Oral administration of encapsulated catechin in chitosan-alginate nanoparticles improves cognitive function and neurodegeneration in an aluminum chloride-induced rat model of Alzheimer's disease.

The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl3)-induced rat model of Alzheimer's disease (AD). The Catechin-loaded Chitosan-Alginate nanocarriers were synthesized through ionotropic gelation (IG) method. Physio-chemical characterization was conducted with the Zetasizer Nano system, the scanning electron microscope, and the Fourier transform infrared spectroscopy. The experiments were performed over 21 days on six groups of male Wistar rats. The control group, AlCl3 treated group, Catechin group, nanocarrier group, treatment group 1 (AlCl3 + Catechin), and treatment group 2 (AlCl3 + nanocarrier). A behavioral study was done by the Morris water maze (MWM) test. In addition, the level of oxidative indices and acetylcholine esterase (AChE) activity was determined by standard procedures at the end of the study. AlCl3 induced a significant increase in AChE activity, along with a significant decrease in the level of Catalase (CAT) and total antioxidant capacity (TAC) in the hippocampus. Moreover, the significant effect of AlCl3 was observed on the behavioral parameters of the MWM test. Both forms of Catechin markedly improved AChE activity, oxidative biomarkers, spatial memory, and learning. The present study indicated that the administration of Catechin-loaded Chitosan-Alginate NPs is a beneficial therapeutic option against behavioral and chemical alteration of AD in male Wistar rats.

In vivo and in silico evaluations of a synthetic pyrano[3,2-c]quinoline derivative as a potent anti-diabetic agent.

Background: The in vivo assessment of a novel compound is a pivotal step in the development of a new drug. In this study, we selected 1-(2-bromophenyl)-1,11-dihydro-3H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H)-dione (2-BDBPQD), identified as an exemplary α-glucosidase inhibitor in preliminary in vitro assays, for further evaluation in an in vivo anti-diabetic context. Methods: The in vivo anti-diabetic effect of 2-BDBPQD was assessed using a streptozotocin (STZ)-induced diabetic Wistar rat model. Recognizing the relevance of lipid factors in diabetes, we also investigated the impact of this compound on the lipid profile of diabetic Wistar rats. In silico studies, encompassing docking studies and pharmacokinetic predictions of 2-BDBPQD, were conducted. Results: The results obtained indicated a significant reduction in blood glucose levels with 2-BDBPQD treatment compared to acarbose. However, no significant effects on the lipid profile were observed. In silico studies revealed that 2-BDBPQD interacted with key residues in the α-glucosidase active site and exhibited favorable pharmacokinetic properties. Conclusion: In summary, the study demonstrated the in vivo anti-hyperglycemic activity of 2-BDBPQD. Nevertheless, further in vivo evaluations are recommended to comprehensively assess its potential as a new drug for the treatment of diabetes.

Crocin attenuates the lipopolysaccharide-induced neuroinflammation via expression of AIM2 and NLRP1 inflammasome in an experimental model of Parkinson's disease.

The underlying mechanisms of inflammasome activation and the following dopaminergic neuron loss caused by chronic neuroinflammation remain entirely unclear. Therefore, this study aimed to investigate the impact of crocin on the inflammasome complex within an experimental model of Parkinson's disease (PD) using male Wistar rats. PD was induced by the stereotaxic injection of lipopolysaccharide (LPS), and crocin was intraperitoneally administrated one week before the lesion, and then treatment continued for 21 days. Open field (OF) and elevated plus maze tests were applied for behavioral assays. Furthermore, hematoxylin and eosin (H&E) and immunostaining were performed on whole brain tissue, while dissected substantia nigra (SN) was used for immunoblotting and real-time PCR to evaluate compartments involved in PD. The time spent in the center of test was diminished in the LPS group, while treatment with 30 mg/kg of crocin significantly increased it. H&E staining showed a significant increase in cell infiltration at the site of LPS injection, which was ameliorated upon crocin treatment. Notably, crocin-treated animals showed a reduced number of caspase-1 and IL-1ß positive cells, whereas the number of positive cells was increased in the LPS group (P < 0.05). A significant decrease in tyrosine hydroxylase (TH) expression was also found in the LPS group, while crocin treatment significantly elevated its expression. IL-1ß, IL-18, NLRP1, and AIM2 genes expression significantly increased in the LPS group. On the other hand, treatment with 30 mg/kg of crocin significantly downregulated the expression levels of these genes along with NLRP1 (P < 0.05). In summary, our findings suggest that crocin reduces neuroinflammation in PD by diminishing IL-1ß and caspase-1 levels, potentially by inhibiting the expression of AIM2 and NLRP1 genes.

