Genistein: a promising modulator of apoptosis and survival signaling in cancer.

Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies.

Nano-mediated strategy for targeting and treatment of non-small cell lung cancer (NSCLC).

Lung cancer is the most common type of cancer, with over 2.1 million cases diagnosed annually worldwide. It has a high incidence and mortality rate, leading to extensive research into various treatment options, including the use of nanomaterial-based carriers for drug delivery. With regard to cancer treatment, the distinct biological and physico-chemical features of nano-structures have acquired considerable impetus as drug delivery system (DDS) for delivering medication combinations or combining diagnostics and targeted therapy. This review focuses on the use of nanomedicine-based drug delivery systems in the treatment of lung cancer, including the use of lipid, polymer, and carbon-based nanomaterials for traditional therapies such as chemotherapy, radiotherapy, and phototherapy. The review also discusses the potential of stimuli-responsive nanomaterials for drug delivery in lung cancer, and the limitations and opportunities for improving the design of nano-based materials for the treatment of non-small cell lung cancer (NSCLC).

Targeting Acanthamoeba proteins interaction with flavonoids of Propolis extract by in vitro and in silico studies for promising therapeutic effects.

Background : Propolis is a natural resinous mixture produced by bees. It provides beneficial effects on human health in the treatment/management of many diseases. The present study was performed to demonstrate the anti- Acanthamoeba activity of ethanolic extracts of Propolis samples from Iran. The interactions of the compounds and essential proteins of Acanthamoeba were also visualized through docking simulation. Methods: The minimal inhibitory concentrations (MICs) of Propolis extract against Acanthamoeba trophozoites and cysts was determined in vitro. In addition, two-fold dilutions of each of agents were tested for encystment, excystment and adhesion inhibitions. Three major compounds of Propolis extract such as chrysin, tectochrysin and pinocembrin have been selected in molecular docking approach to predict the compounds that might be responsible for encystment, excystment and adhesion inhibitions of A. castellanii. Furthermore, to confirm the docking results, molecular dynamics (MD) simulations were also carried out for the most promising two ligand-pocket complexes from docking studies. Results : The minimal inhibitory concentrations (MICs) 62.5 and 125 µg/mL of the most active Propolis extract were assessed in trophozoites stage of Acanthamoeba castellanii ATCC30010 and ATCC50739, respectively. At concentrations lower than their MICs values (1/16 MIC), Propolis extract revealed inhibition of encystation. However, at 1/2 MIC, it showed a potential inhibition of excystation and anti-adhesion. The molecular docking and dynamic simulation revealed the potential capability of Pinocembrin to form hydrogen bonds with A. castellanii Sir2 family protein (AcSir2), an encystation protein of high relevance for this process in Acanthamoeba. Conclusions : The results provided a candidate for the development of therapeutic drugs against Acanthamoeba infection. In vivo experiments and clinical trials are necessary to support this claim.

Factors leading to neonatal mortality due to neonatal purpura fulminans through the lens of a child death review.

A case of neonatal death due to neonatal purpura fulminans (NPF) was brought to community physicians' notice by the auxiliary nurse midwife in her catchment area as part of the routine demographic health surveillance. The community physician then conducted the child death review in the community. The neonate was born out of consanguineous marriage (mother married to her first-degree maternal cousin) with spontaneous conception. This neonate was fourth in the birth order. The second-order and third-order births had also suffered from NPF and died. The baby was delivered in a tertiary care setting, and the paediatric surgeon planned debridement of the affected part on the third day of the birth, as per the mother. However, due to inadequate counselling regarding the procedure, mother left the hospital without seeking care against medical advice, and the child died at home.

Contribution of social factors to maternal deaths in urban India: Use of care pathway and delay models.

