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Abstract Distant metastasis is a significant hallmark affecting to the high death rate of patients with triple-negative breast cancer (TNBC). Thus, it is crucial to identify and develop new therapeutic strategies to hinder cancer metastasis. While emerging studies have hinted a pivotal role of glucose-regulated protein 94 (GRP94) in tumorigenesis, the exact biological functions and molecular mechanisms of GRP94 in modulating cancer metastasis remain to be elucidated. Our study demonstrated an increased expression of GRP94 in TNBC correlated with metastatic progression and unfavorable prognosis in patients. Functionally, we identified that GRP94 depletion significantly diminished TNBC tumorigenesis and subsequent lung metastasis. In contrast, GRP94 overexpression exacerbated the invasiveness, migration, and lung metastasis of non-TNBC cells. Mechanistically, we found that casein kinase 2 alpha (CK2α) active in advanced breast cancer phosphorylated GRP94 at a conserved serine 306 (S306) residue. This phosphorylation increased the stability of GRP94 and enhanced its interaction with LRP6, leading to activation of canonical Wnt signaling. From a therapeutic standpoint, we found that benzamidine, a novel CK2α inhibitor, effectively suppressed GRP94 phosphorylation, LRP6 stabilization, and metastasis of TNBC. Our results point to the critical role of CK2α-mediated GRP94 phosphorylation in TNBC metastasis through activation of Wnt signaling, highlighting GRP94 as a therapeutic target to impede TNBC metastasis.

During testing, an error in software can either propagate to the output variables or be masked before it reaches them. Error propagation and masking characteristics are crucial in software testing because they directly influence testing effectiveness. The testing community has hence focused on developing test mechanisms to promote the propagation and reduce masking of errors in software under test. However, little is known about how severely the errors propagate and are masked during software execution. Moreover, little is known about what influences software’s propagation and masking characteristics. Thus, in this study, we performed experiments to investigate the behavior of errors during software execution. We chose six case examples and created mutants per case example by seeding an error into each one. We then executed the mutants with randomly selected test cases and investigated how many errors were propagated and masked. If an error was masked, we examined the cause. In addition, we investigated what percentage of errors in the mutants reached the output variables. This study provides insight into the characteristics of errors in terms of propagation and masking, which will help testers design test inputs and choose monitoring variables to properly handle the masking of errors during testing.

IntroductionIn 2016, UNAIDS set ambitious targets to reduce global HIV infections by 75% by 2020 and 90% by 2030, based on the 2.1 million new infections reported in 2010. However, by 2022, new HIV infections had only decreased by 38%, from 2.1 million in 2010 to 1.3 million in 2022, raising concerns about reaching the 2030 goal. Female sex workers (FSWs) in sub-Saharan Africa face a disproportionately high risk of HIV acquisition, contributing 5%–20% of all new infections in several countries in the region. This analysis investigates HIV seroconversion and associated factors among FSWs, offering insights into critical interventions for preventing HIV transmission in this population and advancing the goal of ending the HIV pandemic by 2030.MethodsWe conducted a retrospective cohort study involving 17,977 FSWs who initially tested HIV negative upon enrollment in the Sauti project between October 2016 and September 2018. HIV incidence rates were calculated by dividing the number of new HIV cases by observed person-time within the cohort. Cox regression analysis identified factors associated with seroconversion.ResultsThe study revealed an HIV incidence rate of 8.6 per 100 person-years among FSWs [95% confidence interval (CI): 8.1–9.1]. Factors independently associated with HIV seroconversion included age 35 years or older [adjusted hazard ratio (aHR): 2.53; 95% CI: 2.03–3.14], unprotected sex (aHR: 1.27; 95% CI: 1.13–1.42), STI symptoms (aHR: 1.99; 95% CI: 1.67–2.38), and alcohol consumption before sex (aHR: 1.20; 95% CI: 1.07–1.34).ConclusionTargeted interventions are vital in curbing HIV transmission among FSWs, with a focus on expanding access to primary HIV prevention services, particularly for older FSWs who face heightened risk. Tailored sexual health education programs are imperative to encourage consistent condom use and enable informed decision-making. Accessible and timely STI screening and treatment services are crucial to mitigate HIV transmission risk. Collaborative partnerships between healthcare providers, community organizations, and government agencies are essential in implementing these interventions among FSWs.

The incidence of colitis‐associated colorectal cancer (CAC) has increased due to a high‐nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin‐protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING‐type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3‐deficient mice in an azoxymethane/dextran sulphate sodium‐induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll‐like receptor 4 (TLR4)‐mediated inflammation through ubiquitination‐dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation‐mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.

Background The World Health Organization recommends the implementation of maternity waiting homes (MWH) to reduce delays in access to obstetric care, particularly for high-risk pregnancies and mothers living far from health facilities, and as a result, several countries have rolled out MWHs. However, Rwanda has not implemented this recommendation on a large scale. There is only one MWH in the country, hence a gap in knowledge regarding the potential utilisation and benefits of MWHs. Objective To explore providers’ and clients’ perspectives on facilitators and barriers to the use of MWH in rural Rwanda. Methods We conducted a qualitative study to explore health providers’ and clients’ perspectives on facilitators and barriers to the use of MWH in Rwanda, between December 2020 and January 2021. We used key informant interviews and focus group discussions to collect data. Data were analysed using NVivo qualitative analysis software version 11. Results Facilitators included perceptions that the MWH offered either a peaceful and home-like environment, good-quality services, or timely obstetric services, and was associated with good maternal and neonatal outcomes. Barriers included limited awareness of the MWH among pregnant women, fear of health providers to operate the MWH at full capacity, women’s lack of autonomy, uncertainty over funding for the MWH, and perceived high user fees. Conclusion The Ruli MWH offers a peaceful environment for pregnant women while providing quality and timely obstetric care, resulting in positive maternal and neonatal outcomes for women. However, its existence and benefits are not widely known, and its use is limited due to inadequate resources. There is a need for increased awareness of the MWH among healthcare providers and the community, and lessons from this MWH could inform the scale up of MWHs in Rwanda.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a complex gastrointestinal disorder with a multifactorial etiology, including environmental triggers, autoimmune mechanisms, and genetic predisposition. Despite advancements in therapeutic strategies for IBD, its associated mortality rate continues to rise, which is often attributed to unforeseen side effects of conventional treatments. In this context, we explored the potential of Ecklonia cava extract (ECE), derived from an edible marine alga known for its anti-inflammatory and antioxidant properties, in mitigating IBD. This study investigated the effectiveness of ECE as a preventive agent in a murine model of dextran sulfate sodium (DSS)-induced colitis. Our findings revealed that pretreatment with ECE significantly ameliorated colitis severity, as evidenced by increased colon length, reduced spleen weight, and histological improvements demonstrated by immunohistochemical analysis. Furthermore, ECE significantly attenuated the upregulation of inflammatory cytokines and mediators and the infiltration of immune cells known to be prominent features of colitis in mice. Notably, ECE alleviated dysbiosis of intestinal microflora and aided in the recovery of damaged intestinal mucosa. Mechanistically, ECE exhibited protective effects against pathogenic colitis by inhibiting the NLRP3/NF-κB pathways known to be pivotal regulators in the inflammatory signaling cascade. These compelling results suggest that ECE holds promise as a potential candidate for IBD prevention. It might be developed into a functional food for promoting gastrointestinal health. This research sheds light on the preventive potential of natural compounds like ECE in the management of IBD, offering a safer and more effective approach to combating this challenging disease.

