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Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.

The burden of mental, neurological, and substance use (MNS) disorders increased by 41% between 1990 and 2010 and now accounts for one in every 10 lost years of health globally. This sobering statistic does not take into account the substantial excess mortality associated with these disorders or the social and economic consequences of MNS disorders on affected persons, their caregivers, and society. A wide variety of effective interventions, including drugs, psychological treatments, and social interventions, can prevent and treat MNS disorders. At the population-level platform of service delivery, best practices include legislative measures to restrict access to means of self-harm or suicide and to reduce the availability of and demand for alcohol. At the community-level platform, best practices include life-skills training in schools to build social and emotional competencies. At the health-care-level platform, we identify three delivery channels. Two of these delivery channels are especially relevant from a public health perspective: self-management (eg, web-based psychological therapy for depression and anxiety disorders) and primary care and community outreach (eg, non-specialist health worker delivering psychological and pharmacological management of selected disorders). The third delivery channel, hospital care, which includes specialist services for MNS disorders and first-level hospitals providing other types of services (such as general medicine, HIV, or paediatric care), play an important part for a smaller proportion of cases with severe, refractory, or emergency presentations and for the integration of mental health care in other health-care channels, respectively. The costs of providing a significantly scaled up package of specified cost-effective interventions for prioritised MNS disorders in low-income and lower-middle-income countries is estimated at US$3–4 per head of population per year. Since a substantial proportion of MNS disorders run a chronic and disabling course and adversely affect household welfare, intervention costs should largely be met by government through increased resource allocation and financial protection measures (rather than leaving households to pay out-of-pocket). Moreover, a policy of moving towards universal public finance can also be expected to lead to a far more equitable allocation of public health resources across income groups. Despite this evidence, less than 1% of development assistance for health and government spending on health in low-income and middle-income countries is allocated to the care of people with these disorders. Achieving the health gains associated with prioritised interventions will require not just financial resources, but committed and sustained efforts to address a range of other barriers (such as paucity of human resources, weak governance, and stigma). Ultimately, the goal is to massively increase opportunities for people with MNS disorders to access services without the prospect of discrimination or impoverishment and with the hope of attaining optimal health and social outcomes.

The present investigation was executed to reveal the protective mechanism of rosmarinic acid (RA) against cadmium (Cd)-induced nephrotoxicity. RA exhibited a concentration-dependent anti-apoptotic effect against CdCl2 in isolated mouse proximal tubular epithelial cells. Cd treatment significantly (p < 0.01) imparted oxidative stress to the renal cells via excessive ROS production, triggering NO level, NADPH oxidase activation, and impairment of cellular redox defense system. Cd-mediated oxidative stress significantly (p < 0.01) endorsed apoptosis to the murine kidney cells by triggering NF-κB/PKC-δ/TNFR2 activation. In addition, CdCl2 induced renal fibrosis by triggering TGF-β1/SMAD3/α-SMA/collagen signaling within renal cells. On the other hand, RA significantly (p < 0.05–0.01) attenuated Cd-provoked oxidative stress and associated pathological signal transduction in murine renal cells. RA treatment also could significantly (p < 0.05–0.01) reciprocate Cd-mediated pathological changes in blood and urine parameters in mice. In addition, histological data supported the pharmacological findings. In silico chemometric analyses predicted the possible interactions between RA and different signal proteins and anticipated drug-likeness characteristics of RA. Hence, RA can potentially be applied as a therapeutic agent to treat Cd-mediated nephrotoxicity in future.

