoma. The impact of several tween (20, 60, and 80) types with varied hydrophobic tails on BBR/CUR-TNV was evaluated. Additionally, the MDR1 activity and apoptosis rate of the BBR/CUR-TNV combination therapy were assessed. The encapsulation effectiveness of TNV was affected by the type of tween. With the TNV made from tween 60, cholesterol, and PEG (47.5: 47.5:5), more encapsulation effectiveness was attained. By combining CUR with BBR, especially when given in TNV, apoptosis increased. Additionally, when CUR and BBR were administered in combination, they significantly reduced the risk of MDR1 development. The current work suggests that the delivery of berberine and curcumin as a combination medication therapy via tween-based nanovesicles may be a potential lung cancer treatment.

Health risk assessment of workers exposed to lead dust in informal e-waste recycling workshops.

Informal recycling of electronic waste (e-waste) has attracted significant attention due to its economic benefits and rapid growth rate in many parts of the world. Unfortunately, unsafe conditions of recycling workshops possess chronic exposure to workers and lead to elevated blood lead concentrations (BLCs). Upon measuring the lead concentration in the dust of recycling workshops and the e-wastes in southwestern region of Iran, the related health risks were assessed in 30 exposed workers and 30 non-exposed habitants cases based on the determination of BLC. The average BLCs in exposed workers and non-exposed habitants cases were 24 µg/dL and 7 µg/dL, respectively. The geo-accumulation index (Igeo) revealed heavy contamination of dust in informal e-waste recycling workshops (IERWs) (5023 µg/kg) and significantly lower levels in unexposed areas (49 µg/kg). Health risk assessment indicated that lead exposure from IERWs appears to be a potential threat to workers and indirectly to their families.

Quercetin potentiates the anti-osteoporotic effects of alendronate through modulation of autophagy and apoptosis mechanisms in ovariectomy-induced bone loss rat model.

BACKGROUND: Osteoporosis is a bone disease leading to bone fracture and affects 200 million women worldwide. Autophagy and apoptosis are two fundamental mechanisms that are involved in the development of osteoporosis. In this study we aim to investigate the combined effects of quercetin and alendronate on the markers of osteoporosis, autophagy, and apoptosis in the bone of ovariectomized rats. METHODS AND RESULTS: Fifty adult female Sprague-Dawley rats were ovariectomized and treated with alendronate alone (5 µg/kg/day) or alendronate (5 µg/kg/day) in combination with quercetin (15 mg/kg/day) for 12 weeks. Then, ELISA, stereological tests, Real-time PCR analysis, and immunofluorescence assay were used to measure the markers of osteoporosis, autophagy, and apoptosis in the serum and tibia of rats. The serum osteocalcin was significantly decreased in ovariectomized rats that received quercetin and alendronate compared with alendronate only. Stereological data showed that except for osteoclasts, the total trabecular volume, bone weight, bone volume, osteocyte, and osteoblast numbers were increased in an ovariectomized group that was treated with quercetin and alendronate compared with alendronate alone. Except for Bcl2, the autophagy markers (Beclin-1 and LC3B) and Caspase-3 were significantly downregulated in ovariectomized rats that received quercetin and alendronate compared with those treated with alendronate alone. CONCLUSION: Our results show that quercetin enhances the anti-osteoporotic effects of alendronate, possibly through the regulation of autophagy and apoptosis mechanisms. These findings suggest that the combination of quercetin and alendronate could be a useful therapeutic strategy in the treatment of osteoporosis in postmenopausal women.

The effect of natural polyphenols Resveratrol, Gallic acid, and Kuromanin chloride on human telomerase reverse transcriptase (hTERT) expression in HepG2 hepatocellular carcinoma: role of SIRT1/Nrf2 signaling pathway and oxidative stress.