Urtica dioica Extract Leads to Cyst Reduction, Enhanced Cell-Mediated Immune Response, and Antioxidant Activity in Experimental Toxoplasmosis.

BACKGROUND: Toxoplasmosis is a cosmopolitan parasitic infection caused by Toxoplasma gondii which is commonly treated by pyrimethamine (PYR) plus sulfadiazine (SDZ) with several adverse side effects. The present study evaluated the therapeutic effects of Urtica dioica L. aqueous extract (UDE) on acute and chronic toxoplasmosis in mice. METHODS: For this purpose, mice were infected with 20 cysts (acute infection) or 10 cysts (chronic infection) of T. gondii (Me49 strain). The mice were treated with 200 mg/kg of UDE intraperitoneally (IP) and intragastric route (IG). The UDE-treated mice were compared with the PYR + SDZ treatment. The histopathological changes, cyst count, total antioxidant capacity (TAC), malondialdehyde (MDA) assay, and serum INF-γ were also evaluated. RESULTS: In the acute toxoplasmosis, UDE by IP and IG administration significantly reduced the number of brain cysts by 93.74 and 92.55%, respectively, and increased the survival rate to 80% compared with 60% in untreated controls. In the chronic infection, cyst burden decreased at 88.2 and 83.4%, respectively, for IP and IG treatments. Moreover, UDE significantly increased INF- γ levels in acute and chronic toxoplasmosis. Tissue inflammatory lesions were reduced in the UDE-treated subgroups compared to the untreated group. UDE treatment significantly reduced MDA levels and elevated TAC in both acute and chronic infections. CONCLUSION: The results show that U. dioica possesses significant immunostimulant and antioxidant activity with a higher cyst reduction in the brain during acute toxoplasmosis. Further studies are required to investigate the fractionations of UDE against T. gondii and its combination with other standard drugs.

Efficacy of clofazimine against acute and chronic Toxoplasma gondii infection in mice.

Toxoplasmosis is a zoonotic protozoal disease affecting approximately one-third of the world's population. The lack of current treatment options necessitates the development of drugs with good tolerance and effectiveness on the active and cystic stages of the parasite. The present study was established to investigate, for the first time, the potential potency of clofazimine (CFZ) against acute and chronic experimental toxoplasmosis. For this purpose, the type II T. gondii (Me49 strain) was used for induction acute (20 cysts in each mouse) and chronic (10 cysts in each mouse) experimental toxoplasmosis. The mice were treated with 20 mg/kg of CFZ intraperitoneally and orally. The histopathological changes, brain cyst count, total Antioxidant Capacity (TAC), malondialdehyde (MDA) assay, and the level of INF-γ were also evaluated. In the acute toxoplasmosis, both IP and oral administration of CFZ induced a significant reduction in brain parasite burden by 90.2 and 89%, respectively, and increased the survival rate to 100% compared with 60% in untreated controls. In the chronic infection, cyst burden decreased at 85.71 and 76.18% in CFZ-treated subgroups in comparison to infected untreated controls. In addition, 87.5% and 100% of CFZ-treated subgroups survived versus untreated control 62.5%. Moreover, CFZ significantly increased INF-γ levels in acute and chronic toxoplasmosis. Tissue inflammatory lesions were considerably reduced in the CFZ-treated chronic subgroups. CFZ treatment significantly reduced MDA levels and elevated TAC in both acute and chronic infections. In conclusion, CFZ showed a promising finding regarding the ability to reduce cyst burden in acute and chronic infection. Further studies are needed to investigate the therapeutic role of CFZ on toxoplasmosis using the long-term treatment and more advanced approaches. In addition, clofazimine may need to be accompanied by another drug to augment its effect and prevent the regrowth of parasites.

Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy.

PURPOSE: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs. METHODS: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro. RESULTS: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased. CONCLUSION: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.

The effects of Rosa foetida extract along with self-care education on primary dysmenorrhea: study protocol for a randomized clinical trial.