Introduction Tanzania had an estimated 5.400 maternal deaths in 2020. Suboptimal quality of antenatal care (ANC) presents a major challenge. It is not known what precisely the uptake of the various ANC components is, such as counseling on birth preparedness and complication readiness, preventive measures and screening tests. We assessed the level of receiving the various ANC components and associated factors in order to identify opportunities to improve ANC. Methods A cross-sectional household survey using a structured questionnaire through face-to-face interviews, was conducted in April 2016 in Mara and Kagera regions, Tanzania, applying a two-stage, stratified-cluster sampling design. The analysis included 1,162 women aged 15–49 years who attended ANC during their last pregnancy and had given birth not longer than two years prior to the survey. To account for inter- and intra-cluster variations, we used mixed-effect logistic regression to examine factors associated with receiving essential ANC components: counseling around birth preparedness and complication readiness (with presumed effects on knowledge about danger signs) and preventive measures. Results About In 878 (76.1%) women preparedness for birth and its complications was observed to exist. Overall counseling was low where 902 (77.6%) women received adequate counseling. Overall knowledge of danger signs was low in 467 women (40.2%). Uptake of preventive measures was low, with presumptive malaria treatment in 828 (71.3%) and treatment of intestinal worms in 519 (44.7%) women. Screening test levels varied for HIV in 1,057 (91.2%), any blood pressure measurement in 803 (70.4%), syphilis in 367 (32.2%) and tuberculosis in 186 (16.3%) women. After adjusting for age, wealth and parity, the likelihood of receiving adequate counseling on essential topics was less in women without education versus primary education (aOR 0.64; 95% CI 0.42–0.96) and in women who had Conclusion Overall uptake of various essential ANC components was low. Frequent ANC visits and ensuring privacy are all essential to improve the uptake of ANC.

Purpose: Most breast cancers are hormone-receptor-positive, and thus the first-line therapy for them is an anti-estrogen medication such as tamoxifen. If metastasis occurs or resistance to tamoxifen develops, the 5-year survival rates for breast cancer patients significantly decrease. Hence, a better understanding of the molecular mechanisms that contribute to breast cancer aggressiveness is of great importance. ERα36 is an estrogen receptor variant that is known to be upregulated in breast cancer patients receiving tamoxifen treatment or in triple-negative breast cancer cells. However, the specific molecular mechanism underlying ERα36-induced tamoxifen-resistance is not yet fully understood.Methods: ERα36-overexpressing MCF-7 cells were constructed by either plasmid transfection using ERα36 vector or retroviral infection using ERα36-V5-His vector. Target-gene expression was assessed by Western blot analysis and real-time PCR, and YAP activation was evaluated by luciferase assays and immunofluorescence. Cell proliferation and formation of three-dimensional spheroids were evaluated using the IncuCyte S3 Live Cell Analysis System.Results: We found that the expression patterns of Hippo signaling-related genes were significantly changed in ERα36-overexpressing MCF-7 cells compared to MCF-7 cells, which were also similarly observed in tamoxifen-resistant MCF-7 cells. Specifically, the protein expression level and activity of YAP, the core downstream protein of the Hippo pathway, were significantly increased in ERα36-overexpressing MCF-7 cells compared with MCF-7 cells. The aggressive phenotypes acquired by ERα36 overexpression in MCF-7 cells were destroyed by YAP knockout. On this basis, we propose that ERα36 regulates YAP activity by a new mechanism involving Src kinase.Conclusion: Our results suggest that YAP targeting may be a new therapeutic approach to the treatment of advanced breast cancers overexpressing ERα36.

Using mouse models of liver fibrosis, Kim et al examined the mechanisms underlying the antifibrotic inhibition of the NLRP3 inflammasome by auranofin. They demonstrated that auranofin-induced inhibition of the NLRP3 inflammasome in bone marrow-derived macrophages and kupffer cells was mediated via inhibition of the cystine-glutamate antiporter, system Xc, which advances our understanding of the mechanism by which auranofin exerts its therapeutic effects.

Abstract DNAJB9, a member of the heat shock protein 40 family, acts as a multifunctional player involved in the maintenance of their client proteins and cellular homeostasis. However, the mechanistic action of DNAJB9 in human malignancies is yet to be fully understood. In this study, we found that ectopic restoration of DNAJB9 inhibits the migration, invasion, in vivo metastasis, and lung colonization of triple-negative breast cancer (TNBC) cells. Mechanistically, DNAJB9 stabilizes FBXO45 protein by suppressing self-ubiquitination and reduces the abundance of ZEB1 by Lys48-linked polyubiquitination to inhibit the epithelial–mesenchymal transition (EMT) and metastasis. Clinically, the reduction of DNAJB9 expression, concomitant with decreased FBXO45 abundance in breast cancer tissues, correlates with poorer clinical outcomes of patients with breast cancer. Taken together, our results provide a novel insight into the metastasis of TNBC and define a promising therapeutic strategy for cancers with overactive ZEB1 by regulating the DNAJB9–FBXO45 signaling axis.