BACKGROUND: There is evidence that low doses or physiological concentrations of certain natural polyphenols enhance the activity of telomerase. However, the precise mechanism by which natural polyphenols regulate telomerase activity remains unclear. Recent research indicates that NF-E2 related factor 2 (Nrf2) and silent information regulator 1 (SIRT1) are involved in human telomerase reverse transcriptase (hTERT) regulation. Thus, in order to better comprehend the mechanism by which polyphenols regulate hTERT, the present study investigated the effects of the natural polyphenols Resveratrol, Gallic acid, and Kuromanin chloride on hTERT, Nrf2, and SIRT1 expression as well as oxidative stress in HepG2 hepatocellular carcinoma. METHODS: The trypan blue dye exclusion assay was used to assess cell viability. The level of mRNA for hTERT, Nrf2, and SIRT1 was then determined using real-time PCR. A spectrophotometric analysis was conducted to quantify oxidative stress markers. RESULTS: The results demonstrated that Resveratrol induces the expression of hTERT and the SIRT1/Nrf2 pathway in a dose-dependent manner. Gallic acid at concentrations of 10 and 20 µM also increased the expression of the hTERT and SIRT1/Nrf2 pathway. Furthermore, dose-dependent overexpression of hTERT and Nrf2 was induced by Kuromanin chloride at 10 and 20 µM. Moreover, we found that Resveratrol and Kuromanin chloride ameliorated oxidative stress, whereas Gallic acid exacerbated it. CONCLUSIONS: This study demonstrates that low doses of polyphenols (Resveratrol, Gallic acid, and Kuromanin chloride) upregulate the expression of the hTERT gene in the HepG2 hepatocellular carcinoma cell line, possibly via induction of the SIRT1/Nrf2 signaling pathway. Therefore, by targeting this pathway or hTERT, the anti-cancer effect of polyphenols can be enhanced.

Measurement of polycyclic aromatic hydrocarbons in edible oils and potential health risk to consumers using Monte Carlo simulation, southwest Iran.

Persistent organic pollutants, such as polycyclic aromatic hydrocarbons, are hazardous trace contaminants frequently observed in food ingredients, such as edible oils. This study aimed to measure PAHs in forty brands of edible oils marketed in southwest Iran. Additionally, we characterized the daily intake of MOE and ILCR using Monte Carlo simulation. To analyze the content of PAHs, the liquid-liquid extraction method followed by GC-MS was utilized. The average concentration of PAHs was mostly lower than the maximum value for individual PAH (2 µg/Kg); however, the average concentration of fluorene (3.86 µg/Kg) and benzo(a)anthracene (3.13 µg/Kg) was more than the permitted level. The highest residual concentrations of PAHs were mostly observed in canola and corn oils. The daily intake of BaP and 4-PAH for 95% of consumers was 0.01 ng/kg BW/day and 0.04 ng/kg BW/day, respectively. Also, MOE was more than 10,000 for the percentiles of 5%, 50%, and 95%. The modeled ILCR showed that consumption of oil does not currently pose a cancer risk for Iranian consumers due to PAHs exposure. Concerning potential health risks, consumption of edible oils is safe; however, regular monitoring and assessment are required.

The Influence of Probiotics Consumption on Management of Prediabetic State: A Systematic Review of Clinical Trials.

Prediabetes consists of the intermediary stage between normal glucose regulation and overt diabetes mellitus and develops when blood glucose levels are higher than normal but not high enough to confirm a type 2 diabetes mellitus diagnosis (T2DM). Recent evidence suggests that probiotics could be promising approaches to improve this state. In this study, we performed a systematic review to compile the results of clinical trials investigating the effects of pro-/pre-/synbiotics on prediabetes subjects from 2010 to 2020. The article search was carried out in Medline, Embase, Scopus, Web of Science, The Cochrane Library, Clinical trials.gov, ProQuest, Open Grey, and Google Scholar. Search filters were developed using 2 parameters: "prestate diabetes" and "probiotics." Of the 418 studies that were screened, 15 original articles reached the inclusion criteria. Pooling data from these trials showed positive and significant effects of probiotics in the reduction of hyperglycemia, insulin concentration levels, lipid profile, and BMI (Body mass index). Administration of probiotics may provide beneficial and healthful effects in the clinical management of patients with prediabetes and metabolic syndrome. Different probiotics compositions have shown beneficial and noticeable effects on glucose homeostasis, lipid profiles, BMI, and inflammatory markers in subjects with prediabetes, metabolic syndrome, and healthy individuals and could be advantageous in recomposing the gut microbiota back into the normal state during the prediabetic state.

Immunoinformatic Analysis of Calcium-Dependent Protein Kinase 7 (CDPK7) Showed Potential Targets for Toxoplasma gondii Vaccine.

