Development and evaluation of multi-functionalized sialic acid conjugated asiatic acid nanoconstruct to mitigate cognitive deficits in Alzheimer's disease.

Sialic acid (SA) serves a critical role in neuronal repair and cognitive functions. SA is a nine-carbon carboxylated sugar with a glycoconjugate cap that acts as a ligand and surface decoration with SA facilitates delivery to the target site. The present research aimed to develop SA surface modified AA nanostructured lipid carrier (NLCs) with carbodiimide conjugation method. Sterylamine, poloxamer 188 and tween 80 were used as surfactants and several characterization studies including, differential scanning calorimetry, fourier transform infrared spectroscopy and x-ray photon spectroscopy were analyzed. Further, in vitro, neuroprotective efficiency was evaluated in SH-SY5Y cells and hCMEC/D3 cells and found significant potential effects with the treatments of developed NLCs. Pharmacodynamics studies were also assessed in beta-amyloid-injected rats following quantification of Alzheimer's disease (AD) hallmarks like, Aß(1-42), tau-protein, glycogen synthase kinase-3ß levels, interleukin-6 and tumor necrosis factor-α for neuroinflammatory responses. Characterization studies revealed the conjugation on developed NLCs. The in vitro and in vivo results showed significant effects of SA decorated NLCs in reversing the damage by toxicant which was further characterized by the levels of neurotransmitters like acetylcholinesterase, butyrylcholinesterase. The results revealed significant (p < .05) refurbishment of cholinergic functions after 28 days of treatment of developed NLCs. These preclinical findings support the use of SA as a ligand to deliver the AA at targeted site as well as to mitigate the cognitive deficits in AD.

Effect of Shorea robusta resin extract in 3-nitropropionic acid-induced Huntington's disease symptoms in Sprague-Dawley rats.

Background and purpose: Huntington's disease (HD) is a neurodegenerative disease characterized by neuronal death in the striatum. Asiatic acid is an active component of Shorea robusta (Dipterocarpaceae) plants with neuroprotective activity and is considered an acceptable therapeutic candidate for different neurodegenerative diseases. In the present study, the beneficial pharmacological action of Shorea robusta resin extract (SRRE) was assessed in 3-nitropropionic acid (3-NP)-induced HD in rats. Experimental approach: The neuroprotective effect of SRRE (285.7 and 666.7 mg/kg, p.o., 14 days) was studied in 3-NP (10 mg/kg)-induced rats by measuring body weight, behavioral parameters including neurological scoring, motor coordination, spatial memory, and depression-like behavior, neuro-biochemical parameters (gamma-aminobutyric acid and acetylcholinesterase), and oxidative stress parameter in the brain. Histopathology of the rat's brain was also studied. Findings/Results: SRRE treatment (285.7 mg/kg and 666.7 mg/kg) substantially restored body weight, motor coordination, and mitochondrial enzyme complex I function and improved memory impairment as compared to 3-NP-treated rats. Furthermore, SRRE treatment significantly restored the antioxidant enzyme activity in brain tissue and ameliorated the histopathological changes induced by 3-NP. Conclusion and implications: The neuroprotective effect of SRRE on 3-NP-induced HD in rats was mediated by a reduction in oxidative stress which may favor the usefulness of Shorea robusta in HD.

Isolation and characterization of carpaine and dihydroxy derivative of carpaine from leaves of Carica papaya: Development of fast HPLC method and standardization of formulations.

Carpaine, a major alkaloid of Carica papaya leaves, is widely studied for its anti-thrombocytopenic activity. The objective of present work was to isolate carpaine from dried leaves of Carica papaya. Isolation of carpaine was carried out by solvent extraction techniques followed by column chromatography by gradient elution using dichloromethane: methanol (80:20, v/v) as eluent. Dihydroxy derivative of carpaine was also identified for the first time from leaves of Carica papaya. Structures of carpaine and dihydroxy derivative of carpaine were confirmed by LC-MS/MS followed by IR studies. Fast HPLC method was developed using Sunniest C18 column (150 mm × 4.6 mm) as stationary phase and water (pH 8.5): acetonitrile (60: 40, v/v) as mobile phase at flow rate of 1.0 mL/min. Carpaine was eluted with mean retention time of 6.017 min. The developed HPLC method was used to estimate carpaine in extract and marketed formulations containing Carica papaya leaves.