Background: Korean Red ginseng extract (KRGE) has beneficial effects on the cardiovascular system by improving endothelial cell function. However, its pharmacological effect on endothelial cell senescence has not been clearly elucidated. Therefore, we examined the effect and molecular mechanism of KRGE on the senescence of human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were grown in normal or KRGE-supplemented medium. Furthermore, they were transfected with heme oxygenase-1 (HO-1) gene or treated with its inhibitor, a NF-κB inhibitor, and a miR-155-5p mimic or inhibitor. Senescence-associated characteristics of endothelial cells were determined by biochemical and immunohistochemical analyses. Results: Treatment of HUVECs with KRGE resulted in delayed onset and progression of senescence-associated characteristics, such as increased lysosomal acidic β-galactosidase and decreased telomerase activity, angiogenic dysfunction, and abnormal cell morphology. KRGE preserved the levels of anti-senescent factors, such as eNOS-derived NO, MnSOD, and cyclins D and A: however, it decreased the levels of senescence-promoting factors, such as ROS, activated NF-κB, endothelial cell inflammation, and p21 expression. The beneficial effects of KRGE were due to the induction of HO-1 and the inhibition of NF-κB-dependent biogenesis of miR-155-5p that led to the downregulation of eNOS. Moreover, treatment with inhibitors of HO-1, NF-κB, and miR-155-5p abolished the anti-senescence effects of KRGE. Conclusion: KRGE delayed or prevented HUVEC senescence through a signaling cascade involving the induction of HO-1, the inhibition of NF-κB-dependent miR-155-5p biogenesis, and the maintenance of the eNOS/NO axis activity, suggesting that it may protect against vascular diseases associated with endothelial senescence.

Abstract Background Helping Babies Breathe (HBB) is a competency-based educational method for an evidence-based protocol to manage birth asphyxia in low resource settings. HBB has been shown to improve health worker skills and neonatal outcomes, but studies have documented problems with skills retention and little evidence of effectiveness at large scale in routine practice. This study examined the effect of complementing provider training with clinical mentorship and quality improvement as outlined in the second edition HBB materials. This “system-oriented” approach was implemented in all public health facilities (n = 172) in ten districts in Rwanda from 2015 to 2018. Methods A before-after mixed methods study assessed changes in provider skills and neonatal outcomes related to birth asphyxia. Mentee knowledge and skills were assessed with HBB objective structured clinical exam (OSCE) B pre and post training and during mentorship visits up to 1 year afterward. The study team extracted health outcome data across the entirety of intervention districts and conducted interviews to gather perspectives of providers and managers on the approach. Results Nearly 40 % (n = 772) of health workers in maternity units directly received mentorship. Of the mentees who received two or more visits (n = 456), 60 % demonstrated competence (received > 80% score on OSCE B) on the first mentorship visit, and 100% by the sixth. In a subset of 220 health workers followed for an average of 5 months after demonstrating competence, 98% maintained or improved their score. Three of the tracked neonatal health outcomes improved across the ten districts and the fourth just missed statistical significance: neonatal admissions due to asphyxia (37% reduction); fresh stillbirths (27% reduction); neonatal deaths due to asphyxia (13% reduction); and death within 30 min of birth (19% reduction, p = 0.06). Health workers expressed satisfaction with the clinical mentorship approach, noting improvements in confidence, patient flow within the maternity, and data use for decision-making. Conclusions Framing management of birth asphyxia within a larger quality improvement approach appears to contribute to success at scale. Clinical mentorship emerged as a critical element. The specific effect of individual components of the approach on provider skills and health outcomes requires further investigation.

Software-defined networking (SDN) has generated increased interest due to the rapid growth in the amount of data generated by the development of the Internet and communications, the commercialization of 5G, and increasingly complex networks. While SDN is more advantageous than traditional networks in terms of efficient network management, rapid deployment, and dynamic scalability, the correctness of a network configuration must be ensured in advance. In other words, SDN components such as network devices, SDN controllers, and applications need to be deployed correctly and must be free of rule conflicts, particularly between various application policies; otherwise, it may result in network paralysis in the worst case. This paper assumes that the SDN network is free of rule conflicts when the rules in the SDN switches correctly obey firewall application or policies. To solve this problem, this paper proposes a verification framework for SDN using TLA+. We show that the firewall rule behavior of switches can be formalized using TLA+, and this is verified with the TLC model checker that uses TLA+ as the model description language. We check two different types of topology models through our verification framework to ensure that the same firewall rules are maintained even if the topology changes. The findings show that the firewall rules may be inconsistent as the topology changes.

Panax notoginseng (PN) is a traditional herbal medicine containing several active compounds such as saponins and ginsenosides with many therapeutic applications including anti-obesity activity. Fermentation by lactic acid bacteria has the potential to metabolize ginsenosides to more active forms. This study examined whether fermentation has any benefits on the protective effects of a PN extract against obesity using a high-fat diet (HFD)-fed mouse model. PN was fermented with Lactobacillus plantarum which exhibited high β-glucosidase activity. Upon fermentation, the PN extract exhibited an altered ginsenoside profile, a dramatic increase in the lactate level. Treatment of the HFD group with fermented PN (FPN), but not PN, decreased both the food and calorie intake significantly, which was consistent with the more potent suppressing effects of FPN than PN on the signaling pathways involved in appetite and energy intake. The PN treatment also modulated the gut microbial composition. The PN and FPN treatment groups showed clear differences in the population of gut microbiota. The relative abundance of Bacteroidetes, Erysipelotrichaceae, Coprococus, and Dehalobacterium were significantly higher in the FPN group then the normal, HFD, and XEN groups. Furthermore, the relative abundances of Akkermansia, Dehalobacterium, Erysipeliotrichaceae and parpabacteroides were significantly higher in the FPN group than the PN group, but the relative abundances of Allobaculum, Erysipelotrichi and Erysipelotrichale were significantly lower. The relative abundance of Bacteroides and Lactococcus was significantly higher and lower, respectively in the PN and FPN groups than the HFD group. In conclusion, the altered ginsenoside and organic acid’s profile, and altered gut microbial composition are believed to be the major factors contributing to the anti-obesity properties of FPN.