Apicomplexan parasites, including Toxoplasma gondii (T. gondii), express different types of calcium-dependent protein kinases (CDPKs), which perform a variety of functions, including attacking and exiting the host cells. In the current bioinformatics study, we have used several web servers to predict the basic features and specifications of the CDPK7 protein. The findings showed that CDPK7 protein has 2133 amino acid residues with an average molecular weight (MW) of 219085.79 D. The aliphatic index with 68.78 and grand average of hydropathicity (GRAVY) with -0.331 score were estimated. The outcomes of current research showed that the CDPK7 protein included 502 alpha-helix, 1311 random coils, and 320 extended strands with GOR4 method. Considering the Ramachandran plot, the favored region contains more than 92% of the amino acid residues. In addition, evaluation of antigenicity and allergenicity showed that CDPK7 protein has immunogenic and nonallergenic nature. The present research provides key data for more animal-model study on the CDPK7 protein to design an efficient vaccine against toxoplasmosis in the future.

The Probable Association between Chronic Toxoplasma gondii Infection and Type 1 and Type 2 Diabetes Mellitus: A Case-Control Study.

PURPOSE: The probable association between Toxoplasma gondii (T. gondii) infection and diabetes mellitus (DM) is still controversial, and there are several studies with conflicting results. Thus, this study was performed to assess the possible association between chronic T. gondii infection and type 1 diabetes mellitus (T1DM) and T2DM. METHODS: In this case-control study, a total of 105 diabetic subjects including 36 patients with T1DM and 69 patients with T2DM were recruited. In addition, 150 nondiabetic subjects were enrolled as controls. Each case group had its own control group. Each participant completed a structured questionnaire obtaining demographic information. Serum samples were examined for T. gondii-specific IgG antibody using enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Analysis revealed that 69.4% and 34.0% of patients with T1DM and control subjects were serologically positive for T. gondii, respectively (odds ratio (OR): 4.41; 95% confidence interval (CI): 1.75-11.06; P=0.001). Moreover, 72.5% of T2DM patients and 29.0% of healthy individuals were seropositive for T. gondii (OR: 6.44; 95% CI: 3.25-12.74; P < 0.001). Among risk factors, only contact with cats was significantly associated with IgG seroprevalence in both T2DM patients (P < 0.001) and control subjects (P=0.045). CONCLUSION: Although the results showed that chronic T. gondii infection is significantly associated with T1DM and T2DM, there remain many questions regarding the exact mechanisms of T. gondii in the pathogenesis of DM.

Detection of Anti-Toxoplasma gondii IgG and IgM Antibodies and Associated Risk Factors during Pregnancy in Southwest Iran.

Background: This research was aimed at evaluating the seroprevalence of acute and chronic Toxoplasma gondii (T. gondii) infection in pregnant women and related risk factors in southwest Iran. Methods: In this cross-sectional study, eighty-eight pregnant women were included from October 2019 to December 2019. The presence of anti-T. gondii IgM and IgG antibodies was measured using the enzyme-linked immunosorbent assay (ELISA). In addition, a questionnaire consisting of demographic information was completed for each subject. Results: The overall seroprevalence of T. gondii infection was estimated to be 34.09% (30/88). Of these, 1 (1.13%) and 29 (32.95%) samples were found positive for IgM and IgG, respectively. Regarding the risk factors, the consumption of raw/undercooked meat (P value = 0.007) and history of abortion (P value = 0.017) were significantly associated with IgG seroprevalence in pregnant women. Conclusion: The results showed that the pregnant women of southwest Iran might be moderately exposed to T. gondii. Since the risk of acute T. gondii infection in this susceptible group is very important, regular screening tests to diagnose the infection are recommended before pregnancy.

The identification of novel inhibitors of human angiotensin-converting enzyme 2 and main protease of Sars-Cov-2: A combination of in silico methods for treatment of COVID-19.