Maternal gender discrimination and child emotional and behavioural problems: A population-based, longitudinal cohort study in the Czech Republic.

Background: Gender discrimination may be a novel mechanism through which gender inequality negatively affects the health of women and girls. We investigated whether children's mental health varied with maternal exposure to perceived gender discrimination. Methods: Complete longitudinal data was available on 2,567 mother-child dyads who were enrolled between March 1, 1991 and June 30, 1992 in the European Longitudinal Cohort Study of Pregnancy and Childhood-Czech cohort and were surveyed at multiple time points between pregnancy and child age up to 15 years. The Strengths and Difficulties Questionnaire (SDQ) was administered at child age 7, 11, and 15 years to assess child emotional/behavioural difficulties. Perceived gender discrimination was self-reported in mid-pregnancy and child age 7 and 11 years. Multilevel mixed-effects linear regression of SDQ scores were estimated. Mediation was tested using structural equation models. Findings: Perceived gender discrimination, reported by 11.2% of mothers in mid-pregnancy, was related to increased emotional/behavioural difficulties among children in bivariate analysis (slope = 0.24 [95% confidence interval (CI): 0.15, 0.32], p<0.0001) and in the fully adjusted model (slope = 0.18 [95% CI: 0.09, 0.27], p<0.0001). Increased difficulties were evident among children of mothers with more depressive symptoms (slope = 0.04 [95% CI: 0.03, 0.05], p<0.0001), boys (slope = 0.26 [95% CI: 0.19, 0.34], p<0.0001), first children (slope = 0.16 [95% CI: 0.09, 0.23], p<0.0001), and families under financial hardship (slope = 0.09 [95% CI: 0.04, 0.14], p<0.0001). Effects were attenuated for married mothers (slope-0.12 [95% CI: -0.22, -0.01], p<0.05]. Maternal depressive symptoms and financial hardship mediated about 37% and 13%, respectively, of the total effect of perceived gender discrimination on SDQ scores. Interpretation: Perceived gender discrimination among child-bearing women in family contexts was associated with more mental health problems among their children and adolescents, extending prior research showing associations with maternal mental health problems. Maternal depressive symptoms and, to a lesser extent, financial hardship both partially mediated the positive relationship between perceived gender discrimination and child emotional/behavioural problems. This should be taken into consideration when measuring the societal burden of gender inequality and gender-based discrimination. Moreover, gender-based discrimination affects more than one gender and more than one generation, extending to boys in the household even moreso than girls, highlighting that gender discrimination is everyone's issue. Further research is required on the intergenerational mechanisms whereby gender discrimination may lead to maternal and child mental health consequences. Funding: Bill and Melinda Gates Foundation; Ministry of Education, Youth and Sports, Czech Republic and European Structural and Investment Funds.

Protective effect of probiotics and ascorbic acid on bile duct ligation-induced chronic hepatic encephalopathy in rats.

Background and purpose: Hepatic encephalopathy (HE) is a brain dysfunction caused by acute and chronic hepatic failure. The pathogenesis of HE is unknown, although small intestinal bacterial overgrowth associated with chronic liver damage, hyperammonemia, and oxidative stress are considered major factors for HE. Effective lowering of circulating ammonia and neuroinflammation is the main strategy for preventing and treating HE in cirrhosis. In the present study, the protective effect of probiotics (Lactobacillus plantarum and Bacillus clausii) and ascorbic acid in combination was assessed in bile duct ligation (BDL)-induced chronic HE in rats. Experimental approach: Sprague Dawley rats were divided into five groups (n = 6). All groups were subjected to double ligation of the bile duct and fed a hyperammonemia diet, except group I (normal control). Groups III and IV were treated with a low and high dose of combination therapy, respectively, while group V was given lactulose. Four weeks post ligation, behavioral, biochemical, and neurochemical parameters were measured. The liver and brain were dissected for histopathology and protein analyses. Findings / Results: Combination therapy reduced plasma AST, ALT, ALP, and ammonia levels and attenuated hepatic inflammation/fibrosis in cirrhotic rats. Furthermore, combination therapy significantly improved behavioral parameters and restored the antioxidant enzyme activity. Histological changes were observed in the brain and liver of BDL animals. Conclusion and implications: The additive impact of probiotics and ascorbic acid on BDL-induced chronic HE in rats was mediated by a reduction in ammonia and oxidative stress, implying the therapeutic potential of combination therapy in HE.