Radioresistance poses a major challenge in the treatment of advanced rectal cancer. Therefore, understanding the detailed mechanisms of radioresistance may improve patient response to irradiation and the survival rate. To identify the novel targets that modulate the radiosensitivity of rectal cancer, we performed small RNA sequencing with human rectal cancer cell lines. Through bioinformatics analysis, we selected microRNA-310a (miR-130a) as a promising candidate to elucidate radioresistance. miR-130a was dramatically upregulated in radiosensitive rectal cancer cells and overexpression of miR-130a promotes rectal cancer cell radiosensitivity. Mechanically, miR-130a reversed the epithelial-mesenchymal transition phenotype of rectal cancer cells following inhibition of cell invasion upon irradiation. Moreover, miR-130a also inhibited the repair of irradiation-induced DNA damage followed by cell death. We identified that SOX4 was a direct target of miR-130a. Overexpression of SOX4 reversed the promotion activity of miR-130a on radiosensitivity. Together, our findings suggest that miR-130a functions as a radiosensitizer in rectal cancer and reveals a potential therapeutic target and preoperative prognostic marker for radiotherapy.

Abstract Background Recent evidence suggests that mistreatment of women during childbirth is a global challenge facing health care systems. This study seeks to explore the prevalence of mistreatment of women in public health facilities of Ethiopia, and identify associated factors. Methods A two-stage cross sectional sampling design was used to select institutions and women. The study was conducted in hospitals and health centers across four Ethiopian regions. Quantitative data were collected from postpartum women. Mistreatment was measured using four domains: (1) physical abuse, (2) verbal abuse, (3) failure to meet professional standards of care, and (4) poor rapport between women and providers. Percentages of mistreatment and odds ratios for the association between its presence and institutional and socio demographic characteristics of women were calculated using bivariate and multivariable logistic regression modeling. Results A total of 379 women were interviewed, of whom 281 (74%) reported any mistreatment. Physical and verbal abuse were reported by 7 (2%) and 31 (8%) women interviewed respectively. Failure to meet professional standards of care and poor rapport between women and providers were reported by 111 (29%) and 274 (72%) women interviewed respectively. Multivariable logistic regression analysis revealed that the odds of reporting mistreatment were higher among women with four or more previous births (aOR = 3.36 95%CI 1.22,9.23, p = 0.019) compared to women with no previous childbirth, Muslim women (aOR = 3.30 95%CI 1.4,7.77, p = 0.006) and women interviewed in facilities with less than 17 births per MNH staff in a month (aOR = 3.63 95%CI 1.9,6.93, p

Abstract Background Afghanistan faces a high burden of maternal and neonatal morbidity and mortality. Hypertensive disorders of pregnancy, including pre-eclampsia and eclampsia (PE/E), are among the most common causes of maternal and neonatal complications. Hypertensive disorders of pregnancy can lead to fatal complications for both the mother and fetus. The 2016 Afghanistan National Maternal and Newborn Health Quality of Care Assessment assessed quality of early detection and management of PE/E in health facilities and skilled birth attendants’ (SBAs) perceptions of their working environment. Methods All accessible public health facilities with an average of at least five births per day (n = 77), a nationally representative sample of public health facilities with less than five births per day (n = 149), and 20 purposively selected private health facilities were assessed. Methods included a facility inventory and record review, interviews with SBAs, and direct clinical observation of antenatal care (ANC), intrapartum care and immediate postnatal care (PNC), as well as severe PE/E case management. Results Most facilities had supplies and medicines for early detection and management of PE/E. At public health facilities, 357 of 414 (86.2%) clients observed during ANC consultations had their blood pressure checked and 159 (38.4%) were asked if they had experienced symptoms of PE/E. Only 553 of 734 (72.6%) SBAs interviewed were able to correctly identify severe pre-eclampsia described in a case scenario. Of 29 PE/E cases observed, 17 women (59%) received the correct loading dose of magnesium sulfate (MgSO4) and 12 women (41%) received the correct maintenance dose of MgSO4. At private health facilities, 39 of 45 ANC clients had their blood pressure checked and 9 of 45 (20%) were asked about symptoms of PE/E. Fifty-four of 64(84.4%) SBAs in private facilities correctly identified severe pre-eclampsia described in a case scenario. Conclusion Notable gaps in SBAs’ knowledge and clinical practices in detection and management of PE/E in various health facilities increase the risk of maternal and perinatal mortality. Continuing education of health care providers and increased investment in focused quality improvement initiatives will be critical to improve the quality of health care services in Afghanistan.

Alpinia oxyphylla Miq. (Zingiberaceae) extract exerts protective activity against tert-butyl hydroperoxide-induced toxicity in HepG2 cells, and the antioxidant response element (ARE) luciferase activity increased 6-fold at 30 μg/mL in HepG2 cells transiently transfected with ARE-luciferase. To identify active molecules, activity-guided isolation of the crude extract led to four sesquiterpenes (1, 2, 5, 6) and two diarylheptanoids (3 and 4) from an n-hexane extract and six sesquiterpenes (7–12) from an ethyl acetate extract. Chemical structures were elucidated by one-dimensional, two-dimensional nuclear magnetic resonance (1D-, 2D-NMR), and mass (MS) spectral data. Among the isolated compounds, eudesma-3,11-dien-2-one (2) promoted the nuclear accumulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and increased the promoter property of the ARE. Diarylheptanoids, yakuchinone A (3), and 5′-hydroxyl-yakuchinone A (4) showed radical scavenging activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 3-ethylbenzothiazoline-6-sulphonic acid (ABTS) assays. Furthermore, optimization of extraction solvents (ratios of water and ethanol) was performed by comparison of contents of active compounds, ARE-inducing activity, radical scavenging activity, and HepG2 cell protective activity. As a result, 75% ethanol was the best solvent for the extraction of A. oxyphylla fruit. This study demonstrated that A. oxyphylla exerted antioxidant effects via the Nrf2/HO-1 (heme oxygenase-1) pathway and radical scavenging along with active markers eudesma-3,11-dien-2-one (2) and yakuchinone A (3).