This paper uses care pathway and delay models to better understand the possible social reasons for maternal deaths in a city with good public and private health infrastructure. The findings can inform programmes to reduce maternal mortality. During 2007-15, 136 maternal deaths were reported in Chandigarh, India. Using World Health Organisation's verbal autopsy questionnaire, interviews were conducted with primary caregivers of 68 (50%) of the 136 deceased women, as majority of the families had returned to their native places. We used process-tracing techniques to construct the care pathways and identify delays, and explored open-ended responses using thematic analysis. The mean age of the deceased women was 27 years, 51% resided in slums, 32% were primigravida, 25% had their deliveries assisted by traditional birth attendants, and 23% had Caesarean section. Eight percent died at home, and 54% died in tertiary level facilities. Post-partum haemorrhage (26.5%), and complications of puerperium (25%) and labour/delivery (14.7%) were the reported medical causes. Male child preference and norms for home delivery were identified as the distal socio-cultural causes. Individual and family level factors included: shame on multiple pregnancies; fear of discrimination from providers; past successful deliveries at home leading to overconfidence and not seeking institutional care; and lack of awareness about family planning, antenatal care, and danger signs of pregnancy. Healthcare system factors were: non-availability of senior doctors at the time of consultation in the emergency that delayed initiation of immediate treatment, and lack of availability of life-saving equipment due to patient load. Empirical evidence was found on social causes of maternal deaths, which could have been prevented by appropriate actions at individual, family, societal, institutional and policy levels. This study identified potential preventable causes of primarily social origin, which could help in taking actionable steps at several levels to further reduce maternal deaths in India.

Impact of m-health application used by community health volunteers on improving utilisation of maternal, new-born and child health care services in a rural area of Uttar Pradesh, India.

OBJECTIVE: To raise the quality of counselling by community health volunteers resulting in improved uptake of maternal, neonatal and child health services (MNCH), an m-health application was introduced under a project named 'Reducing Maternal and Newborn Deaths (ReMiND)' in district Kaushambi in India. We report the impact of this project on coverage of key MNCH services. METHODS: A pre- and post-quasi-experimental design was undertaken to assess the impact of intervention. This project was introduced in two community development blocks in Kaushambi district in 2012. Two other blocks from the same district were selected as controls after matching for coverage of two indicators at baseline - antenatal care and institutional deliveries. The Annual Health Survey conducted by the Ministry of Health and Family Welfare in 2011 served as pre-intervention data, whereas a household survey in four blocks of Kaushambi district in 2015 provided post-intervention coverage of key services. Propensity score matched samples from intervention and control areas in pre-intervention and post-intervention periods were analysed using difference-in-difference method to estimate the impact of ReMiND project. RESULTS: We found a statistically significant increase in coverage of iron-folic acid supplementation (12.58%), self-reporting of complication during pregnancy (13.11%) and after delivery (19.6%) in the intervention area. The coverage of three or more antenatal care visits, tetanus toxoid vaccination, full antenatal care and ambulance usage increased in intervention area by 10.3%, 4.28%, 1.1% and 2.06%, respectively; however, the changes were statistically insignificant. CONCLUSION: Three of eight services which were targeted for improvement under ReMiND project registered a significant improvement as result of m-health intervention.

Capsaicin-loaded vesicular systems designed for enhancing localized delivery for psoriasis therapy.

The aim of the current investigation is to evaluate the potential of capsaicin (CAP)-containing liposomes, niosomes and emulsomes in providing localized and controlled delivery, to improve the topical delivery of drug. CAP-bearing systems were prepared by the film hydration method and compared through various in vitro and in vivo parameters. The TEM photographs suggested that the carrier systems were spherical in shape and nanometric in size range. Skin retention studies of CAP from in vitro and in vivo experiments revealed significantly higher accumulation of drug in the case of the emul-gel formulation. Based on the results, we concluded that the emul-gel may be a potential approach for the topical delivery of CAP, for an effective therapy for psoriasis.

Magnesium protects against cisplatin-induced acute kidney injury without compromising cisplatin-mediated killing of an ovarian tumor xenograft in mice.