Bio-enhancement of Soy Isoflavones (Genistein & Daidzein) Using Bacillus coagulans in Letrozole Induced Polycystic Ovarian Syndrome by Regulating Endocrine Hormones in Rats.

Soy isoflavone (SIF), a natural phytoestrogen, is used in the condition of hormonal imbalance. These isoflavones generally have low solubility resulting in low bioavailability and bioactivity. It is reported that trans-glycosylation by cyclodextrin glycosyltransferase (CGTase) is widely utilized for increasing the solubility and bioavailability of isoflavones. Present investigation was aimed to study the effect of Bacillus coagulans (a probiotic) in potentiating the bioactivity of soy isoflavones in letrozole-induced PCOS. Initial consideration was focused on proving CGTase assay of B. coagulans. After that, animal study was performed to check the enhancement of bioactivity of SIF along with B. coagulans. A total of 36 rats, separated into six groups (6 rats in each), were used. Group I received vehicles, group II received letrozole (1 mg/kg) for 21 days, and group III animals were administered with soy isoflavones (SIF-100 mg/kg). In the case of group IV, V, and VI, animals received SIF (100 mg/kg) along with B. coagulans 0.65, 3.25, and 6.50 mg/kg, respectively. Treatment was given for 2 weeks after induction of disease. All the animals were sacrificed at the end of the study and endpoint parameters were performed. Present investigation revealed that combination of SIF with B. coagulans showed hormone restoration, reduce oxidative stress, recovery in the menstrual cycle, and improvement in ovarian physiology. SIF (genistein & daidzein) together with B. coagulans exhibits a beneficial role in the enhancement of the bioactivity of soy isoflavones. Further, it showed that a higher dose of B. coagulans (6.50 mg/kg) is more effective in ameliorating the PCOS symptoms.

In vitro models and ex vivo systems used in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal condition. Ulcerative colitis and Crohn's disease are types of inflammatory bowel disease. Over many decades, the disease has been a topic of study, with experts still trying to figure out its cause and pathology. Researchers have established many in vivo animal models, in vitro cell lines, and ex vivo systems to understand its cause ultimately and adequately identify a therapy. However, in vivo animal models cannot be regarded as good models for studying IBD since they cannot completely simulate the disease. Furthermore, because species differences are a crucial subject of concern, in vitro cell lines and ex vivo systems can be employed to recreate the condition properly. In vitro models serve as the starting point for biological and medical research. Ex vivo and in vitro models for replicating gut physiology have been developed. This review aims to present a clear understanding of several in vitro and ex vivo models of IBD and provide insights into their benefits and limits and their value in understanding intestinal physiology.

Therapeutic potential of probiotics - Lactobacillus plantarum UBLP40 and Bacillus clausii UBBC07 on thioacetamide-induced acute hepatic encephalopathy in rats.

PURPOSE: Hepatic encephalopathy (HE) or hepatic coma is a demanding, not utterly understood complication of acute and chronic liver dysfunction and portosystemic shunting. In HE, hyperammonemia and inflammatory responses are believed to act in synergism. Probiotics, Lactobacillus plantarum UBLP40 and Bacillus clausii UBBC07 reduce small intestinal bacterial overgrowth and hyperammonemia, thereby preventing HE development. METHODS: The effect of probiotics-Lactobacillus plantarum UBLP40 (107 CFU/day, 14 days) and Bacillus clausii UBBC07 (107 CFU/day, 14 days) combination and standard drug-lactulose (2.5 ml/kg in 3 divided doses, 14 days) was studied in thioacetamide (250 mg/kg for three days) induced acute HE in rats by measuring behavioural parameters, biochemical parameters (serum AST, ALT, ALP and ammonia level), neurochemical parameters and histopathology study in brain and liver. RESULTS: In contrast to only thioacetamide treated rats, probiotics treatment substantially (p < 0.001) reduced liver function parameters, i.e. serum AST, ALT, ALP, and ammonia, improved behaviour parameters, i.e. decreased motor disruption, improved memory impairment. Probiotics treated rats have also shown a substantial improvement in oxidative stress parameters i.e. reduced lipid peroxidation and increased glutathione level in brain tissue and ameliorated the histopathological changes induced by thioacetamide in the brain and liver. CONCLUSIONS: It can be concluded based on the findings that the combination therapy of Lactobacillus plantarum UBLP40 and Bacillus clausiiUBBC07 proves to be effective in acute hepatic encephalopathy in the preclinical stage, and further studies are required to assess this therapy potential in the clinical setting.

