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Resveratrol (RSV), as a natural polyphenol exhibiting antioxidative properties, is studied in the treatment of neurodegenerative diseases. However, RSV has low oral bioavailability. In this study and in order to overcome the issue, RSV was encapsulated into the solid lipid nanoparticles (SLNs). In this study, RSV‐loaded solid lipid nanoparticles (RSV‐SLNs) were prepared by the solvent emulsification‐evaporation technique, and their physicochemical properties were optimized using Box–Behnken response surface methodology. The morphology of the particles was evaluated using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The neuroprotective effects of the nanoparticles were investigated in animal models using the Morris water maze (MWM). Then after, the rats were sacrificed, their brains were collected, and the extent of lipid peroxidase (LPO) as well as the level of reduced glutathione (GSH) were determined in the hippocampus section samples. Finally, the collected brain tissues were histologically studied. The particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), and drug loading (DL%) of the optimized nanoparticles were 104.5 ± 12.3 nm, 0.322 ± 0.11, −3.1 ± 0.15 mV, 72.9 ± 5.31% and 14.6 ± 0.53%, respectively. The microscopic images revealed spherically shaped and nonaggregated nanoparticles. The in vivo studies demonstrated higher efficiency of RSV‐SLN in the reduction of escape latency time and improvement in the time spent in the target quadrant compared to free RSV. Moreover, it was demonstrated that RSV‐SLN posed a higher potency in the reduction of LPO as well as elevation of the GSH levels in the brain samples. The histological studies revealed a decline in neural degeneration and an improvement in the CA1 pyramidal cell morphology. The obtained data revealed that RSV‐SLNs caused more reduction in Alzheimer‐related symptoms rather than free RSV. [ABSTRACT FROM AUTHOR]

Background: 18KHT01 is a novel synergistic composition of Quercus acutissima, Camellia sinensis, Geranium thunbergii, and a small portion of Citrus limon. Our previous report demonstrated that the 18KHT01 exhibits potent antiobesity effects, with synergistic antioxidant, antiadipogenic, and antiobesity activities in diet‐induced obese mice. This study explores the toxicity profile and quality control parameters of the 18KHT01 formulation. Methods: Broad‐spectrum acute and subacute oral toxicity studies were performed using male and female ICR mice. In order to simultaneous analysis of the 18KHT01 formulation, an ultraperformance liquid chromatography coupled with a diode array detector (UPLC‐DAD) method was developed and validated using six marker compounds. Results: Acute oral toxicity evaluation of 18KHT01, administered at single high doses of 2, 2.5, 3, and 5 g/kg, identified 2 g/kg as the no‐observed adverse effect level (NOAEL). The LD50 (50% lethal dose) and LD100 (100% lethal dose) of 18KHT01 for male ICR mice were 3.99 and 7.77 g/kg, and those for the female mice were 2.94 and 4.70 g/kg, respectively. In addition, a 30‐day repeated dose oral subacute toxicity evaluation indicated that 18KHT01 is safe below 500 mg/kg/day for long‐term administration in ICR mice of either sex. UPLC‐DAD method validation revealed that each calibration curve for the marker compounds showed good linearity, as well as the validation parameters such as precision, specificity, and accuracy met the acceptance criteria. Conclusion: The present study evidenced the toxicological profile of 18KHT01 polyherbal formulation in mice as well as developed a simple, rapid, and accurate chromatographic method for quality control. [ABSTRACT FROM AUTHOR]

Ricinodendron heudelotii is a plant of the Euphorbiaceae family, used in traditional medicine to treat numerous diseases, including high blood pressure. The aim of this study is to evaluate the antioxidant and vasorelaxant effects of the aqueous extract of the stem bark of R. heudelotii. The pharmacological studies were carried out using the aqueous extract obtained by infusion. The antioxidant capacity of R. heudelotii was assessed by in vitro tests with DPPH (2,2‐diphenyl‐1‐picryl‐hydrazyl), ABTS (2,2 ′‐azino‐bis (3‐ethylbenz‐thiazoline‐6‐sulfonic acid), iron‐reducing capacity (FRAP), and inhibition of nitric oxide (NO) release. In vitro studies, the aortic rings obtained from adult Wistar albino rats of both sexes were used to determine the vasorelaxant effects of the extract of R. heudelotii on the NO and prostacyclin (PGI2) pathways as well as its involvement on various potassium channels were determined on intact or naked fragments of rat aorta precontracted with phenylephrine (10-6 M) or KCl (60 mM). The aqueous extract of R. heudelotii exhibited a remarkable DPPH (EC50: 1.68 μg/mL) and ABTS (EC50: 106.30 μg/mL) and nitric oxide (53.71% inhibition at 1000 μg/mL) radical scavenging activities as well as reducing power (absorbance of 1.56 at 1000 μg/mL). The nitric oxide inhibitor, NG‐nitro‐L‐arginine methyl ester (L‐NAME), and prostacyclin inhibitor, indomethacin, significantly attenuated the vasodilatory effect of R. heudelotii. Tetraethylammonium could not inhibit the vasodilatory effect of the extract, unlike glibenclamide and barium chloride. Ricinodendron heudelotii extract possesses antioxidant properties and vasorelaxing effect linked to endothelium‐related factors, and this relaxation was partially mediated mainly through the inhibition of Kir and KATP channels. [ABSTRACT FROM AUTHOR]

This study sought to examine the effects of systemic ozone (O3) treatment on the healing of skin wounds induced on the dorsal surface of Wistar rats. The skin wounds were created using a 10 mm round punch following the sagittal medial plane in 72 rats. Then, the animals were randomly assigned to four groups, each receiving the following treatments: group C, which did not undergo treatment with the O3/O2 mixture; group OZ0.3, administered the O3/O2 mixture at a dose of 0.3 mg/kg; group OZ0.7, given the O3/O2 mixture at a dose of 0.7 mg/kg; and group OZ1.0, provided with the O3/O2 mixture at a dose of 1.0 mg/kg. Six animals from each group were euthanized at 7, 14, and 21 days postoperatively. Clinical, histological, histometric, and immunohistochemical (IHC) analyses were accomplished. Data from clinical and histometric assessments revealed that OZ0.7 and OZ1.0 demonstrated more favorable healing, with greater wound contraction observed in the OZ1.0 group at 14 and 21 days. Histologically, the OZ1.0 group exhibited aspects consistent with an accelerated tissue repair process. IHC analysis revealed greater vascular endothelial growth factor (VEGF) immunostaining in the OZ0.7 (7 days) and OZ1.0 (7 and 14 days) groups compared to the C group. Expression of transforming growth factor beta‐1 was significantly increased in the OZ0.7 (14 days) and OZ1.0 (7 and 14 days) groups compared to the C group. In conclusion, our data suggest that systemic use of O3 enhanced tissue repair in cutaneous wounds in a dose‐dependent manner, with concentrations of 1.0 mg/kg providing the most beneficial effects. Furthermore, the results of this study implicate the use of O3 for the treatment of skin wounds aiming at improving the healing process over time. Our findings suggest the use of O3 as a viable alternative to enhance wound healing and repair. [ABSTRACT FROM AUTHOR]

Objective(s). Given the increasing rate of methicillin‐resistant Staphylococcus aureus (MRSA) resistance to antibiotics, the use of plant‐based antimicrobials to treat the infection has been considered. This study is aimed at evaluating the effect of Myrtus communis leaf extract ointment and silver nanoparticles on the healing of burn wounds caused by MRSA in rats. Materials and Methods. In a research experiment, 48 male Wistar rats were anesthetized and second‐degree burns were induced on their backs. The rats' wounds were then uniformly inoculated with MRSA. Various treatments were applied to the burn wounds daily, including Myrtus ointment, silver nanoparticles, silver nanoparticles‐Myrtus ointment, silver sulfadiazine‐Myrtus ointment, silver sulfadiazine 1%, mupirocin ointment, and a positive control. The study measured the antimicrobial effects, wound area, percentage of wound healing, antioxidant capacities, malondialdehyde, and nitric oxide concentrations in the serum of the rats. Data analysis was performed using GraphPad software, with one‐way ANOVA and Tukey's tests used to determine the statistical significance of the results. Results. Rats treated with Myrtus ointment, silver nanoparticles‐Myrtus ointment, and mupirocin had reduced bacterial growth compared to the positive control group, nanoparticle ointment, and silver sulfadiazine (P < 0.05). The wound area of the Myrtus ointment group decreased significantly on the seventh and fourteenth days, as well as the level of MDA and nitric oxide, compared to the other groups. In Myrtus and silver sulfadiazine‐Myrtus ointment increased the thickness of the epidermis and dermis compared to the other groups. Conclusion. Based on the anti‐inflammatory, antimicrobial, and wound healing properties of Myrtus, with further studies, an ointment of this plant may be used as a main or complementary treatment for burn wound infections caused by MRSA. [ABSTRACT FROM AUTHOR]