BACKGROUND: Dysmenorrhea is one of the most common disorders among young women. Medicinal herbs are one of the alternative methods for the treatment of dysmenorrhea. This study will investigate the effect of Rosa foetida extract, along with self-care behavior education on primary dysmenorrhea among female students of Babol University of medical sciences. METHODS/DESIGN: A randomized clinical trial will be performed on single students, aged 18 to 24 years. The research samples will be divided into three groups. The students will receive self-care behavior education on dysmenorrhea. Following the education, two of the groups will receive Rosa foetida extract capsules and placebo capsules in two consecutive cycles every 8 h for two successive days, respectively. The capsules will have similar physical appearance. The third group will not receive any medication. Data will be collected through demographic characteristic questionnaire, visual analog scale, dysmenorrhea self-care behaviors scale questionnaire, pictorial chart, and menstrual distress scale questionnaire. In order to determine and compare the effect of pharmacological and educational interventions on the severity of dysmenorrhea in groups, an ANOVA analysis of variance test with repeated measures will be used by SPSS software version 22. DISCUSSION: The results will show the effects of Rosa foetida extract along with self-care behavior education on primary dysmenorrhea, and beneficial effects that may be found in the trial of this plant may be of use for women with the same problem. ETHICS AND DISSEMINATION: The study is approved by the Ethics Committee of Babol University of Medical Sciences (IR.MUBABOL.REC.1397.059). TRIAL REGISTRATION: IRCT 20190318043086N1. Registered on 14 June 2019.

Risk assessment of a cold atmospheric physical argon plasma jet on the skin, liver, and biochemical factors in an animal model.

In this study, an argon plasma jet was made for therapeutic purposes. Although cold plasma jet (CAPJ) is considered a safe device, its risk assessment is essential to be approved for a clinical trial. To this end, the safety parameters of the CAPJ were evaluated from both aspects associated with the instrument such as design, construction, and environmental conditions, and also function on living organisms. It was shown that the device is physically safe for the user and the animal. In continue, healthy rats were treated by the plasma at two modes of streamer and plume mode at two distances of 20 and 25 mm from the nozzle for 2, 5, and 10 minutes of exposure time. In the study of blood serum biochemistry, the strongest deviation from the average is observed at alkaline phosphatase in the plume mode in the 10min (P10) group. Also, the amount of Aspartate transaminase (AST) in the blood serum of rats is lower than the control group for all groups except streamer mode at 10 min exposure (S10). And, the mean ALT enzyme in the serum of the S5 group is significantly higher compared to the plume mode in the 5 min (P5) group. The histopathology of the liver is studied to support these results. Shrinkage of the nucleus, cell swelling, and hyperemia are observed in the liver tissue for streamer mode, while in the plasma plume mode, these changes are not tangible. No significant difference is observed in the mean value of total Bilirubin, Direct Bilirubin, Albumin, Na, and K factors in the different groups after the plasma treatment and the histopathology of kidney tissue is performed for all the groups to support this conclusion and it did not show any damage to the kidney tissue. As a result of risk assessment in this study, the treatment with a duration of 2 to 5 minutes is safe with the specifically designed CAPJ nozzle head at a distance of 25 mm from the nozzle.

Therapeutic effect of antihypertensive drug on diabetic nephropathy: Functional and structural kidney investigation.

Due to the growth of diabetic mellitus (DM) and diabetic nephropathy as a significant complication for diabetic patients, study on effective treatment with fewer side effects has been fascinated. In this study for the first time carvedilol effects on both function and structure of kidney in diabetic nephropathy treatment were evaluated. Diabetes was induced by injection of streptozotocin (STZ) intravenously in rats and three groups including control, diabetic, and treatment with carvedilol were considered. Biochemical parameters such as, blood glucose level, BUN, creatinine, uric acid, Na+, K+ was determined. Results showed that glucose (516 to 291 mg/dl), BUN (42 to 21.67 mg/dl), creatinine (0.75 to 0.6 mg/dl), uric acid (4.45 to 1.36 mg/dl), and K+ (7.433 to 5.433 mEq/l) level reduced. Decrease in glucose, BUN, creatinine, uric acid, and K+ and increase in Na+ level (138 to 146.33 mEq/l) confirmed therapeutic effect of carvedilol. Furthermore, the histopathological study was done for each group. Histopathological results confirmed the data obtained by biochemical parameters. For further investigation, SPECT imaging with 99mTc-DMSA, which is a gold standard in diabetic nephropathy detection, was done. SPECT imaging showed that accumulation of 99mTc-DMSA was increased in treated group (5 to 25 kcpm) which means the improvement in renal structure in the treated group compare to the diabetic group (5 kcpm). Finally, obtained results confirmed our hypothesis that carvedilol had a therapeutic effect on diabetic nephropathy.