A brief review on in vivo models for Gouty Arthritis.

Gout is more common in men than in women, by a factor of 3.1-10.1. Gout prevalence and incidence have increased in recent decades, with prevalence reaching 11-13% and incidence reaching 0.4% in people over the age of 80. Age-related renal impairment, altered drug distribution, and increased prevalence of comorbidities have significant consequences for safe and effective gout pharmacotherapy. The Discovery of Fruitful in-vivo animal models needs the effective screening of drugs or formulations used in the treatment of gout. In vivo animal models of Gouty arthritis are extensively used to investigate pathogenic mechanisms governing inflammation-driven bone and cartilage damage. Four commonly utilized models include the Potassium oxonate induced hyperuricemic model, MSU crystals induced gouty arthritis animal model, Animal Model of Acute Gouty Arthritis with Hyperuricemia, and Diet-induced hyperuricemia. These offer unique advantages for correlating different aspects of gouty arthritis with human disease. In-vivo animal models served as testing beds for novel biological therapies, including cytokine blockers and small molecule inhibitors of intracellular signaling that have revolutionized gouty arthritis treatment. This review highlights a brief overview of in vivo experimental models for assessment of hypouricemic, anti-inflammatory, as well as renal protective effects of test compounds with some evaluation parameters in detail.

Perception and practices of menstruation restrictions among urban adolescent girls and women in Nepal: a cross-sectional survey.

BACKGROUND: Menstruation, a natural biologic process is associated with restrictions and superstitious beliefs in Nepal. However, factual data on women's perspectives on menstrual practices and restrictions are scarce. This study aimed to assess socio-cultural perceptions of menstrual restrictions among urban Nepalese women in the Kathmandu valley. METHODS: Using a clustered random sampling, 1342 adolescent girls and women of menstruating age (≥15 years) from three urban districts in the Kathmandu valley completed a survey related to menstrual practices and restriction. This was a cross-sectional survey study using a customized program allowing pull-down, multiple choice and open-ended questions in the Nepali language. The self-administered questionnaire consisted of 13 demographic questions and 22 questions related to menstruation, menstrual hygiene, socio-cultural taboos, beliefs and practices. Univariate descriptive statistics were reported. Unadjusted associations of socio-cultural practices with ethnicity, education, four major social classes, three major religions, marital status and family type were assessed using logistic regression models. RESULTS: More than half (59%) of the participants were aged between 15- < 25 years. The majority were Hindus (84.5%), reported not praying during menstruation (83.1%) and were encouraged by their mothers (72.1%) to practice a range of menstrual restrictions. Purifying either the kitchen, bed, bedsheets or other household things on the fourth day of menstruation was reported by 66.1% of the participants, and 45.4% saw menstruation as a "bother" or "curse." There were differences among social classes, where participants of the Janajati caste, an indigenous group, were more likely to enter places of worship [OR (95%CI): 1.74 (1.06-2.86)] and pray [OR (95%CI): 1.79 (1.18-2.71)] while menstruating, compared to the Brahmins. Participants with a master's degree were more likely to pray while menstruating, compared to participants with less than a high school education [OR (95%CI): 2.83 (1.61-4.96)]. CONCLUSION: This study throws light on existing social discriminations, deep-rooted cultural and religious superstitions among women, and gender inequalities in the urban areas of Kathmandu valley in Nepal. Targeted education and awareness are needed to make changes and balance between cultural and social practices during menstruation.

Potentiation of anti-Alzheimer activity of curcumin by probiotic Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice.

Curcumin, a major component of Indian saffron through clinical studies, revealed its neuroprotective effect in neurodegenerative diseases. However, it has not been utilized alone orally due to its low bioavailability. There are certain strategies to overcome the drawbacks such as poor absorption and low aqueous solubility. Many strategies are utilized to increase the systemic availability of curcumin. Among them, the steady intestinal and liver metabolism of curcumin by a curcumin adjuvant (enzyme inhibitor/inducer) is an important and less engrossed strategy for improving the overall systemic bioavailability of curcumin. Here, we assess the effect of probiotic Lactobacillus rhamnosus as a curcumin adjuvant (potentiate the effect of curcumin) in scopolamine-induced dementia in mice. To induce amnesia, scopolamine was used in a mouse model (1 mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris water maze test), brains and liver were isolated for further neurochemical and histopathology examination. Our results showed a significant increase in antioxidant enzyme levels in curcumin with a probiotic group compared with curcumin alone. Besides, histopathology study results showed less neuronal damage of curcumin with probiotics as compared with the curcumin and scopolamine alone groups. Additionally, curcumin with probiotics improved memory and cognitive functions in the behavioural study with the significance of p ≤ 0.0001. In conclusion, curcumin with probiotics has greater activity as compared with curcumin alone and reverses the hallmarks of Alzheimer's disease (AD).