Introduction. PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2 diabetes mellitus (T2DM). A potential connection between T2DM and PPIs could be an elevated gastrin concentration. This study is aimed at investigating the long-term effects of PPI omeprazole (OZ) on glucose homeostasis and pancreatic gene expression profile in mice. Methods. Healthy adult male BALB/c mice were randomly divided into three equal groups (n = 10 in each one): (1) experimental mice that received OZ 20 mg/kg; (2) control mice that received 30 μl saline per os; (3) intact mice without any interventions. Mice were treated for 30 weeks. Glucose homeostasis was investigated by fasting blood glucose level, oral glucose tolerance test (GTT), insulin tolerance test (ITT), and basal insulin resistance (HOMA-IR). Serum gastrin and insulin concentration were determined by ELISA. Expressions of Sirt1, Pparg, Nfκb1 (p105), Nfe2l2, Cxcl5, Smad3, H2a.z, and H3f3b were measured by RT-PCR. Result. The ROC analysis revealed an increase in fasting blood glucose levels in OZ-treated mice in comparison with control and intact groups during the 30-week experiment. A slight but statistically significant increase in glucose tolerance and insulin sensitivity was observed in OZ-treated mice within 30 weeks of the experiment. The mice treated with OZ exhibited significant increases in serum insulin and gastrin levels, accompanied by a rise in the HOMA-IR level. These animals had a statistically significant increase in Sirt1, Pparg, and Cxcl5 mRNA expression. There were no differences in β-cell numbers between groups. Conclusion. Long-term OZ treatment induced hypergastrin- and hyperinsulinemia and increased expression of Sirt1, Pparg, and Cxcl5 in mouse pancreatic tissues accompanied by specific changes in glucose metabolism. The mechanism of omeprazole-induced Cxcl5 mRNA expression and its association with pancreatic cancer risk should be investigated. [ABSTRACT FROM AUTHOR]

This study accessed the potential antimalarial activity of triterpene glycoside of H. atra through targeting orotidine 5-monophosphate decarboxylase protein (PfOMPDC) in P. falciparum by molecular docking. Nine triterpene glycosides from H. atra extract modeled the structure by the Corina web server and interacted with PfOMPDC protein by using Hex 8.0.0. The docking results were visualized and analyzed by Discovery Studio version 21.1.1. 17-Hydroxyfuscocineroside B showed the lowest binding energy in PfOMPDC interaction, which was -1,098.13 kJ/mol. Holothurin A3, echinoside A, and fuscocineroside C showed low binding energy. Nine triterpene glycosides of H. atra performed interaction with PfOMPDC protein at the same region. Holothurin A1 posed interaction with PfOMPDC protein by 8 hydrogen bonds, 3 hydrophobic interactions, and 8 unfavorable bonds. Several residues were detected in the same active sites of other triterpene glycosides. Residue TYR111 was identified in all triterpene glycoside complexes, except holothurin A3 and calcigeroside B. In summary, the triterpene glycoside of H. atra is potentially a drug candidate for malaria therapeutic agents. In vitro and in vivo studies were required for further investigation. [ABSTRACT FROM AUTHOR]

Background. Rattus norvegicus (R. norvegicus) population plays a significant role in the spread of numerous diseases in urban environments. The present study is aimed at investigating the presence of Campylobacter jejuni (C. jejuni), C. coli, Clostridium difficile (C. difficile), C. difficile toxigenic, and C. perfringens in R. norvegicus captured from urban areas of Tehran, Iran. Methods. From October 2021 to October 2022, 100 urban rats were trapped in 5 different districts of Tehran, Iran. The genomic DNA was extracted from fecal samples, and the presence of C. jejuni, C. coli, C. perfringens, and C. difficile species was evaluated using PCR assay. Moreover, PCR was used to assess the toxicity of C. difficile isolates. Results. Overall, 30% (n = 30 / 100) of fecal samples were positive for zoonotic pathogens. Based on the PCR on hippuricase (hipO), glycine (gly), CIDIF, and phospholipase C (plc) genes, C. perfringens and C. difficile were isolated from 18.2% (n = 14 / 77) and 5.2% (n = 4 / 77) of male rats. The highest frequency of C. perfringens and C. jejuni was 25% (n = 5 / 20) related to the south of Tehran. Toxigenic C. difficile was not detected in all regions. Conclusion. According to the findings, rats are the main reservoirs for diseases. Therefore, rodent control coupled with the implementation of surveillance systems should be prioritized for urban health. [ABSTRACT FROM AUTHOR]

Background. Premature infants are exposed to numerous stressors in neonatal intensive care unit (NICU) during a crucial period for brain development; this period exerts long-term influences on cognitive and behavioral development. Aims. To evaluate the effect of NICU-related stress on neonatal rat pups and explore the effect of Chinese medicine treatment (CMT). Methods. Sixty male rat pups were randomly assigned to three groups: the control group, the NICU group (NICU-related stress), and the CMT group (NICU-related stress plus CMT). All stressors and interventions were administered from 0 to 7 days after birth. Body weight, serum corticosterone levels, and behavior in the open field (OF) test, elevated plus maze (EPM) test, sucrose preference test, and Morris water maze (MWM) test were recorded, and blood samples were collected at five different time points (T0, T1, T2, T3, and T4). Results. The body weights of rats in the CMT and control groups were heavier than those in the NICU group in both early life and adulthood (P < 0.05). Serum corticosterone levels significantly differed with time (except T0 vs. T1 and T3 vs. T4) but did not significantly differ among the three groups (F = 0.441 , P = 0.894). Regardless of age, spatial memory and anxiety-like and depression-like behavior did not differ among the three groups. Conclusion. NICU-related stress exerted a long-term effect on rat growth and development but did not affect spatial memory, anxiety-like behavior, depression-like behavior, or serum corticosterone levels. CMT alleviated the impact of NICU-related stress on rats and promoted the growth and development of neonatal rats. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that controls chloride current. A number of different CFTR transgenic mouse lines have been developed and subjected to both acute and chronic infection models. However, prior studies showed no substantial differences in bacterial clearance between CF and non-CF mice after single inoculations. Here, using F508del transgenic CF mice, we examined the role of repeated acute Pseudomonas aeruginosa (PA) infection, with the second inoculation 7 days after the first. We found that CF mice were more susceptible to PA infection than non-CF mice following the second inoculation, with non-CF mice showing better neutrophil recruitment and effector functions. We further investigated the characteristics of lung immune cells using single-cell RNA sequencing, finding that non-CF lung neutrophils had more prominent upregulation of adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) compared to CF lung neutrophils. Although people with CF are often colonized with bacteria and have high numbers of neutrophils in the airways during chronic infection, these data suggest that CF neutrophils have deficient effector functions in the setting of repeated acute infection. [ABSTRACT FROM AUTHOR]

Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an incurable debilitating disease which attacks the joints and impairs quality of life. Antrocaryon micraster is used to treat RA in African traditional medicine. However, its antiarthritic activity has not been pharmacologically studied. This study, therefore, reports the antiarthritic and antioxidant activities of A. micraster seed extract and its fractions. The seed extract (ASE) was produced by Soxhlet extraction and partitioned into petroleum ether (ASEP), ethyl acetate (ASEE), and aqueous (ASEA) fractions. The total polyphenolic content, DPPH antioxidant activity, and in vitro arthritic activity using the protein denaturation assay were evaluated for ASE and its fractions. The arthritic activity of the crude extract (ASE) and its most effective fraction (ASEA), in the in vitro assay, were then evaluated against CFA-induced arthritis in rats. The polyphenolic constituent of ASE was estimated to be 13.00 ± 0.00 mg/100 mg of GAE. ASEA contained the highest quantity of polyphenolic constituents (10.76 ± 0.00 mg/100 mg of GAE) among the fractions of the extract. ASE and ASEA produced profound antioxidant activity (I C 50 = 20.17 ± 1.291 and 19.35 ± 0.865 , respectively) which were similar to that of ascorbic acid (I C 50 = 17.35 ± 0.500) in the DPPH free radical scavenging assay. Furthermore, in vitro antiarthritic activity of ASEA was 13.63 and 5.75 times higher than the antiarthritic activity of the crude extract and diclofenac sodium, respectively. In the CFA-induced arthritis assay, both ASE and ASEA significantly (P < 0.001) inhibited cachexia, paw edema, infiltration of inflammatory cells, pannus formation, and synovium damage. These results indicate that A. micraster seed extract and its fractions possessed significant antiarthritic activity via inhibition of oxidative stress, inflammation, protein denaturation, infiltration of inflammatory cells, and synovium injury due to its constituents such as polyphenols and phytosterols. [ABSTRACT FROM AUTHOR]

Aim. The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n = 6). Periodontal bone resorption volumes were calculated for each group (nonligated–ligated), and the ratio of bone volume to tissue volume was measured. Results. Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion. Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation. [ABSTRACT FROM AUTHOR]