Cisplatin, a commonly used chemotherapeutic for ovarian and other cancers, leads to hypomagnesemia in most patients and causes acute kidney injury (AKI) in 25-30% of patients. Previously, we showed that magnesium deficiency worsens cisplatin-induced AKI and magnesium replacement during cisplatin treatment protects against cisplatin-mediated AKI in non-tumor-bearing mice (Solanki MH, Chatterjee PK, Gupta M, Xue X, Plagov A, Metz MH, Mintz R, Singhal PC, Metz CN. Am J Physiol Renal Physiol 307: F369-F384, 2014). This study investigates the role of magnesium in cisplatin-induced AKI using a human ovarian tumor (A2780) xenograft model in mice and the effect of magnesium status on tumor growth and the chemotherapeutic efficacy of cisplatin in vivo. Tumor progression was unaffected by magnesium status in saline-treated mice. Cisplatin treatment reduced tumor growth in all mice, irrespective of magnesium status. In fact, cisplatin-treated magnesium-supplemented mice had reduced tumor growth after 3 wk compared with cisplatin-treated controls. While magnesium status did not interfere with tumor killing by cisplatin, it significantly affected renal function following cisplatin. Cisplatin-induced AKI was enhanced by magnesium deficiency, as evidenced by increased blood urea nitrogen, creatinine, and other markers of renal damage. This was accompanied by reduced renal mRNA expression of the cisplatin efflux transporter Abcc6. These effects were significantly reversed by magnesium replacement. On the contrary, magnesium status did not affect the mRNA expression of cisplatin uptake or efflux transporters by the tumors in vivo. Finally, magnesium deficiency enhanced platinum accumulation in the kidneys and renal epithelial cells, but not in the A2780 tumor cells. These findings demonstrate the renoprotective role of magnesium during cisplatin AKI, without compromising the chemotherapeutic efficacy of cisplatin in an ovarian tumor-bearing mouse model.

Capsaicin delivery into the skin with lipidic nanoparticles for the treatment of psoriasis.

The study aims to explore the potential of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) in improving the topical delivery of capsaicin (CAP) by in vitro and in vivo studies. The lipidic nanoparticles were prepared by solvent diffusion method and were characterized for average particle size, zeta potential and entrapment efficiency. TEM photomicrographs revealed that the particles were nanometric in size. Higher amount of CAP can be encapsulated in the NLCs (87.4 ± 3.28) as compared with SLNs (79.7 ± 2.93%). The cumulative amounts of CAP permeated through the skin and retained in the SC were higher in the case of NLCs as compared with plain drug solution and SLNs. SLNs and NLCs exhibited minimum to no irritation. All the results concluded that NLCs and SLNs have shown a good ability to increase drug accumulation in the various skin layers but NLCs may be a more potential carrier for topical delivery of CAP for an effective therapy of psoriasis.

Omega-3 polyunsaturated fatty acids enhance cytokine production and oxidative stress in a mouse model of preterm labor.

OBJECTIVE: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation during pregnancy remains controversial. We sought to examine the effects of ω-3 PUFA on inflammation and oxidative stress in vitro and in vivo using a model of preterm labor. METHODS: In vivo. Female Swiss Webster mice were fed a normal diet or a 5% fish oil (FO) diet for 3 weeks then mated with normal-fed males. On gestational day 15, dams were injected with either saline (n=10 per group) or lipopolysaccharide (LPS, intrauterine) (n=10 per group). Maternal plasma, amniotic fluid, placentas, and uteri were collected 4 h later and assessed for cytokines; maternal plasma and amniotic fluids were analyzed for oxidative stress. In vitro. RAW264.7 mouse macrophage-like cells were treated with either: vehicle, H2O2, docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA) (0, 0.1-100 µM) and analyzed for oxidative stress. RESULTS: In vivo. Administration of the 5% FO diet enhanced LPS-induced cytokines in the placenta (P<0.05-0.01) and increased tumor necrosis factor-α in the uterus (P<0.05) and amniotic fluid (P<0.01) when compared to LPS-treated normal-fed animals. Maternal plasma obtained from FO-fed dams showed higher LPS-induced oxidative stress than control-fed animals (P<0.035). However, no differences in oxidative stress were observed in the amniotic fluid. In vitro. Treatment of macrophage-like cells with ω-3 PUFA significantly and dose-dependently increased oxidative stress (P<0.001-0.0001). CONCLUSIONS: Supplementation with FO for prior to and during pregnancy significantly increased LPS-induced inflammation in the amniotic fluid, uterus, and placenta and significantly increased maternal systemic oxidative stress in vivo. Likewise, DHA and EPA induced oxidative stress in macrophage-like cells in vitro.

Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation.

Despite its success as a potent antineoplastic agent, ∼25% of patients receiving cisplatin experience acute kidney injury (AKI) and must discontinue therapy. Impaired magnesium homeostasis has been linked to cisplatin-mediated AKI, and because magnesium deficiency is widespread, we examined the effect of magnesium deficiency and replacement on cisplatin-induced AKI in physiologically relevant older female mice. Magnesium deficiency significantly increased cisplatin-associated weight loss and markers of renal damage (plasma blood urea nitrogen and creatinine), histological changes, inflammation, and renal cell apoptosis and modulated signaling pathways (e.g., ERK1/2, p53, and STAT3). Conversely, these damaging effects were reversed by magnesium. Magnesium deficiency alone significantly induced basal and cisplatin-mediated oxidative stress, whereas magnesium replacement attenuated these effects. Similar results were observed using cisplatin-treated LLC-PK1 renal epithelial cells exposed to various magnesium concentrations. Magnesium deficiency significantly amplified renal platinum accumulation, whereas magnesium replacement blocked the augmented platinum accumulation after magnesium deficiency. Increased renal platinum accumulation during magnesium deficiency was accompanied by reduced renal efflux transporter expression, which was reversed by magnesium replacement. These findings demonstrate the role of magnesium in regulating cisplatin-induced AKI by enhancing oxidative stress and thus promoting cisplatin-mediated damage. Additional in vitro experiments using ovarian, breast, and lung cancer cell lines showed that magnesium supplementation did not compromise cisplatin's chemotherapeutic efficacy. Finally, because no consistently successful therapy to prevent or treat cisplatin-mediated AKI is available for humans, these results support developing more conservative magnesium replacement guidelines for reducing cisplatin-induced AKI in cancer patients at risk for magnesium deficiency.

Options and opportunities for clinical management and treatment of psoriasis.

Psoriasis is a complex, multifactorial disease that appears to be influenced by immune-mediated components. For many years the pathogenesis of psoriasis has been discordant; the clinical picture suggested that the psoriasis was secondary to abnormal keratinocyte proliferation and differentiation, but later the role of the T cell was revealed. A variety of treatment options range from topical agents (e.g., coal tar, dithranol, and emollients for milder forms) to systemic agents (i.e., methotrexate or cyclosporin), and phototherapy. Recently, biologics have been added to this list that target particular steps in the immune or inflammatory pathways. Various nanocarriers (e.g., liposomes, niosomes, and microemulsions) have been successfully exploited for the delivery of several antipsoriatic drugs. This review provides insight into various psoriasis treatment strategies-from conventional to novel-currently in use or in development as well as the novel targets that have been explored and/or investigated for anti-psoriatic therapy. The pathogenesis of psoriasis and some of the topical, systemic biological, and novel approaches currently in use or in development are reviewed here. The pros and cons of each treatment strategy are presented, as are some of the animal models used to study features reminiscent of psoriasis. This information can be used to better the understanding of treatment options for this disease.