Gender discrimination and depressive symptoms among child-bearing women: ELSPAC-CZ cohort study.

BACKGROUND: Depression is approximately two-fold more prevalent among women than men. Social theories suggest that discrimination is a pathway through which gender inequalities affect women's lives, but data are lacking. This cohort study evaluates whether perceived gender discrimination is linked to depressive symptoms among child-bearing women. METHODS: Data were obtained from 4,688 participants enrolled in pregnancy in 1991-92 in the European Longitudinal Cohort Study of Pregnancy and Childhood, Czech Republic. Perceived gender discrimination was assessed in mid-pregnancy, year seven, and year eleven. Depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale at eight time-points between mid-pregnancy and year eleven post-delivery. Linear mixed error-component models of depressive symptoms were estimated. FINDINGS: Perceived gender discrimination, reported by 10.7% of women, was related to higher depressive symptoms, both in the unadjusted analysis (b = 0.15 [95% confidence interval (CI): 0.12, 0.19], p < 0.001) and in the fully adjusted model (b = 0.12 [95% CI: 0.09, 0.16], p < 0.001). Covariates linked to higher depressive symptoms included financial hardship (b = 0.12 [95% CI: 0.10, 0.14], p < 0.001), childhood emotional/physical neglect (b = 0.18 [95% CI: 0.14, 0.22], p < 0.001), and childhood sexual abuse (b = 0.04 [95% CI: 0.03, 0.06], p < 0.001); an inverse relationship was evident for social support (-0.05 [95% CI: -0.07, -0.04], p < 0.001) and having a partner who performs female-stereotypical household tasks (b=-0.03 [95% CI: -0.05, -0.01], p = 0.001). INTERPRETATION: The findings provide the first evidence that perceived gender discrimination is associated with depressive symptoms among child-bearing women. Social intervention programs aimed at reducing gender discrimination can potentially contribute to better mental health of women. FUNDING: Bill and Melinda Gates Foundation.

Caste Differences in Hypertension Among Women in India: Diminishing Health Returns to Socioeconomic Status for Lower Caste Groups.

INTRODUCTION: The caste system is a relatively rigid system of social hierarchy in India. The caste membership defines one's access to resources and life opportunities. A growing body of research suggests that lower caste groups have an excess burden of morbidity and mortality in India. However, it is not clear as to what extent caste differences in health are conditioned by socioeconomic status (SES) indicators. PURPOSE: This study examined the caste differences in hypertension and tested whether caste differences in hypertension are conditioned by education and household wealth in a representative sample of women in India. METHODS: This study used data from the National Family Health Survey (NFHS) 2015-2016, India. The analysis is based on a nationally representative sample of 648,064 adult women aged 15-49 years. We used logistic regression to examine whether the association between caste and hypertension varied by education and wealth index using interactions and controlling for potential confounders. RESULTS: The regression models suggest that scheduled tribes and non-caste members have the highest odds of hypertension compared with privileged upper caste members. Interaction models indicate complex intersections of caste, education, and wealth index. The predicted probabilities derived from these interaction models suggest that while SES indicators are inversely associated with the odds of hypertension, the inverse patterning was significantly weaker in other backward classes and more protective in non-caste members compared with upper caste. Additionally, caste difference in predictive risk of hypertension tends to diverge at the lower levels of SES and become narrower at the higher levels of SES. CONCLUSIONS: These findings provide evidence of differential returns to SES and have implications for understanding the causes of SES patterning in health among disadvantaged caste groups in India.

Therapeutic Prospective of a Spore-Forming Probiotic-Bacillus clausii UBBC07 Against Acetaminophen-Induced Uremia in Rats.