Background. Traditional herbal medicine practitioners in the Ashanti region of Ghana use the fruit peels of Citrus limon (L.) Osbeck (C. limon) in preventive and curative treatment of many cancers including liver cancer. This ethnobotanical claim remains to be verified scientifically. Aim of the Study. This study investigated prophylactic hepatoprotective and anti-HCC effects of C. limon peel extract (LPE) in CCl4/olive oil-induced HCC-like rats. Materials and Methods. After preparation of LPE, it was subjected to phytochemical screening using standard phytochemical methods. A total of 30 healthy adult male Sprague-Dawley rats (weighing 150-200 g) were randomly assigned into six groups of 5 rats each. Rats in the control group received olive oil (5 mL/kg ip) twice weekly for 16 weeks. Rats in the model group received CCl4/olive oil (2 mL/kg, ip) twice weekly for 16 weeks. Rats in capecitabine (10 mg/kg po) and LPE (50, 100, and 200 mg/kg po) groups received CCl4/olive oil (2 mL/kg, i.p) in the morning and their respective treatments in the afternoon twice a week for 16 weeks. Rats in all groups had free access to food and water ad libitum. Body weight and survival rates were monitored. Rats were sacrificed under deep anesthesia, blood was collected, and liver and other organs were isolated. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), prothrombin time, bilirubin, C-reactive protein (CRP), alpha- (α-) fetoprotein (AFP), and liver histology were assessed. Results. Alkaloids, tannins, flavonoids, terpenoids, and saponins were detected in LPE. Model rats demonstrated increased serum levels of AFP, CRP, ALP, GGT, ALT, and AST, prothrombin time, total bilirubin, direct bilirubin, blood lymphocyte, and monocyte counts, but decreased serum albumin and total protein compared to control rats. Unlike the control, model rats demonstrated fat accumulation in periportal and centrilobular hepatocytes and neoplastic transformation. Semiquantitation of periodic acid Schiff- (PAS-) stained liver sections showed decreased glycogen storage in hepatocytes of model rats compared to control rats. Compared to the model, LPE treatment protected against CCl4-induced hepatocarcinogenesis, which was evidenced by decreased AFP, CRP, liver enzymes, total and direct bilirubin, prothrombin time, and blood lymphocyte and monocyte counts; attenuation of fat accumulation; and increased glycogen storage, albumin, and total protein. Conclusion. LPE abates CCl4-induced hepatocarcinogenesis by attenuating liver inflammation and improving metabolic, biosynthetic, and detoxification functions of the liver. The prophylactic hepatoprotective and anti-hepatocarcinogenic effects of LPE are attributable to its phytochemical composition raising hopes of finding potential anticancer bioactive compounds from C. limon fruit peels. [ABSTRACT FROM AUTHOR]

The Barnes maze, a well-known spatial-learning paradigm, is based on the innate fear of rodents of large open spaces and their drive to hide. However, additional aversive stimuli (strong light and threatening sounds) are often necessary to provoke the hiding response while rendering the method cumbersome and more stressful. Our objective was to establish a Barnes maze-learning paradigm in mice using palatable food as a reward. After habituating male C57BL6/J or NMRI mice to the reward, the experimenter and the apparatus, either a slow (2 trials/day) or a massive conditioning schedule (4 trials/day), was run. Acquisition training was carried out until mice could locate the reward box with a maximum of one hole error. Then, the box was replaced to another location (reversal phase). Mice needed to relearn the new position with the same criterion. One week later, retention trials were performed. Both strains could reach the learning criteria; in the massive training within a shorter period. Spatial memory was demonstrated in the reversal and retention trials. Our results show that palatable food can be used as an efficient motivator to acquire allocentric navigation in the Barnes maze with the additional advantage of being less stressful. [ABSTRACT FROM AUTHOR]

The Kir4.1 channel, an inwardly rectifying potassium ion (K+) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K+ homeostasis in supporting cells, with K+ concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient. [ABSTRACT FROM AUTHOR]

Peganum harmala L. and Lavandula angustifolia are two traditional herbs with probable antiseizure effects. This study evaluated the effects of these two herbal extracts on pentylenetetrazol- (PTZ-) induced seizures in mice. We prepared hydroalcoholic extracts using P. harmala seeds and the aerial parts of L. angustifolia and then randomly divided 190 mice into 19 groups. Normal saline (10 mg/kg), diazepam (2 mg/kg), P. harmala (2.5, 5, 10, 15, 30, 45, and 60 mg/kg), and L. angustifolia (200, 400, 600, and 800 mg/kg) were intraperitoneally (IP) administrated 30 min before an IP administration of PTZ (90 mg/kg). Animals were observed for behavioral changes for one hour. In addition, the effects of flumazenil and naloxone on the antiseizure activity of P. harmala and L. angustifolia were assessed. P. harmala showed antiseizure activity at the dose of 10 mg/kg; it prolonged the seizure latency and decreased the seizure duration. The mortality protection rate was 90% for this herbal extract. L. angustifolia (600 mg/kg) prolonged the seizure latency and decreased both seizure duration and mortality. Neither flumazenil nor naloxone significantly reversed the antiseizure activities of P. harmala and L. angustifolia. In mice, the hydroalcoholic extracts of P. harmala and L. angustifolia showed antiseizure activity against PTZ-induced seizures. We could not delineate the exact antiseizure mechanisms of these extracts in the current study. [ABSTRACT FROM AUTHOR]

Goldenberry (GB) is a promising fruit that can be a constituent in many possible nourishments. No notifications were obtained regarding the impact of exposure to goldenberry extract in the viewpoint of blood rheological properties as well as erythrocyte osmotic fragility of red blood cells (RBCs) in obese rats. A substantial reduction in plasma triglyceride, total cholesterol, and LDL, with a considerable increment in HDL levels relative to the obese group (p ≤ 0.05), was observed in rats receiving low and high doses of GB, accompanied by restoration of SOD activity and GSH levels. Rheological parameters of rats' blood have been studied over a wide range of shear rates (225–1875 s–1). A significant decrease in blood viscosity in rats who received low and high doses of GB extract was compatible with every shear rate compared to the control group. The shear stress values of the obese rats reduced appreciably (p ≤ 0.05) in all values of shear rate (from 75 to 500 s-1) proportional to the control group, while in the groups that received low and high doses of GB extract, shear stress was restored to the control values. Finally, administration of GB extract significantly decreased yield stress and indices of whole blood aggregation, with an extremely substantial increment in flow rate, in rats given low or high doses of GB compared to obese ones. The result also showed a decrease in both the average raised osmotic fragility and the hemolysis rate in rats after supplementation with low and high doses of GB extract. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E2 (PGE2), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE2 induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8+ T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8+ T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8+ T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy. [ABSTRACT FROM AUTHOR]

Introduction. Helicobacter pylori (H. pylori) induces gastritis by stimulating Th17 cells and related cytokines. The aim of our study was to investigate the synergistic effect of metformin with amoxicillin as an antibiotic in inhibiting H. pylori and modulating the immune response in a rat model. Methods. Forty-five male Sprague-Dawley rats were divided into seven groups and infected with H. pylori. Over the course of 14 days, all animals were treated with metformin and amoxicillin alone and in combination. The antibacterial activity of metformin was evaluated by growth curves and colony counts. The immunoregulatory effect on Treg/Th17 balance was assessed by flow cytometry, and the cytokine profile of IL-17A, IL-1β, IL-6, IL-8, TGF-β, and IL-10 was determined by ELISA. The effect of metformin on gene expression of cagA and IL-8 was investigated by RT-PCR. Pathological changes were assessed by hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining. Results. Metformin showed weak antibacterial activity against clinically isolated H. pylori. However, the combination of metformin and amoxicillin (AMX) showed strong synergistic antibacterial activity (Σ FIC = 0.24). Compared with AMX, metformin reduced inflammation and tissue damage but resulted in increased bacterial growth. During metformin administration, both TGF-β levels and Treg cells increased dramatically (P = 0.002). In synergy with AMX, metformin decreased the effective dose of antibiotic to eradicate H. pylori. Conclusions. The combination of metformin with potential antibiotics such as AMX had a positive effect on the relief of H. pylori-related inflammation by inducing Treg cells while successfully eliminating H. pylori. [ABSTRACT FROM AUTHOR]

Purpose. To investigate whether ADSC-derived miR-23-enriched exosomes could protect against calcium oxalate stone formation in a hyperoxaluria rat model. Methods. An ethylene glycol- (EG-) induced hyperoxaluria rat model and an in vitro model of COM-induced HK-2 cells coculturing with RAW264.7 cells were established to explore the protective mechanisms of ADSC-derived miR-23-enriched exosomes. Results. The results showed that treatment with miR-23-enriched exosomes from ADSCs protected EG-induced hyperoxaluria rats, and cell experiments confirmed that coculturing with miR-23-enriched exosomes alleviated COM-induced cell autophagy. Overexpressed miR-23 suppressed M1 macrophage polarization by inhibiting IRF1 expression. Furthermore, the predicted binding site between the IRF1 messenger RNA 3 ′ -untranslated region (3 ′ -UTR) and miR-23 was confirmed by the dual-luciferase reporter assay. Conclusion. In conclusion, our research gave the first evidence that ADSC-derived miR-23-enriched exosomes affected the polarization of M1 macrophages by directly inhibiting IRF1 and protecting against calcium oxalate stone formation in a hyperoxaluria rat model. [ABSTRACT FROM AUTHOR]