Synthesis of biocompatible nanocrystalline cellulose against folate receptors as a novel carrier for targeted delivery of doxorubicin.

We designed amine-functionalized nanocrystalline cellulose grafted folic acid/magnetic nanoparticles (AF-NCC/Fe3O4 NPs) against folate receptors for targeted delivery of doxorubicin (DOX). Toxicity is a major side effect of DOX, damaging vital organs such as the heart, kidney, and liver; for example, it causes dilated cardiomyopathy and hepatotoxicity. Accordingly, we aimed to reduce this adverse effect and increase the targeted delivery of DOX to the right point of cancer cells by using the unique features of cancer cells. The characterizations were approved in each step using Fourier transform infrared (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), zeta potential, and dynamic light scattering (DLS) analysis techniques. Encapsulation efficacy of AF-NCC/Fe3O4 NPs was 99.6%; drug release investigations showed excellent stability in physiological conditions (pH âˆ¼ 7.4) and a high release rate in the low pH condition of cancer environments (pH âˆ¼ 5.0). The hemolysis assay and Masson's trichrome and hematoxylin and eosin (H&E) staining results showed that the nanocarrier was entirely biocompatible. In vitro cell viability study approved that the designed nanocarrier increased the therapeutic effects of DOX on Saos-2 cells. The cellular internalization results displayed a high percentage of uptake within 2 h. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was applied for the evaluation of tumor protein p53 (p53), p21, and Bcl-2-associated X protein (Bax). DOX exerted its effects through DNA damage and oxidative stress that led to p53 upregulation, and p53 inhibited cell cycle progression. This arrest initiated apoptosis and inhibited cell migration. In summary, encapsulating DOX in AF-NCC/Fe3O4 NPs dramatically decreases the toxic effects of this chemotherapeutic agent on vital organs, especially on the heart. This smart nanocarrier increases the delivery of DOX using acid folic on its surface and also enhances the DOX release in the acidic environment of cancer cells. DOX exerts its therapeutic effects by the initiation of apoptosis and inhibition of migration.

The inhibitory effect of PLGA-encapsulated berberine on hepatotoxicity and α-smooth muscle actin (α-SMA) gene expression.

BACKGROUND: Liver injury results in excessive extracellular matrix (ECM) deposition in the liver, which is mainly produced by hepatic stellate cells (HSC). Alpha-smooth muscle actin (α-SMA) and liver enzymes are the two hallmarks of liver injury. Previously, it has been confirmed that berberine (BBR) attenuates liver injury. This study aimed to investigate the protective effect of Poly Lactic-co-Glycolic Acid (PLGA) encapsulated BBR against liver injury. METHODS: Nanoprecipitation, encapsulation, and physio-chemical characterization of BBR-PLGA nanoparticles (BBR-PLGA-NP) have been done. The protective effects of BBR-PLGA-NPs and BBR against carbon tetrachloride (CCl4)-treated Wistar rats were investigated. The serum levels of alanine aminotransferase and aspartate transaminase were measured, and the expression level of α-SMA was quantified by qRT-PCR. To evaluate the liver changes, morphological and histological staining was done. RESULTS: BBR-PLGA-NPs markedly reduced serum ALT and AST in rats treated with CCl4. Although the expression level of α-SMA was downregulated in the CCl4-injected rats that were treated with BBR, α-SMA expression in this group was still remarkably higher than the control group. α-SMA mRNA was significantly under-expressed (p < 0.05) by BBR-PLGA-NPs and the hepatic histology revealed BBR-PLGA-NPs made further improvements than free BBR. CONCLUSION: The use of nanoparticle to encapsulate BBR is a worthy approach to enhance the curative effect of BBR against liver injuries, which donate a safe and effective drug delivery strategy to treat liver injuries.

Fabrication and evaluation of aptamer-conjugated paclitaxel-loaded magnetic nanoparticles for targeted therapy on breast cancer cells.