To screen Bacillus clausii UBBC07 as a putative probiotic strain and to examine the protective effect of probiotic-B. clausii UBBC07 spore on uremia on rats induced by acetaminophen. In vitro tests performed to screen potential probiotic strains were gastric and bile acid resistance and ability to reduce pathogen adhesion to surfaces. An in vivo study was performed on rats (n = 18) which were randomly divided into three groups: group I, control-receives normal food and water, groups II and III receive acetaminophen i.p. at the dose of 550 mg/kg/day for 10 days, groups III was treated with B. clausii UBBC07 at a dose of 1 × 109 CFU/day for 15 days. Urea, creatinine, malondialdehyde (MDA), and GSH levels and antioxidant enzymes like super oxide dismutase (SOD) and catalase activity were considered to analyze renal failure. Plasma urea and creatinine levels (p < 0.05) significantly increase and SOD, catalase, and GSH activity level significantly decrease in group II as compared with the control group. After treatment with probiotic, there was a significant increase in SOD and catalase (p < 0.05) and a significant decrease in serum urea, creatinine, and MDA (p < 0.05) in group III in response to group II. The results also revealed that probiotic was able to tolerate pH 3.0-9.0 and 0.3% bile salt. The present study suggests that B. clausii UBBC07 could be used as a novel alternative natural therapy for uremia, a major syndrome of CKD.

Neuroprotective effects of bergenin in Alzheimer's disease: Investigation through molecular docking, in vitro and in vivo studies.

Alzheimer's disease (AD) is an enervating and chronic progressive neurodegenerative disorder, occurring frequently in the elderly and adversely affecting intellectual capabilities and the cognitive processes. Bergenin possesses efficacious antioxidant, antiulcerogenic, anti-HIV, hepatoprotective, neuroprotective, anti-inflammatory and immunomodulatory activity along with antinociceptive effect and wound healing properties. Previous studies have shown that bergenin has in vitro bovine adrenal tyrosine hydroxylase inhibitory activity, mushroom tyrosinase inhibitory activities, ß-secretase (BACE-1) enzyme inhibitory activity and prevented neuronal death in the primary culture of rat cortical neurons. Protein tyrosine phosphatase-1B (PTP1B) is an intriguing target for anticancer and antidiabetic drugs and has recently been implicated to act as a positive regulator of neuroinflammation. Bergenin is also found to inhibit human protein tyrosine phosphatase-1B (hPTP1B) in vitro. Thus, bergenin was screened by molecular docking study using GOLD suite (version 5.2), CCDC for predicting its activity against targets of AD management like acetylcholinesterase (AChE) (1B41), butyrylcholinesterase (BuChE) (1P0I), Tau protein kinase 1 (GSK-3ß) (1J1B), BACE-1 (1FKN) wherein the GOLD score and fitness of bergenin were comparable to those of standard drugs like donepezil, galanthamine, physostigmine, etc. Bergenin demonstrated dose-dependent inhibition of both AChE and BuChE in vitro and found to be safe up to 50 µM when screened in vitro on SH-SY5Y cell lines by cytotoxicity studies using MTT and Alamar blue assays. It also led to dose-dependent prevention of NMDA induced toxicity in these cells. Pretreatment with bergenin (14 days) in rats at three dose levels (20, 40 and 80 mg/kg; p.o.) significantly (p < 0.01) and dose-dependently alleviated amnesia induced by scopolamine (2 mg/kg, i.p.). The therapeutic effect of bergenin supplementation for 28 days, at three dose levels, was also evaluated in streptozotocin (3 mg/kg, ICV, unilateral) induced AD model in Wistar rats using Morris water maze and Y maze on 7th, 14th, 21st and 28th days. STZ caused significant (p < 0.001) cognitive impairment and cholinergic deficit and increased oxidative stress in rats. Bergenin could significantly ameliorate STZ induced behavioral deficits, inhibit the AChE and BuChE activity in parallel with an increase in the diminished GSH levels in a dose-dependent fashion. The histopathological investigations were also supportive of this datum. The bergenin treatment at 80 mg/kg led to significant (p < 0.05) abatement of the raised Aß-1-42 levels and alleviated the perturbed p- tau levels leading to significantly low (p < 0.01) levels of p-tau in brain homogenates of rats as compared to ICV STZ injected rats. In conclusion, the observed effects might be attributed to the cholinesterase inhibitory activity of bergenin coupled with its antioxidant effect, anti-inflammatory activity and reduction of Aß-1-42 and p-tau levels which could have collectively helped in the attenuation of cognitive deficits. The current findings of the study are indicative of the promising preventive and ameliorative potential of bergenin in the management of AD through multiple targets.