The present study is aimed at investigating the long-term effects of the aluminum hydroxide administration in the small intestine, lung, liver, and kidney of male BALB/c mice. The mice received via orogastric gavage phosphate buffered or 10 mg/kg aluminum hydroxide 3 times a week for 6 months. Administration of aluminum hydroxide decreased hemoglobin, hematocrit, and erythrocyte. In the blood, kidney and liver function markers were evaluated, and long-term administration of aluminum hydroxide led to an increase in AST levels and a decrease in urea levels. The animals exposed to aluminum showed higher lipid and protein oxidation in all the organs analyzed. In relation to the enzymes involved in antioxidant defense, the lungs showed lower superoxide dismutase (SOD) and catalase activity and a lower reduced and oxidized glutathione (GSH/GSSG) ratio. In the liver, aluminum administration led to a decrease in catalase activity and the GSH/GSSG ratio. Lower catalase activity was observed in the small intestine, as well as in the lungs and liver. In addition to alterations in antioxidant defense, increased levels of the chemokine CCL-2 were observed in the lungs, lower levels of IL-10 in the liver and small intestine, and decreased levels of IL-6 in the intestine of the animals that received aluminum hydroxide for 6 months. Long-term exposure to aluminum promoted steatosis in the liver. In the kidneys, mice treated with aluminum presented a decreased glomerular density than in the naive control group. In the small intestine, exposure caused villi shortening. Our results indicate that long-term oral administration of aluminum hydroxide provokes systemic histological damage, inflammation, and redox imbalance. [ABSTRACT FROM AUTHOR]

Background. Emergence of Plasmodium resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need for the development of new and effective antimalarial agents. Senna occidentalis (L.) link extract has exhibited in vitro antiplasmodial activity in many pharmacological studies. To our knowledge, data on its in vivo antimalarial efficacy is still very limited. A recent study demonstrated that polar extracts from the plant roots inhibit Plasmodium berghei proliferation in a mouse model. This study further describes the efficacy and safety of a methanolic root extract of the plant as an antimalarial agent by demonstrating its effect on hematological, biochemical, and histological parameters of Plasmodium berghei-infected BALB/c mice. Methods. Rane's test, a curative approach, was used to evaluate the antimalarial efficacy of Senna occidentalis methanolic root extract in Plasmodium berghei-infected BALB/c mice. The effect of the extract on both hematological and biochemical parameters was evaluated using automated analyzers. Kidney, liver, lung, spleen, and brain tissues were harvested from euthanized mice and examined for changes in organ architecture. Results. This study demonstrates that methanolic root extract of Senna occidentalis significantly inhibited Plasmodium berghei parasitemia in BALB/c mice (p < 0.01). Infected mice that were treated with the extract depicted a significantly low level of total leucocytes (p < 0.01), red blood cell distribution width (p < 0.01), and a significantly high hemoglobin concentration (p < 0.001) compared to the infected animals that were administered with the vehicle only. The infected animals that were treated with the extract exhibited a significantly low level of urea, creatinine, bilirubin, and alkaline phosphatase (p < 0.05), compared to the infected animals that were given the vehicle only. The level of sodium, potassium and chloride ions, lymphocytes, granulocytes, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein, albumin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total platelets, mean platelet volume (MPV), and platelet distribution width of the infected animals treated with the extract was not significantly different from those of the infected animals that were given the vehicle only (p > 0.05). The extract alleviated organ pathological changes in the infected mice. The extract did not induce any remarkable adverse effect on the growth, hematological, and biochemical parameters of uninfected animals (p > 0.05). In addition, administration of the extract did not alter the gross appearance and histological architecture of the organs, implying that the extract was well tolerated in mice. Conclusions. Senna occidentalis methanolic root extract exhibited good antimalarial activity against Plasmodium berghei and may be safe in mice. [ABSTRACT FROM AUTHOR]

Tramadol abuse is a common problem in the Middle East in conjunction with smoking. The current study applied immunohistochemistry, western blot, real-time PCR, and ELISA to test the combination toxicity. Low toxic doses of tramadol induced animal brain cortex inflammation and hippocampus injury. Adding nicotine reverted hippocampus pathological changes without triggering marked brain injury. The expression of CHOP protein with real-time PCR showed mild endoplasmic reticulum stress (ER) in rat's brain. Histological, immunohistochemical, and western blotting analysis of CHOP (CCAAT-enhancer-binding protein homologous protein) and BIP (immunoglobulin heavy chain-binding protein) chaperones demonstrated endoplasmic reticulum stress in the brains of animals. Furthermore, the levels of apoptosis and autophagy markers demonstrated a mild reaction. The blood level of serotonin was high in all study groups, with a marked increase in the combined one. The high serotonin levels in the blood can be critical and associated with a high risk of serious withdrawal and pathological consequences. Serotonin receptor blockers such as olanzapine may increase systemic serotonin levels and need further investigation to utterly pinpoint their roles in managing mood disorders. In conclusion, the combination of tramadol and nicotine is less harmful than expected. However, serious withdrawal effects can occur as a result of high systemic serotonin effects. [ABSTRACT FROM AUTHOR]

The anti-dementia effect following ischemic stroke with metabolic syndrome (MetS) of the polyherbal functional ingredient comprising ginger, Chinese date, and wood ear mushroom (GCJ) was hypothesized due to its neuroprotective effect against stroke. This study was performed to test this hypothesis and to explore the underlying mechanism. Male Wistar rats weighing 180-220 g were induced metabolic syndrome (MetS) with a 16-week high-carbohydrate high-fat diet (HCHF) feeding. The rats with MetS characteristics were orally administered GCJ at various doses (GCJ100, GCJ200, and GCJ300 mg kg-1 BW) 21 days pre-induction and 21 days post-induction of reperfusion injury (I/R) at the right middle cerebral artery (MCAO). Memory was evaluated every 7 days during the study period. At the end of the study, neuron density, AChE activity, and the expressions of eNOS, BDNF, and pERK/ERK in the prefrontal cortex, and hippocampus were also determined. MetS rats with GCJ treatment improved memory impairment, enhanced neuron density, and increased the expressions of eNOS, BDNF, and pERK/ERK but suppressed AChE in both areas. Therefore, the anti-dementia effect following ischemic stroke with metabolic syndrome of GCJ may involve the improvement of AChE, eNOS, BDNF, pERK/ERK, and neural plasticity. However, this required confirmation by clinical study. [ABSTRACT FROM AUTHOR]

Background and Objective. Studies have shown that physical activity not only reduces cardiovascular risk factors but also improves cardiac protection against ischemia-reperfusion. One of the protective pathways of the heart against ischemia is mitochondrial function protection, and the role of exercise preconditioning in this mechanism is important. We investigated the exercise pretraining on mitochondrial biogenesis effect, angiogenesis, and cardiac tissue injury in male rats following stroke. Materials and Methods. Twenty-four male rats were divided into 4 groups including MI, Sham, HIIT, and HIIT+MI (N = 6). HIIT and HIIT+MI which underwent high-intensity interval training (HIIT) for 4 weeks (5 days a week). The training protocol included 10 intervals of 1-minute running, with 2 minutes rest between each interval. The training intensity was different every week according to the peak treadmill running speed (v peak) percentage of each rat. Isoproterenol injection was used to induce myocardial infarction (MI). Expressions of creatine kinase-MB (CK-MB), PGC-1α troponin-I, mitochondrial transcription factor A (TFAM), vascular endothelial growth factor (VEGF), and microRNA 126 (miR-126) genes were measured. The variables were measured using biochemical and RT-PCR methods. The significance level (P value≤0.05) was analyzed using ANOVA test. Results. The results showed that 4 weeks of HIIT training led to a significant increase in PGC-1α, TFAm, and VEGF levels in the MI, HIIT, and HIIT+MI groups compared to the sham group (P = 0.001). HIIT exercises increased miR-126 in the different groups compared to the sham group; however, it was not significant. Conclusion. The results obtained showed that HIIT exercise exerts cardio-protective effects to reduce cardiac tissue injury and necrosis against MI. These effects increase mitochondrial biogenesis and angiogenesis by inducing the increased expression of VEGF, TFAM, PGC-1α, and miR-126 genes in the heart tissue. Therefore, HIIT training, as a preconditioning program, was able to protect the cardiac tissue against MI. [ABSTRACT FROM AUTHOR]

Current approaches are incurable for rheumatoid arthritis (RA). Regulatory T (Treg) cells and T helper cells (Th1 and Th17) are crucial in controlling the process of RA, which is characterized by inflammatory cell infiltration and bone destruction. Carnosol is an orthodiphenolic diterpene that has been extensively applied in traditional medicine for the treatment of multiple autoimmune and inflammatory diseases. Herein, we indicate that administration of carnosol dramatically alleviated the severity of collagen-induced arthritis (CIA) model with a decreased clinical score and inflammation reduction. Cellular mechanistically, carnosol inhibits the Th17 cell differentiation and maintains Treg cell suppressive function in vitro and in vivo. Meanwhile, it also restrains Treg cells from transdifferentiation into Th17 cells under inflammatory milieu. Furthermore, carnosol modulates the function of Th17 and Treg cells possibly via limiting IL-6R (CD126) expression. Collectively, our results suggest that carnosol can alleviate the severity of CIA via hiding Th17 cell differentiation and maintain the stability of Treg cells. Administration of carnosol can be applied as a potential therapy for patients with RA. [ABSTRACT FROM AUTHOR]