BackgroundIn response to longstanding concerns around the quality of female sterilization services provided at public health facilities in India, the Government of India issued standards and quality assurance guidelines for female sterilization services in 2014. However, implementation remains a challenge. The Maternal and Child Survival Program rolled out a package of competency-based trainings, periodic mentoring, and easy-to-use job aids in parts of five states to increase service providers' adherence to key practices identified in the guidelines.MethodsThe study employed a before-and-after quasi-experimental design with a matched comparison arm to examine the effect of the intervention on provider practices in two states: Odisha and Chhattisgarh. Direct observations of female sterilization services were conducted in selected public health facilities, using a checklist of 30 key practices, at two points in time. Changes in adherence to key practices from baseline to endline were compared at 12 intervention and 12 comparison facilities using a difference in difference analysis.ResultsSeveral key practices were well-established prior to the intervention, with adherence levels over 90% at baseline, including hemoglobin and urine testing, use of sterile surgical gloves and instruments, and recommended surgical technique. However, adherence to many other practices was extremely low at baseline. The program significantly increased adherence to nine practices, including those related to ascertaining client's medical eligibility, client-provider interaction, the consent process, and post-operative care. The greatest improvement was observed in the provision of written instructions for clients prior to discharge. At endline, however, adherence remained below 50% for 14 practices.ConclusionLow adherence to key practices at baseline confirmed the need for quality improvement interventions in female sterilization services. While the intervention improved adherence to certain practices around admission and post-operative care, inadequate human resources and infrastructure, among other factors, may have blunted the impact of the intervention.

Abstract Background Tanzania has a maternal mortality ratio of 556 per 100,000 live births, representing 21% of all deaths of women of reproductive age. Hemorrhage, mostly postpartum hemorrhage (PPH), is estimated to cause at least 25% of maternal deaths in Tanzania. In 2008, the Ministry of Health, Community Development, Gender, Elderly and Children launched interventions to improve efforts to prevent PPH. Competency-based training for skilled birth attendants and ongoing quality improvement prioritized the practice of active management of the third stage of labor (AMTSL). Methods A cross-sectional study was conducted in 52 health facilities in Tanzania utilizing direct observations of women during labor and delivery. Observations were conducted in 2010 and, after competency-based training and quality improvement interventions in the facilities, in 2012. A total of 489 deliveries were observed in 2010 and 558 in 2012. Steps for AMTSL were assessed using a standardized structured observation checklist that was based on World Health Organization guidelines. Results The proportion of deliveries receiving all three AMTSL steps improved significantly by 19 percentage points (p

The aim of our study was to investigate the effect of three lignans (schisandrol A, schisandrol B, and schisandrin C) on insulin secretion in rat INS-1 pancreatic β-cells and glucose uptake in mouse C2C12 skeletal muscle cells. Schisandrol A and schisandrin C enhanced insulin secretion in response to high glucose levels with no toxic effects on INS-1 cells. The effect of schisandrin C was superior to that of gliclazide (positive control), a drug commonly used to treat type 2 diabetes (T2D). In addition, western blot analysis showed that the expression of associated proteins, including peroxisome proliferator-activated receptor γ (PPARγ), pancreatic and duodenal homeobox 1 (PDX-1), phosphatidylinositol 3-kinase (PI3K), Akt, and insulin receptor substrate-2 (IRS-2), was increased in INS-1 cells after treatment with schisandrin C. In addition, insulin secretion effect of schisandrin C were enhanced by the Bay K 8644 (L-type Ca2+ channel agonist) and glibenclamide (K+ channel blocker), were abolished by the nifedipine (L-type Ca2+ channel blocker) and diazoxide (K+ channel activator). Moreover, schisandrin C enhanced glucose uptake with no toxic effects on C2C12 cells. Western blot analysis showed that the expression of associated proteins, including insulin receptor substrate-1 (IRS-1), AMP-activated protein kinase (AMPK), PI3K, Akt, glucose transporter type 4 (GLUT-4), was increased in C2C12 cells after treatment with schisandrin C. Schisandrin C may improve hyperglycemia by enhancing insulin secretion in pancreatic β-cells and improving glucose uptake into skeletal muscle cells. Our findings may provide evidence that schisandrin C may be beneficial in devising novel anti-T2D strategies.

The pharmacokinetic (PK) change in a drug by co-administered herbal products can alter the efficacy and toxicity. In the circumstances that herb–drug combinations have been increasingly attempted to alleviate Alzheimer’s disease (AD), the PK evaluation of herb–drug interaction (HDI) is necessary. The change in systemic exposure as well as target tissue distribution of the drug have been issued in HDIs. Recently, the memory-enhancing effects of water extract of mangosteen pericarp (WMP) has been reported, suggesting a potential for the combination of WMP and donepezil (DNP) for AD treatment. Thus, it was evaluated how WMP affects the PK change of donepezil, including systemic exposure and tissue distribution in mice after simultaneous oral administration of DNP with WMP. Firstly, co-treatment of WMP and donepezil showed a stronger inhibitory effect (by 23.0%) on the neurotoxicity induced by Aβ(25–35) in SH-SY5Y neuroblastoma cells than donepezil alone, suggesting that the combination of WMP and donepezil may be more effective in moderating neurotoxicity than donepezil alone. In PK interaction, WMP increased donepezil concentration in the brain at 4 h (by 63.6%) after administration without affecting systemic exposure of donepezil. Taken together, our results suggest that WMP might be used in combination with DNP as a therapy for AD.