Building on long-term benefits of early intervention (Paper 2 of this Series) and increasing commitment to early childhood development (Paper 1 of this Series), scaled up support for the youngest children is essential to improving health, human capital, and wellbeing across the life course. In this third paper, new analyses show that the burden of poor development is higher than estimated, taking into account additional risk factors. National programmes are needed. Greater political prioritisation is core to scale-up, as are policies that afford families time and financial resources to provide nurturing care for young children. Effective and feasible programmes to support early child development are now available. All sectors, particularly education, and social and child protection, must play a role to meet the holistic needs of young children. However, health provides a critical starting point for scaling up, given its reach to pregnant women, families, and young children. Starting at conception, interventions to promote nurturing care can feasibly build on existing health and nutrition services at limited additional cost. Failure to scale up has severe personal and social consequences. Children at elevated risk for compromised development due to stunting and poverty are likely to forgo about a quarter of average adult income per year, and the cost of inaction to gross domestic product can be double what some countries currently spend on health. Services and interventions to support early childhood development are essential to realising the vision of the Sustainable Development Goals.

Postpartum depression and anxiety are highly prevalent worldwide. Fisher et al., estimated the prevalence of depression and anxiety at 15.6% during the antenatal and 19.8% during the postpartum period. Their impact on maternal and child health is well-recognized among the public health community, accounting for high societal costs. The public health impact of these conditions has highlighted the need to focus on the development and provision of effective prevention and treatment strategies. In recent decades, some advances have been made in the development of effective universal and targeted screening programmes for perinatal depression and anxiety disorders. Recent research has shown potential benefits of universal and targeted screening for perinatal depression, to identify and treat undiagnosed cases, and help thwart its deleterious consequences. Ethical implications, however, for these screening programmes, without the provision of treatment have often been emphasized. The present mixed-methods systematic review and meta-analysis was conducted to collate evidence for screening programmes for perinatal depression and anxiety. It aims to answer the following questions, in a global context: For women in the perinatal period, do screening programmes for perinatal depression and anxiety compared with no screening improve maternal mental health and infant outcomes? A series of meta-analyses reveal a reduction in perinatal depression and anxiety among perinatal women undergoing screening programmes. For the outcome of depressive disorder, meta-analysis indicates a positive impact in favour of the intervention group (OR = 0.55, 95% CI: 0.45 to 0.66, n = 9009), with moderate quality of evidence. A significant improvement (high quality) was also observed in symptoms of anxiety among perinatal women (SMD = - 0.18, 95% CI: - 0.25 to - 0.12, n = 3654). (ZPID).

The present study evaluated the therapeutic potential of myricitrin (Myr), a glycosyloxyflavone extracted from Myrica esculenta bark, against diabetic nephropathy. Myr exhibited a significant hypoglycemic effect in high fat-fed and a single low-dose streptozotocin-induced type 2 diabetic (T2D) rats. Myr was found to improve glucose uptake by the skeletal muscle via activating IRS-1/PI3K/Akt/GLUT4 signaling in vitro and in vivo. Myr significantly attenuated high glucose (HG)-induced toxicity in NRK cells and in the kidneys of T2D rats. In this study, hyperglycemia caused nephrotoxicity via endorsing oxidative stress and inflammation resulting in the induction of apoptosis, fibrosis, and inflammatory damages. Myr was found to attenuate oxidative stress via scavenging/neutralizing oxidative radicals and improving endogenous redox defense through Nrf-2 activation in both in vitro and in vivo systems. Myr was also found to attenuate diabetes-triggered renal inflammation via suppressing NF-κB activation. Myr inhibited hyperglycemia-induced apoptosis and fibrosis in renal cells evidenced by the changes in the expressions of the apoptotic and fibrotic factors. The molecular docking predicted the interactions between Myr and different signal proteins. An in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) study predicted the drug-likeness character of Myr. Results suggested the possibility of Myr to be a potential therapeutic agent for diabetic nephropathy in the future.