Background. Both high-fat diet (HFD) and 4-nonylphenol (4-NP) could affect fat formation in adipose tissue individually. We investigated whether HFD promote abnormal adipose tissue formation caused by early exposure to 4-NP in life and preliminarily explore the possible mechanisms involved. Methods. The first-generation rats were treated with HFD on postnatal day after pregnant rats exposure to 5 ug/kg/day 4-NP. Then, the second generation rats started to only receive normal diet without 4-NP or HFD. We analyzed organ coefficient and histopathology of fat tissues, biochemical index, and gene level involved in lipid metabolism in female offspring rats. Results. HFD and 4-NP interaction synergistically increased birth weight, body weight, and organ coefficients of adipose tissue in offspring female rats. HFD accelerately aggravated abnormal lipid metabolism and increased the adipocyte mean areas around the uterus of the offspring female rats induced by prenatal exposure to 4-NP. HFD also facilitate the regulation of gene expression involved lipid metabolism in offspring female rats induced by perinatal exposure to 4-NP, even passed on to the second generation of female rats. Moreover, HFD and 4-NP interaction synergistically declined the gene and protein expression of estrogen receptor (ER) in the adipose tissue of second-generation female rats. Conclusion. HFD and 4-NP synergistically regulate the expression of lipid metabolism genes in adipose tissue of F2 female rats and promote adipose tissue generation, leading to obesity in offspring rats, which is closely related to low expression of ER. Therefore, ER genes and proteins may be involved in the synergistic effect of HFD and 4-NP. [ABSTRACT FROM AUTHOR]

Angiogenesis is crucial to the development of cancer because it allows the transport of oxygen, nutrients, and growth factors as well as the spread of tumors to distant organs. Inhibitors of angiogenesis prevent the formation of blood vessels that allow tumor cells to shrink, rather than promote tumor growth. Chitosan acts as a carrier for many drugs, since the compound has various properties such as biodegradable, less toxicity, more stable, simple, easy to prepare, and biocompatible. The aim of the current study was to evaluate the efficacy of chitosan nanoparticles encapsulated with troxerutin (Chi-Trox NPs) against angiogenesis and cancer in ova chick chorioallantoic membrane (CAM) model. Chi-Trox NPs were synthesized using a nanoprecipitation method and were characterized by various analyses. 24 hours' fertilized eggs (6 eggs/group) were treated with native Trox and Chi-Trox NPs for 5 days. The antiangiogenic activity was evaluated by morphometric, histopathological, immunohistochemical (CD104 and vimentin), and mRNA expression of MMP and FGF2 using RT-PCR. The anticancer activity was evaluated by histopathological, immunohistochmical (CD44), and mRNA expression of FGF2 and MMP. The synthesized chitosan NPs were successfully encapsulated with troxerutin, and the loading efficiency of chitosan NPs was found to be 86.4 ± 0.12 % and 13.2 ± 0.16 % respectively. Morphometric analysis of Chi-Trox NPs showed a considerable decrease in the number of blood vessels compared with control and native Trox. The histopathological observation of CAM confirmed that Chi-Trox NPs induce a significant reduction in inflammatory cells and the thickness of blood capillaries compared to control and native Trox. The immunohistochemical evaluation of CAM revealed Chi-Trox decreased CD104, vimentin and CD44 protein levels were compared with control and native Trox. Furthermore, the mRNA expression levels of FGF2 and MMP were significantly downregulated compared to their native forms. From the obtained results, Chi-Trox NPs possess significant inhibition of angiogenesis and can be used as therapeutic agents for cancer in the future. [ABSTRACT FROM AUTHOR]

Background. In the present work, we investigated the effect of exogenous glutathione in old rats on the expression of ATP-sensitive potassium (KATP) channels, the mitochondrial permeability transition pore (mPTP) opening in the heart, and the vasorelaxation responses of isolated aortic rings to activation of KATP channels. Methods. Experiments were performed on adult (6 months) and old (24 months) male Wistar rats, which were divided into three groups: adult, old, and glutathione-treated old rats. Glutathione was injected intraperitoneally at a dose of 52 mg/kg 1 hour before the studies. The mRNA expression of KATP channels was determined using reverse transcription and real-time polymerase chain reaction analysis. The effect of glutathione administration on mPTP opening, relaxation responses of isolated aortic rings, and oxidative stress markers was studied. Results. It was shown that the expression levels of Kir6.1, Kir6.2, and SUR1 subunits of KATP channels and levels of reduced glutathione were significantly increased in glutathione-treated old rats (by 8.3, 2.8, 13.1, and 1.5-fold, respectively), whereas the levels of oxidative stress markers (hydrogen peroxide, diene conjugates, malondialdehyde, and rate of superoxide generation) in heart mitochondria and mPTP opening were significantly reduced. Relaxation of aortic rings was significantly increased in response to the actions of KATP channel openers flocalin and pinacidil in glutathione-treated animals, which was prevented by glibenclamide. Conclusions. Thus, the administration of exogenous glutathione to old rats resulted in a significant increase in the expression levels of the Kir6.1, Kir6.2, and SUR1 subunits of KATP channels and a decrease in oxidative stress. This was accompanied by inhibition of mPTP opening and enhancement of vasorelaxation responses to activation of KATP channels. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF) is a major natural antimicrobial agent secreted in body fluids as a natural innate immunity protein. The action and structure of LF are closely related to its iron-binding capacity with structural reporting in open and closed conformations. This study looked at how lactoferrin structures change in camel (cLF), bovine (bLF), and human (hLF) lactoferrin closed forms after iron is removed from their binding sites. Initially, the sequence comparison between cLF and the LFs of marine mammals, bats, and domestic animals was the most intriguing conclusion. Camel LF is revealed to be more closely related to marine animals (~80.36% identity) and bats (~79.3% identity) than to terrestrial mammal species (~75.5% identity). Results indicated that cLF was more dynamic in nature than bLF and hLF by showing higher RMSD values. The cLF is known to be half lactoferrin half transferrin; in this study, we show that there are different MD behavior of both iron-binding sites. While LF contains two lobes (C- and N-lobes), the C-lobe showed high fluctuations as N-lobe was more stable in the absence of ferric ions. The C-lobe and N-lobe of cLF react differently at physiological pH, revealing distinct molecular interactions between these components. In addition, cLF showed higher system flexibility derived from its larger RMSD, RMSF, lower intermolecular hydrogen bonds, and higher solvent accessible surface area (SASA). [ABSTRACT FROM AUTHOR]

Clostridioides (Clostridium) difficile (C. difficile) is one of the essential enteropathogens in humans and livestock and is a severe health threat, according to the Centre for Disease Control and Prevention. Also, antimicrobials are one of the most critical risk factors for C. difficile infection (CDI). The present study examined the infection, antibiotic resistance, and genetic diversity of the C. difficile strains in the meat and feces of some native birds (chicken, duck, quail, and partridge) in the Shahrekord region, Iran, from July 2018 to July 2019. Samples were grown on CDMN agar after an enrichment step. To determine the toxin profile, the tcdA, tcdB, tcdC, cdtA, and cdtB genes were detected via multiplex PCR. The antibiotic susceptibility of these isolates was examined using the disk diffusion method and followed based on MIC and epsilometric test. 300 meat samples of chicken, duck, partridge, and quail and 1100 samples of bird feces were collected from six traditional farms in Shahrekord, Iran. Thirty-five meat samples (11.6%) and 191 fecal samples (17.36%) contained C. difficile. Moreover, five toxigenic samples isolated had 5, 1, and 3 tcdA/B, tcdC, and cdtA/B genes. Out of the studied strains isolated from the 226 samples, two isolates belonging to ribotype RT027 and one isolated RT078 profile related to native chicken feces were observed from chicken sample. The antimicrobial susceptibility testing showed that all the strains are resistant to ampicillin, 28.57% are resistant to metronidazole, and 100% were susceptible to vancomycin. Based on the results, it can be concluded that the raw meat of birds might be a source of resistant C. difficile that poses a hygienic threat to the consumption of native bird meat. Nevertheless, further studies are essential to understand additional epidemiological features of C. difficile in bird meat. [ABSTRACT FROM AUTHOR]

Canine pyometra, which is accompanied by bacterial contamination of the dog uterus, is defined as a complex disease associated with the activation of several systems, including the immune system. This study uses text mining and microarray data analysis methods to discover some existing targeted gene drugs and expand potential new drug indications. Text mining ("canine pyometra") and microarray data analysis (GSE99877) were used to obtain a common set of genes. These genes and protein-protein interaction (PPI) networks were analyzed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Then, the important genes clustered in the PPI network were selected for gene-drug interaction analysis to provide evidence for potential drug discovery. Through text mining and data analysis, we obtained 17,544 text mining genes (TMGs) and 399 differentially expressed genes (DEGs), respectively. There were 256 repeat genes between TMGs and DEGs, including 70 upregulated genes and 186 downregulated genes. Thirty-seven genes clustered in three significant gene modules. Eight of the 37 genes can target 23 existing drugs. In conclusion, the discovery of 8 immune response-related genes (BTK, CSF2RA, CSF2RB, ITGAL, NCF4, PLCG2, PTPRC, and TOP2A) targeting 23 existing drugs may expand the drug indications for pyometra-related diseases in dogs. [ABSTRACT FROM AUTHOR]