Targeted drug delivery vehicles make it possible to deliver anti-cancer drugs to the cells or tissues of interest. Aptamers are peptide or oligonucleotide molecules that can serve as targeting elements of drug carriers. In the current study, we evaluated the capacity of an aptamer-based drug carrier to deliver Paclitaxel (PTX) to cancer cells. After being synthesized, SPIONs@PTX-SYL3C aptamer was characterized using different methods, including differential light scattering (DLS), infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), X-ray diffraction (XRD), Thermal gravimetric analysis (TGA), and vibrating sample magnetometer (VSM). Encapsulation efficiency (EE) and loading efficiency (LE) were also evaluated. The carrier was applied on 4T1, MCF 7, and MCF-10A breast cell lines to evaluate its drug delivery potency and specificity. EE and LE were calculated to be 77.6% and 7.76%, respectively. MTT results revealed that aptameric SPIONs@PTX was more toxic than non-aptameric SPIONs@PTX. Flowcytometry analysis and DAPI staining confirmed that SPIONs@PTX-Aptamer had higher cell internalization rate when compared to non-targeted SPIONs@PTX. Our results indicate that aptamer-conjugated SPIONs@PTX has a good capacity in recognizing its target cells and inhibiting their growth and division.

Pistacia atlantica's effect on ovary damage and oxidative stress in streptozotocin-induced diabetic rats.

OBJECTIVE: Diabetes mellitus (DM) is associated with numerous complications, including gonadal dysfunction. There are specific traditional medicine remedies for DM, including medicinal herbs. Our study aimed to evaluate the role of Pistacia atlantica's extract in the protection against ovary damage by streptozotocin (STZ)-induced DM in rats. METHODS: We ran this experimental study on 40 adult female Wistar rats. We divided the animals into five groups, control (A); DM (STZ by 60 mg/kg- intraperitoneally) (B); DM + hexane extract of P. atlantica (200 mg/kg -orally) (C); P. atlantica extract (D) and DM + glibenclamide (200 mg/kg -orally) (F). The experiment continued for four weeks, and we administered the extract daily. After slaughtering the rats, we removed the ovaries. We assessed parameters, such as blood glucose and levels of oxidative stress markers as well as histological ovary structure. RESULTS: Blood glucose, malondialdehyde (MDA) levels, and the number of atretic follicles were elevated; catalase (CAT), superoxide dismutase (SOD) levels and the number of corpora lutea were significantly decreased in the untreated diabetic rats. These changes returned to normal or diminished with P. atlantica extract and glibenclamide in the treated rats. CONCLUSIONS: The extract of P. atlantica has antihyperglycemic and antioxidative properties, and it decreased ovarian complications in experimental diabetes mellitus.

Neuroprotective effects of Ellagic acid against acrylamide-induced neurotoxicity in rats.

Acrylamide (ACR) is an environmental contaminant and a well-known neurotoxin. Ellagic acid (EA), a natural plant polyphenol, has shown a variety of beneficial effects. The present study was designed to explore whether EA could attenuate ACR-induced neurotoxicity in rats and to explore the underlying mechanisms. Animals were divided into five groups. Group 1 was treated with normal saline (2 mL/kg) for 30 days. Group 2 was treated with ACR (20 mg/kg, orally) for 30 days. Groups 3 and 4 were treated with ACR and EA (10 and 30 mg/kg, orally) for 30 days. Group 5 was treated with EA (30 mg/kg, orally) for 30 days. Open field, rotarod and passive avoidance test were conducted to evaluate behavioral changes, respectively. The brain cortex was used for histological examination. Different oxidative parameters and inflammatory biomarkers were assessed in the brain cortex. ACR-administered rats showed a considerable impairment in exploratory behavior, motor performance as well as cognition. Our data also showed that ACR administration significantly increases malondialdehyde, nitric oxide, interleukin-1ß and tumor necrosis factor-α levels. Moreover, it decreases brain glutathione level, superoxide dismutase, glutathione peroxidase, catalase activity. Co-administration of EA (especially 30 mg/kg, p.o.) prevented these changes; however, it did not affect the glutathione peroxidase activity. These results were supported by histopathological observations of the brain. Our results suggest that EA can be useful for protecting brain tissue against ACR-induced neurotoxicity through ameliorative effects on inflammatory indices and oxidative stress parameters.