Perinatal Maternal Stress and Susceptibility to Infectious Diseases in Later Childhood: An Early Life Programming Perspective.

There is evidence of transmission of stress-related dysregulation from parents to offspring during early developmental stages, leading to adverse health outcomes. This study investigates whether perinatal stress is linked to the risk of infectious diseases in children aged 7-11 years. We hypothesize that stress exposure during pregnancy and the first 6 months after birth independently predict common infectious diseases. Data are obtained from ELSPAC-CZ, a prospective birth cohort. Maternal stress, operationalized as the number of life events, is examined for pregnancy and the first 6 months postpartum. Children's diseases include eye infection, ear infection, bronchitis/lung infection, laryngitis, strep throat, cold sores, and flu/flu-like infection. More prenatal and postnatal life events are both independently linked to a higher number of infectious diseases between the ages of 7-11 years. The effect is larger for postnatal vs. prenatal events, and the effect of prenatal events is attenuated after maternal health in pregnancy is controlled. The results suggest that perinatal stress is linked to susceptibility to infectious diseases in school-age children. Interventions to address stress in pregnant and postpartum women may benefit long-term children's health.

Fabrication of peptide-linked albumin nanoconstructs for receptor-mediated delivery of asiatic acid to the brain as a preventive measure in cognitive impairment: optimization, in-vitro and in-vivo evaluation.

The aim of the study was to evaluate the neuroprotective activity of glutathione (GU)-conjugated asiatic acid (AA) loaded albumin nanoparticles and establishing the drug targeting efficiency (DTE) of GU as a selective ligand for brain-targeted delivery. Albumin nanoparticles were prepared by desolvation technique and optimized using quality by design (QbD) approach. GU was conjugated with nanoparticles by carbodiimide reaction and characterized by its size and zeta potential using dynamic light scattering phenomenon. Dialysis bag technique was employed for in-vitro release study and in-vivo brain targeting efficiency was evaluated in Sprague-Dawley rats (75 mg/kg, i.p.). Neuroprotective activity was evaluated against scopolamine-induced dementia in rats. Resultant brain bioavailability of nanoparticles with 100.2 nm size and 71.59% entrapment efficiency (EE), was found 7-fold higher than AA dispersion with 293% DTE for the brain. Conjugated nanoparticles showed significantly high percentage correct alternation (p < .05), low escape latency time (p < .01), cholinesterase inhibition (p < .01) and ameliorated GU levels (p < .01) as compared to diseased animals. GU showed potential to enhance the brain delivery of AA with ameliorated neuroprotective activity due to enhanced bioavailability. This concept can serve as a platform technology for similar potential neurotherapeutics, whose clinical efficacy is still challenging owing to poor bioavailability.

Neuroprotective effects of Bergenia ciliata on NMDA induced injury in SH-SY5Y cells and attenuation of cognitive deficits in scopolamine induced amnesia in rats.

Bergenia ciliata (Haw) Sternb. possess immunomodulatory, anti-inflammatory, antioxidant, anti-urolithiatic, wound healing, anti-malarial, anti-diabetic and anti-cancer properties. Moreover, the methanolic extracts of the rhizomes of the plant were found to demonstrate beneficial neuroprotective effects in the intracerebroventricular streptozotocin-induced model in rats. Thus, the present study was undertaken to further explore the neuroprotective potential of the aqueous (BA) and methanolic extracts (BM) of B. ciliata through various in-vitro and in-vivo studies. Both the extracts at all tested concentrations i.e. 50-50,000 ng/mL did not cause any significant reduction of cell viability of SH-SY5Y cells when tested for 48 h when assessed through MTT and resazurin metabolism- based cell viability assays. The pre-treatment with the extracts could confer significant (p < 0.001) and dose-dependent protective effects against NMDA induced injury in SH-SY5Y cells. BM [IC50: 5.7 and 5.19 µg/mL for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) respectively] led to more potent inhibition of both the enzymes as compared to BA (IC50: 227.12 and 23.25 µg/mL for AChE and BuChE respectively). BM also proved to be a 1.85-fold better scavenger of the DPPH free radicals as compared to BA. Thus, BM was taken further for the evaluation of the beneficial effects of 14-day pre-treatment in rats in the scopolamine (2 mg/kg, i.p.) induced amnesia model at 125, 250 and 500 mg/kg, p.o. BM pre-treatment at 250 and 500 mg/kg could significantly ameliorate the cognitive impairment (p < 0.001), inhibit AChE (p < 0.001) and BuChE (p < 0.05) activity, restore GSH levels (p < 0.05) in serum and brain homogenates and recover the morphology of hippocampal neurons back to normal. Moreover, the BM administration at 500 mg/kg also showed beneficial effects through the significant (p < 0.05) reduction of Aß1-42, phosphorylated tau (p-tau) and GSK-3ß immunoreactivity in the brain homogenates of the intracerebroventricularly streptozotocin (ICV STZ) injected rats as observed from the results of the ELISA assays. The outcomes of the study unveiled that BM exerts its beneficial effects through prevention of NMDA induced excitotoxic cell death, dual cholinesterase inhibition, antioxidant activity coupled with the reduction of the immunoreactivity for the Aß1-42, p-tau and GSK-3ß indicating its potential to be screened further for various other models to determine the exact mechanism of action.