Sonneratia caseolaris (L.) is a common mangrove plant which has significant medicinal value in traditional medicine. Ethanol extract from the fruits of S. caseolaris (SCE) was used in this project to explore its different pharmacological effects considering its traditional usage. In the castor oil-induced diarrheal method, SCE significantly lengthened the latency of the first defecation period up to 95.8 and 119.4 min as well as lowering stool count by 43.3% and 64.4% at the doses of 250 and 500 mg/kg, respectively. In evaluating the neuropharmacological effect using the open-field model, a significant central nervous system (CNS) depressant nature was observed after a reduction in the no. of squares crossed by mice at various time intervals. In evaluating the blood coagulation effect, SCE significantly reduced blood clotting time at 5.86, 5.52, and 5.01 min at 25, 50, and 100 mg/ml doses, respectively. In the assessment of the anthelmintic effect, SCE significantly killed Paramphistomum cervi (P. cervi) where the death times of the nematodes were 40.3, 36.8, and 29.9 min at 12.5, 25, and 50 mg/ml doses, respectively. The extract showed a very poor cytotoxic effect in brine shrimp lethality bioassay. In molecular docking analysis, maslinic acid, oleanolic acid, luteolin, luteolin 7-O-β-glucoside, myricetin, ellagic acid, and R-nyasol showed the best binding affinities with the selected proteins which might be the credible reasons for eliciting pharmacological responses. Among these seven compounds, only luteolin 7-O-β-glucoside had two violations in Lipinski's rule of five. [ABSTRACT FROM AUTHOR]

Trypanosomiasis is an important but neglected tropical diseases which continues to cause morbidity and mortality on a large scale in sub-Saharan Africa. In the present study, the aqueous leaf extract, flavonoid fraction, and subfractions of the flavonoid from A. senegalensis leaves were evaluated for their antitrypanosomal activities, effects on some hematological parameters, and some liver-based enzymes in mice infected with Trypanosoma brucei brucei. Mice treated with aqueous extract at a concentration range of 100–400 mg kg bw exhibited parasite inhibition range between 66.08 and 73.09% while mice treated with the flavonoid fraction (50-200 mg/kg bw) exhibited higher parasite inhibition (83.37-86.38%). Mice treated with subfractions of the flavonoids showed a significant decrease in parasite count (p < 0.05), with subfraction 3 completely clearing parasites in the circulation after twenty-one days of treatment. Biochemical analysis revealed that the subfraction 3 restored the alterations in the serum aspartate transaminase (AST), alanine transaminase (ALT), and total protein concentrations that were observed in the infected nontreated mice. The subfraction 3 was subsequently characterized by HPLC analysis which revealed the presence of rutin (RT: 22.26, 65.34 ppm) as the most abundant bioactive compound that could be attributed to the bioactivity of the subfraction 3. Other polyphenolic compounds identified included gallic acid (RT: 4.39, 0.578 ppm), quercetin (RT: 37.27, 0.729 ppm), kaempferol (RT: 38.33, 1.52 ppm), and luteolin (RT; 39.173, 32.77 ppm). Taken together, subfraction 3 of the flavonoid fraction from of A. senegalensis demonstrated potent antitrypanosomal activities and therefore represents a reserve of bioactive metabolite worthy of further exploration for the treatment of trypanosomiasis. [ABSTRACT FROM AUTHOR]

Background. Stroke is the third main reason of mortality, which is the leading reason for adult disability in the globe. Poststroke inflammation is well known to cause acute ischemic stroke- (AIS-) induced brain injury (BI) exacerbation. Celastrol (CL) has exhibited anti-inflammatory activities in various inflammatory traits though underlying mechanisms remain unknown. So, the present investigation is aimed at studying CL protective mechanism against AIS-induced BI. Methods. A mouse model regarding middle cerebral artery occlusion and an oxygen-glucose deprivation (OGD) cell model with or not CL treatment were constructed to study CL protective effects. NF-E2-related factor 2 (Nrf2) was then silenced in BV2 microglia cells (BV2) to study Nrf2 role regarding CL-mediated neuroprotection. Results. The results showed that CL treatment suppressed AIS-induced BI by inhibiting NLRP3/caspase-1 pathway activations and induction of apoptosis and pyroptosis in vivo and in vitro. NLRP3/caspase-1 pathway blocking activation suppressed OGD-induced cell pyroptosis and apoptosis. Also, CL treatment reversed OGD-induced microglial injury by promoting Nrf2/heme oxygenase-1 (HO-1) pathway activations. Nrf2 downregulation reversed CL protective effects against OGD-induced microglial injury, pyroptosis, and apoptosis. Conclusion. The findings advise that CL treatment ameliorated AIS-induced BI by inhibiting microglial injury and activating the Nrf2/HO-1 pathway. [ABSTRACT FROM AUTHOR]

Introduction. Bile duct ligation (BDL) and subsequent cholestasis are associated with oxidative stress and liver injury and fibrosis. Hesperidin (3,5,7-trihydroxyflavanone 7-rhamnoglucoside) is a flavanone glycoside abundant in citrus fruits. It has positive effects on diabetic retinopathy, reduced platelet aggregation, and blood flow alterations and has the potential to reduce liver injury in oxidative stress. The aim of this study was to evaluate the hepatoprotective effects of hesperidin on BDL-induced liver injury in rats. Methods. A total of 48 adult male Wistar rats were equally allocated to six eight-rat groups, namely, a healthy group, a sham group, a BDL+Vehicle group (BDL plus treatment with distilled water), a BDL+VitC group (BDL plus treatment with vitamin C 4.25 μg/kg), a BDL+Hesp100 group (BDL plus treatment with hesperidin 100 mg/kg/day), and a BDL+Hesp200 group (BDL plus treatment with hesperidin 200 mg/kg/day). Treatments were orally provided for 21 consecutive days. Finally, rats were sacrificed through heart blood sampling. Blood samples were centrifuged, and liver function, oxidative stress, and antioxidant parameters were assessed. Liver tissue was also assessed for oxidative stress, antioxidant, and histological parameters. The expression of inflammatory genes, namely, TGFβ1, iNOS, Caspase-3, and α-SMA, was measured through polymerase chain reaction. Findings. Hesperidin supplementation was associated with significant decrease in the levels of liver enzymes, bilirubin, nitric oxide, malondialdehyde, protein carbonyl, and inflammatory gene expression; significant increase in the levels of total antioxidant capacity, glutathione, and superoxide dismutase and catalase enzyme activity; and significant improvement in the histological morphology and structure of the liver parenchyma. Conclusion. Hesperidin has significant positive effects on liver morphology and structure, inflammation, fibrosis, and oxidative stress in rats with BDL-induced cholestatic liver injury. [ABSTRACT FROM AUTHOR]

Bupivacaine (BUP) may cause neurotoxic effects after spinal anesthesia. Resveratrol (RSV), a natural agonist of Silent information regulator 1 (SIRT1), protects various tissues and organs from damage by regulating endoplasmic reticulum (ER) stress. The aim of this study is to explore whether RSV could alleviate the neurotoxicity induced by bupivacaine via regulating ER stress. We established a model of bupivacaine-induced spinal neurotoxicity in rats using intrathecal injection of 5% bupivacaine. The protective effect of RSV was evaluated by injecting intrathecally with 30 μg/μL RSV in total of 10 μL per day for 4 consecutive days. On day 3 after bupivacaine administration, tail-flick latency (TFL) tests and the Basso, Beattie, and Bresnahan (BBB) locomotor scores were assessed to neurological function, and the lumbar enlargement of the spinal cord was obtained. H&E and Nissl staining were used to evaluate the histomorphological changes and the number of survival neurons. TUNEL staining was conducted to determine apoptotic cells. The expression of proteins was detected by IHC, immunofluorescence, and western blot. The mRNA level of SIRT1 was determined by RT-PCR. Bupivacaine caused spinal cord neurotoxicity by inducing cell apoptosis and triggering ER stress. RSV treatment promoted the recovery of neurological dysfunction after bupivacaine administration by suppressing neuronal apoptosis and ER stress. Furthermore, RSV upregulated SIRT1 expression and inhibited PERK signaling pathway activation. In summary, resveratrol suppresses bupivacaine-induced spinal neurotoxicity in rats by inhibiting endoplasmic reticulum stress via SIRT1 modulation. [ABSTRACT FROM AUTHOR]