The aim of this study was to examine the estrogen-like effects of gentiopicroside, macelignan, γ-mangostin, and three lignans (schisandrol A, schisandrol B, and schisandrin C), and their possible mechanism of action. Their effects on the proliferation of the estrogen receptor (ER)-positive breast cancer cell line (MCF-7) were evaluated using Ez-Cytox reagents. The expression of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), AKT, and estrogen receptor α (ERα) was measured by performing Western blot analysis. 17β-estradiol (E2), also known as estradiol, is an estrogen steroid and was used as a positive control. ICI 182,780 (ICI), an ER antagonist, was used to block the ER function. Our results showed that, except for gentiopicroside, all the compounds promoted proliferation of MCF-7 cells, with schisandrol A being the most effective; this effect was better than that of E2 and was mitigated by ICI. Consistently, the expression of ERK, PI3K, AKT, and ERα increased following treatment with schisandrol A; this effect was slightly better than that of E2 and was mitigated by ICI. Taken together, the ERα induction via the PI3K/AKT and ERK signaling pathways may be a potential mechanism underlying the estrogen-like effects of schisandrol A. This study provides an experimental basis for the application of schisandrol A as a phytoestrogen for the prevention of menopausal symptoms.

Abstract Background Despite much progress recently, Ethiopia remains one of the largest contributors to the global burden of maternal and newborn deaths and stillbirths. Ethiopia’s plan to meet the sustainable development goals for maternal and child health includes unprecedented emphasis on improving quality of care. The purpose of this study was to assess the quality of midwifery care during labor, delivery and immediate postpartum period. Methods A cross-sectional study using multiple data collection methods and a 2-stage cluster sampling technique was conducted from January 25 to February 14, 2015 in government health facilities of the Amhara National Regional State of Ethiopia. Direct observation of performance was used to determine competence of midwives in providing care during labor, delivery, and the first 6 h after childbirth. Inventory of drugs, medical equipment, supplies, and infrastructure was conducted to identify availability of resources in health facilities. Structured interview was done to assess availability of resources and performance improvement opportunities. Data analysis involved calculating percentages, means and chi-square tests. Results A total of 150 midwives and 56 health facilities were included in the study. The performance assessment showed 16.5% of midwives were incompetent, 72.4% were competent, and 11.1% were outstanding in providing routine intrapartum care. Forty five midwives were observed while managing 54 obstetric and newborn complications and 41 (91%) of them were rated competent. Inventory of resources found that the proportion of facilities with more than 75% of the items in each category was 32.6% for drugs, 73.1% for equipment, 65.4% for supplies, 47.9% for infection prevention materials, and 43.6% for records and forms. Opportunities for performance improvement were inadequate, with 31.3% reporting emergency obstetric and newborn care training, and 44.7% quarterly or more frequent supportive supervision. Health centers fared worse in provider competence, physical resources, and quality improvement practices except for supportive supervision visits and in-service training. Conclusions Although our findings indicate most midwives are competent in giving routine and emergency intrapartum care, the major gaps in the enabling environment and the significant proportion of midwives with unsatisfactory performance suggest that the conditions for providing quality intrapartum care are not optimal.

Abstract Although the biological role of melatonin in osteogenic differentiation has been suggested, the mechanism of osteoblast differentiation remains unclear. Thus, the present study investigated the underlying molecular mechanisms based on osteoblast-specific transcription factors. We found that melatonin enhanced BMP-4-induced osteogenic differentiation and increased the expression of osteogenic markers, especially Osterix, which is an essential transcription factor for the differentiation of preosteoblasts into mature osteoblasts in the late stage of osteoblast differentiation. Melatonin treatment increased the expression of Osterix during osteoblast differentiation and stabilized its expression by the inhibition of ubiquitin-proteasome-mediated degradation of Osterix, leading to up-regulated Osterix transcriptional activity on the osteogenic promoter and promoting alkaline phosphatase activity and bone mineralization. Furthermore, treatment with protein kinase A (PKA) inhibitor H89 and protein kinase C (PKC) inhibitor Go6976 blocked the melatonin-induced transcriptional activity and phosphorylation of Osterix, indicating that melatonin regulates Osterix expression via the PKA and PKC signaling pathways. Overall, these findings suggest that melatonin directly regulates the late stage of osteoblast differentiation by enhancing Osterix expression; this provides further evidence of melatonin as a potent agent for treating osteoporosis.

Abstract Background Disrespect and abuse of women during institutional childbirth services is one of the deterrents to utilization of maternity care services in Ethiopia and other low- and middle-income countries. This paper describes the prevalence of respectful maternity care (RMC) and mistreatment of women in hospitals and health centers, and identifies factors associated with occurrence of RMC and mistreatment of women during institutional labor and childbirth services. Methods This study had a cross sectional study design. Trained external observers assessed care provided to 240 women in 28 health centers and hospitals during labor and childbirth using structured observation checklists. The outcome variable, providers’ RMC performance, was measured by nine behavioral descriptors. The outcome, any mistreatment, was measured by four items related to mistreatment of women: physical abuse, verbal abuse, absence of privacy during examination and abandonment. We present percentages of the nine RMC indicators, mean score of providers’ RMC performance and the adjusted multilevel model regression coefficients to determine the association with a quality improvement program and other facility and provider characteristics. Results Women on average received 5.9 (66%) of the nine recommended RMC practices. Health centers demonstrated higher RMC performance than hospitals. At least one form of mistreatment of women was committed in 36% of the observations (38% in health centers and 32% in hospitals). Higher likelihood of performing high level of RMC was found among male vs. female providers ( β ^ = 0.65 $$ \widehat{\beta}=0.65 $$ , p = 0.012), midwives vs. other cadres ( β ^ = 0.88 $$ \widehat{\beta} = 0.88 $$ , p = 0.002), facilities implementing a quality improvement approach, Standards-based Management and Recognition (SBM-R©) ( β ^ = 1.31 $$ \widehat{\beta}=1.31 $$ , p = 0.003), and among laboring women accompanied by a companion β ^ = 0.99 $$ \widehat{\beta} = 0.99 $$ , p = 0.003). No factor was associated with observed mistreatment of women. Conclusion Quality improvement using SBM-R© and having a companion during labor and delivery were associated with RMC. Policy makers need to consider the role of quality improvement approaches and accommodating companions in promoting RMC. More research is needed to identify the reason for superior RMC performance of male providers over female providers and midwives compared to other professional cadre, as are longitudinal studies of quality improvement on RMC and mistreatment of women during labor and childbirth services in public health facilities.