The angiotensin-converting enzyme 2 (ACE2) and main protease (MPro), are the putative drug candidates for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we performed 3D-QSAR pharmacophore modeling and screened 1,264,479 ligands gathered from Pubchem and Zinc databases. Following the calculation of the ADMET properties, molecular docking was carried out. Moreover, the de novo ligand design was performed. MD simulation was then applied to survey the behavior of the ligand-protein complexes. Furthermore, MMPBSA has utilized to re-estimate the binding affinities. Then, a free energy landscape was used to find the most stable conformation of the complexes. Finally, the hybrid QM-MM method was carried out for the precise calculation of the energies. The Hypo1 pharmacophore model was selected as the best model. Our docking results indicate that the compounds ZINC12562757 and 112,260,215 were the best potential inhibitors of the ACE2 and MPro, respectively. Furthermore, the Evo_1 compound enjoys the highest docking energy among the designed de novo ligands. Results of RMSD, RMSF, H-bond, and DSSP analyses have demonstrated that the lead compounds preserve the stability of the complexes' conformation during the MD simulation. MMPBSA data confirmed the molecular docking results. The results of QM-MM showed that Evo_1 has a stronger potential for specific inhibition of MPro, as compared to the 112,260,215 compound.

Bioinformatics analysis of calcium-dependent protein kinase 4 (CDPK4) as Toxoplasma gondii vaccine target.

OBJECTIVES: Toxoplasma gondii (T. gondii), an obligate intracellular apicomplexan parasite, could affect numerous warm-blooded animals, such as humans. Calcium-dependent protein kinases (CDPKs) are essential Ca2+ signaling mediators and participate in parasite host cell egress, outer membrane motility, invasion, and cell division. RESULTS: Several bioinformatics online servers were employed to analyze and predict the important properties of CDPK4 protein. The findings revealed that CDPK4 peptide has 1158 amino acid residues with average molecular weight (MW) of 126.331 KDa. The aliphatic index and GRAVY for this protein were estimated at 66.82 and - 0.650, respectively. The findings revealed that the CDPK4 protein comprised 30.14% and 34.97% alpha-helix, 59.84% and 53.54% random coils, and 10.02% and 11.49% extended strand with SOPMA and GOR4 tools, respectively. Ramachandran plot output showed 87.87%, 8.40%, and 3.73% of amino acid residues in the favored, allowed, and outlier regions, respectively. Also, several potential B and T-cell epitopes were predicted for CDPK4 protein through different bioinformatics tools. Also, antigenicity and allergenicity evaluation demonstrated that this protein has immunogenic and non-allergenic nature. This paper presents a basis for further studies, thereby provides a fundamental basis for the development of an effective vaccine against T. gondii infection.

Curcumin as an indirect methylation inhibitor modulates the effects of Toxoplasma gondii on genes involved in male fertility.

Toxoplasma gondii is a common protozoan parasite, which infects warm-blooded mammals, including mice and humans, throughout the world. The negative effects of T. gondii infection on the human reproductive system have been documented, especially in females. However, only few studies have examined the effects of T. gondii infection on the male reproductive system. Previous research shows that T. gondii can induce DNA methylation in some gene promoters, which are key regulators of spermatogenesis. Therefore, this study aimed to evaluate the effects of curcumin on the activity of DNA methyltransferases (DNMTs), as well as selected genes, involved in spermatogenesis in spermatogenic cells. In the spermatogenic cells exposed to T. gondii, there was a significant increase in DNMT1 and DNMT3A gene expression and a significant reduction in HSPA1A, MTHR, and DAZL gene expression, compared to the controls. The present results showed that curcumin could regulate changes in T. gondii-mediated gene expression. The effect of T. gondii on DNMT activity was also investigated in this study. A 40 % increase in DNMT activity was observed due to T. gondii infection. However, DNMT activity was restored by treatment with 20 µM curcumin for eight hours. The results revealed that T. gondii increases the NF-κB activity, compared to the control group. The increase in NF-κB activity, induced by T. gondii, was inhibited by curcumin. In conclusion, T. gondii, by increasing DNMT expression and activity, leads to an increase in NF-κB activity in cells. On the other hand, curcumin reduced DNA methylation, induced by T. gondii, owing to its NF-κB-inhibiting properties. Therefore, curcumin, as a hypomethylating agent, can be potentially used to alleviate the negative effects of T. gondii on the male reproductive system.

In-depth computational analysis of calcium-dependent protein kinase 3 of Toxoplasma gondii provides promising targets for vaccination.