Objective. Ulcerative colitis is an intestinal condition that severely affects the life quality of a patient. Jiawei Zhengqi powder (JWZQS) has some therapeutic benefits for ulcerative colitis. The current study investigated the therapeutic mechanism of JWZQS for ulcerative colitis using a network pharmacology analytical approach. Methods. In this study, network pharmacology was used to investigate the potential mechanism of JWZQS in treating ulcerative colitis. The common targets between the two were identified, and a network map was created with the Cytoscape software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of JWZQS was performed using the Metascape database. Protein-protein interaction networks (PPI) was created to screen core targets and main components, and molecular docking was conducted between the main components and core targets. The expression levels of IL-1β, IL-6, and TNF-α were detected in animal experiments. Their effect on the NF-κB signaling pathway and the protective mechanism of JWZQS on the colon by tight junction protein were investigated. Results. There were 2127 potential ulcerative colitis targets and 35 components identified, including 201 non-reproducible targets and 123 targets shared by drugs and diseases. Following the analysis, we discovered 13 significant active components and 10 core targets. The first 5 active ingredients and their corresponding targets were molecularly docked, and the results showed a high level of affinity. GO analysis showed that JWZQS participate in multiple biological processes to treat UC. KEGG analysis showed that JWZQS may be involved in regulating multiple pathways, and the NF-κB signaling pathway was selected for analysis and verification. JWZQS has been shown in animal studies to effectively inhibit the NF-κB pathway; reduce the expression of IL-1β, TNF-α, and IL-6 in colon tissue; and increase the expression of ZO-1, Occludin, and Claudin-1. Conclusion. The network pharmacological study provides preliminary evidence that JWZQS can treat UC through multiple components and targets. JWZQS has been shown in animal studies to effectively reduce the expression levels of IL-1β, TNF-α, and IL-6, inhibit the phosphorylation of the NF-κB pathway, and alleviate colon injury. JWZQS can be used in clinical, but the precise mechanism of UC treatment requires further investigation. [ABSTRACT FROM AUTHOR]

Huoxiang Zhengqi Oral Liquid (HZOL) is a classic Chinese patent medicine used in China for more than 1,000 years in treating gastrointestinal and respiratory diseases. Clinically applied HZOL in early respiratory disease stages can reduce the proportion of lung infection patients that progress to severe acute lung injury (ALI). However, few pharmacological studies evaluated its level of protection against ALI. We explored mechanisms of HZOL against ALI by employing network pharmacology, molecular docking, and rat experiments. Firstly, network pharmacology prediction and published biological evaluation of active ingredients of HZOL suggested that HZOL exerted the protective effect in treating ALI mainly in the areas of regulation of cell adhesion, immune response, and inflammatory response and closely related to the NF-κB pathway. Secondly, molecular docking results demonstrated that imperatorin and isoimperatorin combined well with targets in the NF-κB pathway. Finally, ALI rats induced by lipopolysaccharides (LPS) were used to validate prediction after pretreatment with HZOL for 2 weeks. Results confirmed that lung and colon injury occurred in ALI rats. Furthermore, HZOL exerts anti-inflammatory effects on LPS-induced ALI and gut injury by repairing lung and colon pathology, reducing and alleviating pulmonary edema, inhibiting abnormal enhancement of thymus and spleen index, modulating hematologic indices, and increasing levels of total short-chain fatty acids (SCFAs) in the cecum. Additionally, abnormal accumulation of inflammatory cytokines IL-6, IL-1β, TNF-α, and IFN-γ in serum and bronchoalveolar lavage fluid was significantly reduced after pretreating with HZOL. Furthermore, HZOL downregulated the expression of TLR4, CD14, and MyD88 and phosphorylation of NF-κB p65 in lung tissue. Altogether, HZOL was found to exert an anti-inflammatory effect regulation by increasing levels of SCFAs, inhibiting the accumulation of inflammatory cytokines, and attenuating the activation of the TLR4/NF-κB p65 pathway. Our study provided experimental evidences for the application of HZOL in preventing and treating ALI. [ABSTRACT FROM AUTHOR]

Hard tissues make up the vast majority of teeth and are mineralized from the surrounding matrix. If the development of tooth germ is affected during mineralization, hypoplasia of the tooth tissue can occur. To better understand the mechanisms mediating hypoplasia, we need to first study normal development. Using a rodent model, we highlight the transcriptomic changes that occur from the differentiation to secretion stages of mandibular molar germs. The tooth germ was dissected from rats at postnatal day 1.5 or 3.5 for high-throughput sequencing. Combining transcriptome analysis and DNA methylation, we identified 590 differentially expressed genes (436 upregulated and 154 downregulated) and 551 differentially expressed lncRNAs (long noncoding RNA; 369 upregulated and 182 downregulated) which were linked to the biological processes of odontogenesis, amelogenesis, tooth mineralization, and the alteration of extracellular matrix (ECM), especially matrix metalloproteinases (MMPs) and elastin. We found DNA methylation changes in 32 selected fragments involved in 5 chromosomes, 26 targets, and 2 haplotypes. Finally, three novel genes were identified: MMP20, Tgfb3, and Dusp1. Further analysis revealed that MMP20 has a role in odontogenesis and amelogenesis by influencing Slc24a4 and DSPP; Tgfb3 is involved in epithelial cell proliferation, cellular component disassembly process, ECM cellular component, and decomposition of cell components. But lncRNA expression could affect DNA methylation and mRNA expression. Moreover, the degree of DNA methylation could also affect the transcriptome level. Thus, Tgfb3 had no difference in DNA methylation, and Dusp1 conferred no difference at the transcriptome level. These three genes were all enriched in the MAPK pathway and played an important role in ECM remodeling. These data suggest that during the period of the bell differentiation stage to the secretory stage, along with enamel/dentin matrix secretion and hard tissue occurrence, the ECM is remodeled via MAPK signaling. [ABSTRACT FROM AUTHOR]

In response to current trends in the modification of guided bone regeneration (GBR) materials, we aimed to build upon our previous studies on epigallocatechin-3-gallate (EGCG) by immersing a commonly used bone graft primarily composed of hydroxyapatite (HA) in EGCG solution, expecting to obtain superior bone material integration after implantation. Bone grafts are commonly used for bone repair, in which the bone extracellular matrix is stimulated to promote osteogenesis. However, due to its profibrosis effect, this osteoconductive material commonly exhibits implant failure. In addition to providing a basic release profile of EGCG-modified bone graft (E-HA) to clarify the relationship between this material and the environment, we have examined the integration effect via subcutaneous implantation experiments. In this manner, we have assessed the aggregation of proinflammatory macrophages, the formation of fibrous capsules, and an enhanced cell viability observed in cultured RAW 264.7 cells. Among these results, we focus on proinflammatory macrophages due to their close relationship with fibrosis, which is the most important process in the immune response. Immunofluorescent staining results showed that E-HA substantially compromised the formation of fibrous capsules in hematoxylin-eosin-stained sections, which exhibited less proinflammatory macrophage recruitment; meanwhile, the cell viability was improved. This work lays the foundation for future studies on GBR. [ABSTRACT FROM AUTHOR]

Stroke seriously affects human health. Many studies have shown that enriched environment (EE) can promote functional recovery after stroke, but the intrinsic mechanisms remain unclear. In order to study the internal mechanisms of EE involved in functional recovery after ischemic stroke and which mechanism plays a leading role in the recovery of limb function after cerebral infarction, key proteins potentially involved in neuronal protection and synaptic remodeling in the ischemic penumbra have been investigated. In this study, adult C57BL/6 mice after permanent middle cerebral artery occlusion (pMCAO) were assigned to the EE and standard housing (SH) groups 3 days after operation. The EE house was spacious that contained a large variety of small toys; the SH was a normal sized cage. Sham-operated mice without artery occlusion were housed under standard conditions and were fed a normal diet. On days 3, 7, 14, and 21, postoperative motor functional recovery was tested using the modified neurological severity score (mNSS) and the Rotarod test. The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), growth-associated protein-43 (GAP-43), and synaptophysin (SYN) was examined by western blotting and immunofluorescence staining. The motor functional recovery (based on the mNSS and Rotarod test 3, 7, 14, and 21 days post operation) of mice in the EE group improved significantly compared to the SH group. The expression of GAP-43 and SYN and the ratio of Bcl-2/Bax were all upregulated in the EE group compared to the SH group. In addition, we also explored the relationship between neuronal protection and synaptic remodeling in the EE-mediated recovery of limb function after cerebral infarction by correlation analysis. Correlation analysis showed that compared with the increase of Bcl-2/Bax ratio, the increased expression of GAP-43 and SYN was more closely related to the recovery of limb function in ischemic mice. These data support the hypothesis that EE can promote the process of improvement of limb dysfunction induced by ischemic stroke, and this behavior restoration may, via promoting neuroprotection in the ischemic penumbra, be dependent on the regulation of the expression of GAP-43, SYN, Bcl-2, and Bax. A limitation of the study was that we only observed several representative key indicators of synaptic remodeling and neuronal apoptosis, without an in-depth study of the potential mechanisms involved. [ABSTRACT FROM AUTHOR]

Background. Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Methods. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. Results. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. Conclusions. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice. [ABSTRACT FROM AUTHOR]