Persistent hyperglycemia, impairment of redox status and establishment of inflammatory pathophysiology integrally play important role in the pathogenesis of diabetic cardiomyopathy (DC). Present study examined the therapeutic potential of protocatechuic acid isolated from the rhizomes against DC employing rodent model of type 2 diabetes (T2D). T2D was induced by high fat diet + a low-single dose of streptozotocin (35 mg/kg, i.p.). T2D rats exhibited significantly ( < 0.01) high fasting blood glucose level. Alteration in serum lipid profile ( < 0.01) and increased levels of lactate dehydrogenase ( < 0.01) and creatine kinase ( < 0.01) in the sera of T2D rats revealed the occurrence of hyperlipidemia and diabetic pathophysiology. A significantly ( < 0.01) high levels of serum C-reactive protein and pro-inflammatory mediators revealed the establishment of inflammatory occurrence in T2D rats. Besides, significantly high levels of troponins in the sera revealed the establishment of cardiac dysfunctions in T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly reverse the changes in serum biochemical parameters related to cardiac dysfunctions. Molecular mechanism studies demonstrated impairment of signaling cascade, IRS1/PI3K/Akt/AMPK/p 38/GLUT4, in glucose metabolism in the skeletal muscle of T2D rats. Significant ( < 0.01) activation of polyol pathway, enhanced production of AGEs, oxidative stress and up-regulation of inflammatory signaling cascades (PKC/NF-κB/PARP) were observed in the myocardial tissue of T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly ( < 0.05-0.01) stimulate glucose metabolism in skeletal muscle, regulated glycemic and lipid status, reduced the secretion of pro-inflammatory cytokines, and restored the myocardial physiology in T2D rats near to normalcy. Histological assessments were also in agreement with the above findings. molecular docking study again supported the interactions of protocatechuic acid with different signaling molecules, PI3K, IRS, Akt, AMPK PKC, NF-κB and PARP, involved in glucose utilization and inflammatory pathophysiology. ADME study predicted that protocatechuic acid would support the drug-likeness character. Combining all, results would suggest a possibility of protocatechuic acid to be a new therapeutic agent for DC in future.

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05–0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-β1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity.

To describe the magnitude and variation of the epilepsy treatment gap worldwide. We conducted a systematic review of the peer-reviewed literature published from 1 January 1987 to 1 September 2007 in all languages using PubMed and EMBASE. The purpose was to identify population-based studies of epilepsy prevalence that reported the epilepsy treatment gap, defined as the proportion of people with epilepsy who require but do not receive treatment. Negative binomial regression models were used to assess trends and associations. The treatment gap was over 75% in low-income countries and over 50% in most lower middle- and upper middle-income countries, while many high-income countries had gaps of less than 10%. However, treatment gaps varied widely both between and within countries. They were significantly higher in rural areas (rate ratio, RR: 2.01; 95% confidence interval, CI: 1.40-2.89) and countries with lower World Bank income classification (RR: 1.55; 95% CI: 1.32-1.82). There was no significant trend in treatment gap over time (RR: 0.92; 95% CI: 0.79-1.07). There is dramatic global disparity in the care for epilepsy between high- and low- income countries, and between rural and urban settings. Our understanding of the factors affecting the treatment gap is limited; future investigations should explore other potential explanations of the gap.

At the First WHO Ministerial Conference on Global Action Against Dementia in March, 2015, 160 delegates, including representatives from 80 WHO Member States and four UN agencies, agreed on a call for action to reduce the global burden of dementia by fostering a collective effort to advance research. To drive this effort, we completed a globally representative research prioritisation exercise using an adapted version of the Child Health and Nutrition Research Initiative method. We elicited 863 research questions from 201 participants and consolidated these questions into 59 thematic research avenues, which were scored anonymously by 162 researchers and stakeholders from 39 countries according to five criteria. Six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers. Other priorities related to diagnosis, biomarkers, treatment development, basic research into disease mechanisms, and public awareness and understanding of dementia. Research priorities identified by this systematic international process should be mapped onto the global dementia research landscape to identify crucial gaps and inform and motivate policy makers, funders, and researchers to support and conduct research to reduce the global burden of dementia. Efforts are needed by all stakeholders, including WHO, WHO Member States, and civil society, to continuously monitor research investments and progress, through international platforms such as a Global Dementia Observatory. With established research priorities, an opportunity now exists to translate the call for action into a global dementia action plan to reduce the global burden of dementia.