Bergenia ciliata ameliorates streptozotocin-induced spatial memory deficits through dual cholinesterase inhibition and attenuation of oxidative stress in rats.

Bergenia ciliata (Haw.) Sternb. rhizomes, family Saxifragaceae, are claimed to possess an array of beneficial effects like antioxidant, anti-inflammatory, immunomodulatory, antibacterial and anticancer activities. The plant has also been reported to be used by Nepalese folk to alleviate symptoms related to Parkinson's disease. Oxidative stress is one of the major reasons for cognitive decline observed in sporadic Alzheimer's disease (AD). Bergenia ciliata rhizomes have depicted potent antioxidant properties, but their role in the treatment of Alzheimer's disease is yet unexplored. Therefore, the present study was intended to explore the beneficial effects of methanolic extracts of rhizomes of B. ciliata (BM) in a streptozotocin-induced model of Alzheimer's disease in Wistar rats. Streptozotocin (STZ) was injected intracerebroventricularly (ICV) on day 1 (3 mg/kg, unilaterally) in Wistar rats. BM was thereafter administered (125, 250 and 500 mg/kg b.w./day p.o.), daily for 28 days. Morris water maze and Y maze test were used to evaluate learning and memory in rats on 7th, 14th, 21st and 28th days following initiation of dosing. Terminally, acetylcholinesterase activity, butyrylcholinesterase, and levels of oxidative stress markers were assessed in the serum as well as in brain homogenates of rats. Additionally, histopathological studies were carried out to observe effects in brain tissues at the cellular level. STZ produced significant (p < 0.001) learning and memory impairment, oxidative stress as well as a cholinergic deficit in rats. Whereas, BM treatment at various dose levels was able to significantly and dose-dependently diminish STZ induced behavioral deficits and biochemical anomalies in rats. The observed cognitive improvement following BM administration in STZ injected rats may be accredited to its antioxidant activity and refurbishment of cholinergic functions. The results of the study are indicative of the therapeutic potential of Bergenia ciliata in cognitive disorders such as AD as well as other such neurodegenerative disorders.

Polymeric Immunonanoparticles Mediated Cancer Therapy: Versatile Nanocarriers for Cell-Specific Cargo Delivery.

The major drawback with conventional therapeutic approaches for cancer therapy is decreased efficacy and redundant therapy associated toxicity and side effects causing increased patient discomfort. With the aim of minimizing these limitations, a vast amount of attention has been given to targeted nanocarrier-based drug delivery systems that possess a several-fold advantage over conventional therapy. Increased research in targeted nanoparticulate systems has led to the development of immunonanoparticles with enhanced efficacy and targeting efficiency along with decreased drug-resistant cancer- and dose-related toxicity. These immunonanoparticle- based therapies, which can be extended to immunotherapy, have gained wide attention, but few formulations will be approved by regulatory agencies in the near future. This review details the various immunonanoparticle systems explored in cancer therapy, with particular emphasis on polymeric nanoparticles. This review describes the mechanisms of immunotherapy and the pathways for targeting dendritic cells for immunotherapy. It also focuses on present status of clinical trials of immunonanoparticles and related patents, as well as various FDA-approved monoclonal antibodies (mAbs) for immunotherapy. Toxicity issues related to immunonanoparticles along with regulatory guidelines for these therapeutic nanoparticles are also discussed.