Maternal magnesium supplementation reduces intrauterine growth restriction and suppresses inflammation in a rat model.

OBJECTIVE: Intrauterine growth restriction (IUGR) is associated with increased inflammatory responses. We sought to investigate whether magnesium (Mg) attenuates inflammation and IUGR in a rat model. STUDY DESIGN: Pregnant Wistar rats (12 weeks, gestational day 18) were randomly assigned to 1 of 4 groups: normal diet with bilateral uterine artery ligation (BL) (n = 6) or sham surgery (SH) (n = 5); and Mg chloride (MgCl2) 1% (wt/vol) in the drinking water throughout gestation + BL (MgBL) (n = 6) or SH (MgSH) (n = 5). Dams were euthanized 24 hours postsurgery (gestational day 19). Maternal plasma, fetal plasma (pooled), individual amniotic fluid (AF) samples, and placentas (PL) were collected and assessed from live fetal pups only (BL, n = 36; SH, n = 20; MgBL, n = 20; MgSH, n = 20). All samples were analyzed for cytokines/chemokines (interleukin [IL]-6, IL-1ß, chemokine [C-X-C motif] ligand 1 [CXCL1], chemokine [C-C motif] ligand 2 [CCL2], and tumor necrosis factor [TNF-α] sensitivity <3 pg/mL) using a multiplex platform. Data were analyzed using Mann Whitney, analysis of variance, and Fisher exact tests. RESULTS: The incidence of IUGR (pup weight <10th percentile of SH) in the MgBL group was significantly lower (31%) than the BL group (86.3%) (relative risk, 0.36; 95% confidence interval, 0.2-0.6; P < .0001). BL significantly increased AF levels of IL-6, IL-1ß, TNF-α (P < .05), and CCL2 (P < .001) vs SH and PL levels of IL-6, IL-1ß, CCL2 and CXCL1 (P < .001), and TNF-α (P < .05) vs SH. Maternal MgCl2 supplementation significantly decreased IL-1ß, TNF-α, and CCL2 levels in AF and IL-1ß in PL tissues of MgBL vs BL rats (P < .0001). CONCLUSION: Maternal oral MgCl2 supplementation reduced BL-induced IUGR by 64% and suppressed cytokine/chemokine levels in the AF and PL.

Knowledge and skills of primary health care workers trained on integrated management of neonatal and childhood illness: follow-up assessment 3 years after the training.

BACKGROUND: The primary health care workers of a district in northern India were trained in the year 2006 for Integrated Management of Neonatal and Childhood Illness (IMNCI) using two different training methods: conventional 8-day training and new interrupted 5-day training. Knowledge and skills may decline over a period of time. Rate of decline may be associated with the type of training. A study was thus conducted to see the retention of knowledge and skills in the two training groups, 3 years after the initial training. MATERIALS AND METHODS: This study was done in the Panchkula district of Haryana state in northern India. In the year 2006, 50 primary health care workers were given new interrupted 5-day training and another 35 workers were given conventional 8-day training on IMNCI. Knowledge and skills of the same workers were evaluated in the year 2009, using the same methodology and tools as were used in the year 2006. Data analysis was done to see the extent of decline in knowledge and skills in these 3 years and whether decline was more in any particular training group. RESULTS: Compared to post-training score in the year 2006, composite knowledge and skill scores for Auxilliary Nurse Midwives (ANMs) and Anganwari workers (AWWs) together declined significantly in the year 2009 from 74.6 to 58.0 in 8-day training group and from 73.2 to 57.0 in 5-day training group (P < 0.001). Follow-up composite scores in the two training groups were similar. Whereas the decline was more for knowledge scores in 8-day training group and for skill score in 5-day training group, the pattern of decline was inconsistent for different health conditions and among ANMs and AWWs. CONCLUSION: Long-term retention of knowledge and skills in 5-day group was equivalent to that in 8-day training group. Refresher trainings may boost up the decline in the knowledge and skills.