PURPOSE: The Toxoplasma gondii calcium-dependent protein kinase-3 (CDPK3) is a key enzyme for parasite egress, control of calcium-dependent permeabilization in parasitophorous vacuole membrane and tissue cyst formation. In this study, we comprehensively explored the bioinformatics features of this protein to improve vaccine design against T. gondii. MATERIALS AND METHODS: Various web servers were employed for the analysis of physico-chemical properties, post-translational modifications, localization in the subcellular milieu, secondary and tertiary structures, as well as B-cell, major histocompatibility complex (MHC)-binding and cytotoxic T-lymphocyte (CTL) epitopes. RESULTS: This protein was a 537 amino acid antigenic and non-allergenic molecule with a molecular weight of 60.42 kDa, a grand average of hydropathicity score of -0.508, and aliphatic index of 79.50. There exists 46.74% alpha helix, 12.48% extended strand, and 40.78% random coil in the secondary structure. Ramachandran plot of the refined model demonstrated 99.3%, 0.7%, and 0.0% of residues in the favored, allowed and outlier areas, respectively. Besides, various potential B-cell (continuous and conformational), MHC-binding and CTL epitopes were predicted for Toxoplasma CDPK3 protein. CONCLUSION: This article provides a foundation for further investigations, and laid a theoretical basis for the development of an appropriate vaccine against T. gondii infection.

Spermatogonia apoptosis induction as a possible mechanism of Toxoplasma gondii-induced male infertility.

OBJECTIVES: The protozoan Toxoplasma gondii as an intracellular protozoan is widely prevalent in humans and animals. Infection generally occurs through consuming food contaminated with oocysts and tissue cysts from undercooked meat. The parasite is carried in sexual fluids like semen but there is little information about the effect of T. gondii on the male reproductive system. In this study, we examined the effect of T. gondii tachyzoites on apoptosis induction in type B spermatogonia (GC-1) cells. MATERIALS AND METHODS: Fresh tachyzoites taken of infected BALB/c mice, GC-1 spg cells were infected with increasing concentrations of tachyzoites of T. gondii, then apoptotic cells were identified and quantified by flow cytometry. The genes associated with apoptosis were evaluated by RT2 Profiler PCR Array. RESULTS: PCR array analysis of 84 apoptosis-related genes demonstrated that 12 genes were up-regulated at least 4-fold and that one gene was down-regulated at least 2-fold in the T. gondii infection group compared with levels in the control group. The number of genes whose expression had increased during the period of infection with T. gondii was significantly higher than those whose expressions had decreased (18 versus 1) and Tnfrsf11b had the highest rate of gene expression. CONCLUSION: T. gondii induce in vitro apoptosis of GC-1 spg cells. This effect shows a trend of concentration-dependent increase so that with an increase in the ratio of parasite burden to spermatogonial cells, in addition to an increase in the number of genes whose expression has changed, the fold of these changes has increased as well.

Greener synthesis of Rod Shaped Zinc Oxide Nanoparticles using Lilium ledebourii tuber and evaluation of their Leishmanicidal activity.

BACKGROUND: Nanoparticles (NPs) with unique chemical and physical properties can be used for therapeutic purposes because of their strong antimicrobial activates. Nanoparticles have been used as an antimicrobial agents to inhibit microbial growth. OBJECTIVES: In view of the strong antimicrobial activity of nanoparticles, the biogenic synthesis and leishmanicidal activity of rod-shaped zinc oxide (R-ZnO) nanoparticles was explored using Lilium ledebourii tuber extract. MATERIALS AND METHODS: The ensuing nanoparticles are characterized by UV-visible spectroscopy, X-ray diffraction and transmission electron microscopy and their leishmanicidal activity evaluated against the Leishmania major (L. major) by MTT assay. RESULTS: The R-ZnO nanoparticles displayed excellent leishmanicidal activity against the L. major as they significantly inhibited the amastigotes. The IC50 values of R-ZnO nanoparticles being ~ 0.001 mg.mL-1. R-ZnO nanoparticles can inhibit L. major growth in a dose-dependent manner under in vitro conditions. CONCLUSION: A simple, low-cost feasible and eco-friendly procedure was developed for biosynthesis of R-ZnO nanoparticles using natural bioresource that can inhibit human parasite cells growth in a dose-dependent manner under in vitro conditions.