Donor lung ventilation and inflation during the warm ischemia could attenuate ischemia-reperfusion injury (IRI) after lung transplantation. Hydrogen sulfide (H2S), as a kind of protective gas, has demonstrated the antilung IRI effect. This study is aimed at observing the different methods of administering H2S in the setting of warm ischemia, ventilation, and inflation on the lung graft from a rat non-heart-beating donor. After 1 h of cardiac arrest, donor lungs in situ were inflated with 80 ppm H2S (FS group), ventilated with 80 ppm H2S (VS group), or deflated (control group) for 2 h. Then, the lung transplantation was performed after 3 h cold ischemia. The rats without ischemia and reperfusion were in the sham group. Pulmonary surfactant in the bronchoalveolar lavage fluid was measured in donor lung. The inflammatory response, cell apoptosis, and lung graft function were assessed at 3 h after reperfusion. The lung injury was exacerbated in the control group, which was attenuated significantly after the H2S treatment. Compared with the FS group, the pulmonary surfactant in the donor was deteriorated, the lung oxygenation function was decreased, and the inflammatory response and cell apoptosis were increased in the graft in the VS group (P < 0.05). In conclusion, H2S inflation during the warm ischemia phase improved the function of lung graft via regulating pulmonary surfactant stability and decreased the lung graft IRI via decreasing the inflammatory response and cell apoptosis. [ABSTRACT FROM AUTHOR]

Background. Renal ischemia-reperfusion injury (RIRI) plays an important role in the poor prognosis of patients with renal transplants. However, the potential targets and mechanism of IRI are still unclear. Method. Differential gene expression (DEG) analysis and weighted correlation network analysis (WGCNA) were performed on the GSE27274 dataset. Pathway enrichment analysis on the DEGs was performed. To identify the hub DEGs, we constructed a protein-protein interaction (PPI) network. Finally, the hub genes were verified, and candidate drugs were screened from the DsigDB database. Results. A hundred DEGs and four hub genes (Atf3, Psmb6, Psmb8, and Psmb10) were screened out. Pathway enrichment analysis revealed that 100 DEGs were mainly enriched in apoptosis and the TNF signaling pathway. The four hub genes were verified in animal models and another dataset (GSE148420). Thereafter, a PPI network was used to identify the four hub genes (Atf3, Psmb6, Psmb8, and Psmb10). Finally, eight candidate drugs were identified as potential drugs. Conclusion. Three hub genes (Psmb6, Psmb8, and Psmb10) were associated with RIRI and could be potential novel biomarkers for RIRI. [ABSTRACT FROM AUTHOR]

The objective of the present study was to develop a novel nanogel containing Beta vulgaris L. hydroalcoholic extract and assess its efficacy for treating testosterone-induced alopecia. Beta vulgaris L. leaf hydroalcoholic extract nanogel (BVEN) was prepared by ionic gelation method, incorporated in carbopol 934 gel. Optimization of particle size and entrapment efficiency as the responses was carried out by central composite design response surface methodology. Prepared nanoparticles were evaluated for entrapment efficiency, particle size, zeta potential, polydispersity index, Fourier transform infrared spectroscopy, transmission electron microscopy, and differential scanning calorimetry. Nanogel was evaluated for pH, colour, appearance and homogeneity, viscosity, spreadability, in vitro release study, and stability studies. Further, 2.5% and 5% BVEN were also evaluated for antialopecic activity in Swiss albino mice by using parameters as hair growth initiation, testosterone content, total protein, prostate weight measurement, hair follicular density, anagen/telogen ratio, and histopathological studies. The resulting nanoparticles had better entrapment efficiency with particle size of 274 nm, polydispersity index of 0.259, and zeta potential of +28.8. BVEN pH 6.5, drug content, i.e., quercetin 99.84 ± 1.30 % and stigmasterol 99.89 ± 1.52 % , spreadability 20.3 ± 0.5925 g cm / sec , and viscosity 110 × 10 5 cps were observed. Stability studies showed that nanogel was stable at 4 ° C ± 2 ° C / 60 % ± 5 % RH. It was found that 5% BVEN showed better antialopecic activity as compared to 2.5% BVEN. [ABSTRACT FROM AUTHOR]

Background. Tuberculosis (TB) of the spine is a highly disruptive disease, especially in underdeveloped and developing countries. This condition requires standard TB treatment for 9–18 months, which increases patient risk of drug-resistant TB. Consequently, this raises the concern of adopting additional therapies to shorten the treatment duration, improve the efficacy of anti-TB drugs, and further decrease damage in the affected tissues and organs. Matrix metalloproteinase- (MMP-) 1 is a key regulator of the destruction of the extracellular matrix and associated proteins and is a new potential target for TB treatment research. In the present study, we investigated the effects of doxycycline as an MMP-1 inhibitor in patients with spondylitis TB. Methods. Seventy-two New Zealand white rabbits with spondylitis TB were divided into 12 different groups based on incubation period (2, 4, 6, and 8 weeks) and doxycycline administration (without, 1 mg/kg body weight (BW), and 5 mg/kg BW). We observed the course of infection through the blood concentration changes and immunohistochemical examination of MMP-1, in addition to BTA staining, culture, polymerase chain reaction (PCR), and histopathological examination. Results. Treatment with once daily 5 mg/kg BW doxycycline significantly improved the blood MMP-1 level (p < 0.05) compared with the placebo and 1 mg/kg BW doxycycline. A significantly reduced ongoing infection and a higher healing rate were demonstrated in rabbits with a higher doxycycline dose through BTA staining, culture, PCR, and histopathology. Various degrees of vertebral endplates, vertebral body, and intervertebral disc destruction were observed in 32 rabbits with positive histopathological findings, in addition to positive inflammatory cell infiltration, characterized by numerous lymphocytes, macrophages, and epithelial cells, as well as abundant granulation tissue and necrotic substances proximal to the inoculated vertebral area. Bone and intervertebral disc destructions were more apparent in the untreated rabbits. Conclusion. Our study demonstrated the potential of doxycycline as an adjunctive treatment in spondylitis TB. However, limitations remain regarding the differences in the pathogenesis and virulence of Mycobacterium tuberculosis between rabbit and human systems, sample size, and the dose-dependent effect of doxycycline. Further studies are needed to address these issues. [ABSTRACT FROM AUTHOR]

Purpose. The purpose of this study was to investigate the effect of bariatric surgery on pancreatic thioredoxin-interacting protein (TXNIP) and insulin expression levels. The research question is does bariatric surgery induce changes in the pancreatic TXNIP level, given that TXNIP has been proposed as a key glucose control factor? Methods. Using nondiabetic and diabetic rats, we investigated whether our streptozotocin-induced diabetic rat models exhibited changes in pancreatic TXNIP regulation. Following this confirmation, we randomly divided the diabetic rats into the following three groups: the gastric bypass group (n = 16), pair-fed group (n = 10), and sham group (n = 10). Preoperatively and 3 weeks postoperatively, all the rats underwent an oral glucose tolerance test, insulin tolerance test, and blood sampling procedures for hormonal analysis. Results. The TXNIP messenger ribonucleic acid (mRNA) and protein expression levels were significantly lower in the gastric bypass group than in the other groups. Regarding the gastric bypass group, the pancreatic mRNA expression levels of microRNA-204 (miR-204) and MafA were significantly lower and higher, respectively, than in the other groups. Furthermore, the levels of pancreatic insulin expression at the mRNA and protein levels were also significantly higher in the gastric bypass group than in the other groups. Conclusion. Bariatric surgery significantly improved glucose control and regulated the pancreatic insulin production pathways of TXNIP, miR-204, and MafA. The regulation of TXNIP, miR-204, and MafA might play an important role in the mechanism of diabetes remission following bariatric surgery. [ABSTRACT FROM AUTHOR]

The present study was carried out to investigate the anti-inflammatory activity of a methanolic extract and fractions of Uvaria comperei stems. The crude extract was obtained by maceration of the powder in methanol and fractions by vacuum chromatography from the methanolic extract. To study the anti-inflammatory activity in vitro, red blood cell lysis inhibition assay and albumin denaturation inhibition were performed, while in vivo measurements of carrageenan-induced paw oedema and formalin-induced pain in albino mice were performed. Acute toxicity and cytotoxicity studies of the fraction F2 were performed, as well as its HPLC, and some biochemical parameters were quantified. Uvaria comperei crude extract (UCCE) at 250 and 500 μg/mL completely inhibited albumin denaturation, while decreasing 75.5% of heat blood cell lysis at 500 μg/mL. The fractions 128-136 (F3), 10-11 (F1), and 56-62 (F2) at 500 μg/mL displayed a significant anti-inflammatory activity with percentages of inhibition of 60.5, 67.4, and 100%, respectively. Administration of fraction F2 (25, 50, and 100 mg/kg, p.o.) produced a dose-dependent inhibition of formalin-induced pain of 60.2% at 50 mg/kg in the neurogenic phase (p < 0.05) and 70.2% at 25 mg/kg in the inflammatory phase (p < 0.05). Similarly, the time-dependent increase in carrageenan-induced paw circumference induced by carrageenan was inhibited by pretreatment with F2: 50% of inhibition at 25 mg/kg after 30 min (p < 0.05) and 96.5% inhibition at 25 mg/kg after 6 h (p < 0.05). In this research, the fraction F2 presented its maximum analgesic property at 50 mg/kg, while it presented the highest anti-inflammatory property at 25 mg/kg. The oral lethal median dose (LD50) of F2 was determined to be greater than 2000 mg/kg; further low cytotoxicity in RAW cells was also observed. Overall, this work shows that the methanolic crude extract and fractions, mainly F2, of Uvaria comperei stem have interesting anti-inflammatory properties. [ABSTRACT FROM AUTHOR]