Objective Untimely vaccination refers to receiving the given dose before (early) or after (delayed) the recommended time window. The purpose of this study was to assess the extent of timeliness of childhood vaccinations and examine the determinants of vaccination timeliness in Sindh province, Pakistan.Design Cross-sectional analysis of data from the 2013 and 2014 Maternal and Child Health Program Indicator Surveys.Setting Community-based maternal and child health surveys.Participants Among 10 200 respondents of Maternal and Child Health Program Indicator Surveys, 1143 women who had a live birth in the 2 years preceding the survey were included.Outcomes At the participants’ home, an interviewer asked mothers to show their children’s vaccination cards, which contained information regarding vaccinations. Children’s vaccination status was categorised into timely or early/delayed compared with vaccination schedule. A logistic regression analysis using Firth’s penalised likelihood was performed to identify factors associated with timeliness of vaccinations.Results 238 children (20.8% of children who received a full set of basic vaccinations) received all vaccinations on schedule among children who received a full set of basic vaccinations. The percentages of timely vaccinations ranged from 2.3% for second measles vaccination to 89.3% for bacillus Calmette-Guérin. Child’s age and place of delivery were associated with timely vaccinations. Older child age and institutional delivery were associated with decreased timely vaccination rate.Conclusions Home-based vaccination record is a key tool to improve the timeliness of vaccinations. The redesigned vaccination cards, the new electronic registries for vaccination card information and the vaccination tracking system to remind the second/third vaccination visits may be helpful to improve timely vaccinations for children under 2 years old.

BackgroundAntenatal care (ANC) is critical to decrease maternal and neonatal mortality. However, little is known about the utilization of ANC services in Pakistan. This study assessed the utilization of ANC in Sindh province, Pakistan, and identified the factors that affect its use.MethodsWe analysed a subset of data from Maternal and Child Health (MCH) Program Indicator Surveys conducted in Sindh province, Pakistan in 2013 and 2014. Respondents included 10,200 women who had given birth in the past two years. The outcome measure was making at least four ANC visits. Logistic regression models were used to identify demographic, socioeconomic, characteristics of ANC, and informational factors associated with ANC use.ResultsMost women (83.5%) received one or more ANC, mostly by doctors (95%), but only 57.3% of them made the recommended four or more visits, and just 53.7% received their initial ANC care during the first trimester. Making four or more ANC visits was associated with: fewer household occupants (odds ratio [OR] = 0.98; 95% confidence interval [CI] = [0.97, 0.99]), large city residence (OR = 1.92; 95% CI = [1.57, 2.35]), higher women's education (OR = 1.70; 95% CI = [1.33, 2.15]), greater household wealth (OR = 5.66; 95% CI = [4.22, 7.60]), and receiving MCH information from lady health worker (OR = 1.17; 95% CI = [1.00, 1.37]), mother-in-law (OR = 1.17; 95% CI = [1.01, 1.36]), other relatives/friends (OR = 1.19; 95% CI = [1.03, 1.38]), or nurse/midwife (OR = 1.31; 95% CI = [1.06, 1.61]).ConclusionsThis study demonstrates that both socioeconomic factors and health information sources are associated with women's use of ANC. Therefore, programs should target socially disadvantaged and vulnerable groups, particularly rural, less educated, and poor women, to improve utilization of ANC. In addition, strategies to increase exposure to MCH information sources should be a priority in Sindh, Pakistan.

Phytochemical investigation on the n-BuOH-soluble fraction of the aerial parts of Epimedium koreanum using the PCSK9 mRNA monitoring assay led to the identification of four previously undescribed acylated flavonoid glycosides and 18 known compounds. The structures of new compounds were elucidated by NMR, MS, and other chemical methods. All isolated compounds were tested for their inhibitory activity against PCSK9 mRNA expression in HepG2 cells. Of the isolates, compounds 6, 7, 10, 15, and 17–22 were found to significantly inhibit PCSK9 mRNA expression. In particular, compound 7 was shown to increase LDLR mRNA expression. Thus, compound 7 may potentially increase LDL uptake and lower cholesterol levels in the blood.

Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool is expected to expedite the dereplication of secondary metabolites. In this study, using this tool, two new dilignans with a 2-phenyl-3-chromanol motif, obovatolins A (1) and B (2), were discovered from the stem barks of Magnolia obovata Thunb. along with six known compounds (3–8), expanding chemical diversity of lignan skeletons in this natural source. Their structures and configurations were elucidated using spectroscopic data. All isolates were evaluated for their PCSK9 mRNA expression inhibitory activity. Obovatolins A (1) and B (2), and magnolol (3) showed potent lipid controlling activities. To identify transcriptionally controlled genes by 1 along with downregulation of PCSK9, using small set of genes (42 genes) related to lipid metabolism selected from the database, focused bioinformatic analysis was carried out. As a result, it showed the correlations between gene expression under presence of 1, which led to detailed insight of the lipid metabolism caused by 1.

The aim of the present study was to examine the protective effect of γ-mangostin, a component of the mangosteen shell, against oxidative damage to nerve cells induced by excessive glutamate, a known excitatory neurotransmitter. To investigate the effect of γ-mangostin on apoptosis, 5 mM of glutamate was used to induce apoptotic cell death in mouse hippocampal HT22 cells. In this study, γ-mangostin was found to exert a stronger protection than N-acetyl cysteine against glutamate-induced cell damage. γ-Mangostin showed prevented glutamate-induced apoptosis in HT22 cells by reducing the production of reactive oxygen species and stimulating the expression of heme oxygenase-1 protein. In addition, glutamate significantly induced the accumulation of intracellular calcium ions, whereas treatment with γ-mangostin markedly reduced it. Hoechst 33342 staining showed an improvement in glutamate-induced nuclear condensation following γ-mangostin treatment. Furthermore, the number of annexin V-positive cells was significantly reduced following treatment with γ-mangostin. Western blot analysis showed the inhibition of glutamate-induced mitogen-activated protein kinase phosphorylation by γ-mangostin. γ-mangostin also inhibited the regulation of the intrinsic mitochondrial apoptotic pathway. Thus, the results of this study suggest that γ-mangostin is an active ingredient of mangosteen and exerts neuroprotective activities in HT22 cells.

Mangosteen has long been utilized as a traditional medicine in Southeast Asia. Diverse extracts of mangosteen pericarp and its bioactive xanthones exhibit various bioactivities. However, the pharmacological potential of mangosteen pericarp water extract (MPW) has not been reported yet. This study used primary cultured rat cortical cells to investigate the effect of MPW on neurotoxicity. We found that MPW inhibited neurotoxicity and production of reactive oxygen species triggered by Aβ(25–35) or excitatory amino acids. MPW inhibited caspase 3 activation and DNA fragmentation in Aβ(25–35)- or N-methyl-D-aspartate-treated cells, suggesting an anti-apoptotic action. Additionally, MPW reduced lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl radicals, assuring its antioxidant property. Furthermore, MPW suppressed β-secretase and acetylcholinesterase activities. These findings prompted us to evaluate its effect on memory dysfunction in scopolamine-treated mice using Morris water maze test. Oral administration of MPW at the dosage of 50, 100, or 300 mg/kg for four days significantly decreased the latency time to find the platform and markedly increased the swimming time in the target quadrant. Taken together, our results suggest that MPW exerts memory-enhancing effect through antioxidative neuroprotection and anti-apoptotic action. Accordingly, MPW may have a potential to prevent or treat memory impairment associated with Alzheimer’s disease.

Issues related to global energy and environment as well as health crisis are currently some of the greatest challenges faced by humanity, which compel us to develop new pollution-free and sustainable energy sources, as well as next-generation biodiagnostic solutions. Optical functional nanostructures that manipulate and confine light on a nanometer scale have recently emerged as leading candidates for a wide range of applications in solar energy conversion and biosensing. In this review, recent research progress in the development of photonic and plasmonic nanostructures for various applications in solar energy conversion, such as photovoltaics, photothermal conversion, and photocatalysis, is highlighted. Furthermore, the combination of photonic and plasmonic nanostructures for developing high-efficiency solar energy conversion systems is explored and discussed. We also discuss recent applications of photonic–plasmonic-based biosensors in the rapid management of infectious diseases at point-of-care as well as terahertz biosensing and imaging for improving global health. Finally, we discuss the current challenges and future prospects associated with the existing solar energy conversion and biosensing systems.

Hepatosteatosis (HS), a clinical feature of fatty liver with the excessive intracellular accumulation of triglyceride in hepatocytes, is manifested by perturbation of the maintenance of liver lipid homeostasis. Samjunghwan (SJH) is an herbal formula used mostly in Korean traditional medicine that is effective against a number of metabolic diseases, including obesity. Herbal drugs, enriched with numerous bioactive substances, possess health-protective benefits. Meanwhile, fermented herbal products enriched with probiotics are known to improve metabolic processes. Additionally, current lines of evidence indicate that probiotics-derived metabolites, termed as postbiotics, produce the same beneficial effects as their precursors. Herein, the anti-HS effects of 5-weeks naturally fermented SJH (FSJH) was investigated with FSJH-mixed chow diet in vivo using Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats as animal models of HS and controls, respectively. In parallel, the anti-HS effects of postbiotic-metabolites of three bacterial strains [Lactobacillus brevis (LBB), Lactococcus lactis (LCL) and Lactobacillus plantarum (LBP)] isolated from FSJH were also evaluated in vitro using the FFAs-induced HepG2 cells. Feeding OLETF rats with FSJH-diet effectively reduced body, liver, and visceral adipose tissue (VAT) weights, produced marked hypolipidemic effects on serum and hepatic lipid parameters, decreased serum AST and ALT levels, and upregulated the HMGCOR, SREBP, and ACC, and downregulated the AMPK and LDLR gene expressions levels. Additionally, exposure of FFAs-induced HepG2 cells to postbiotic metabolic media (PMM) of bacterial strains also produced marked hypolipidemic effects on intracellular lipid contents and significantly unregulated the HMGCOR, SREBP, and ACC, and downregulated the AMPK and LDLR genes expressions levels. Overall, our results indicate that FSJH enriched with fermented metabolites could be an effective anti-HS formulation.

In Tanzania, maternal mortality has stagnated over the last 10 years, and some of the areas with the worst indicators are in the Lake and Western Zones. This study investigates the factors associated with institutional deliveries among women aged 15-49 years in two regions of the Lake Zone. Data were extracted from a cross-sectional household survey of 1,214 women aged 15-49 years who had given birth in the 2 years preceding the survey in Mara and Kagera regions. Logistic regression analyses were conducted to explore the influence of various factors on giving birth in a facility. About two-thirds (67.3%) of women gave birth at a health facility. After adjusting for possible confounders, six factors were significantly associated with institutional delivery: region (adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.54 [0.41-0.71]), number of children (aOR, 95% CI: 0.61 [0.42-0.91]), household wealth index (aOR, 95% CI: 1.47 [1.09-2.27]), four or more antenatal care visits (aOR, 95% CI: 1.97 [1.12-3.47]), knowing three or more pregnancy danger signs (aOR, 95% CI: 1.87 [1.27-2.76]), and number of birth preparations (aOR, 95% CI: 6.09 [3.32-11.18]). Another three factors related to antenatal care were also significant in the bivariate analysis, but these were not significantly associated with place of delivery after adjusting for all variables in an extended multivariable regression model. Giving birth in a health facility was associated both with socio-demographic factors and women's interactions with the health care system during pregnancy. The findings show that national policies and programs promoting institutional delivery in Tanzania should tailor interventions to specific regions and reach out to low-income and high-parity women. Efforts are needed not just to increase the number of antenatal care visits made by pregnant women, but also to improve the quality and content of the interaction between women and service providers.

BACKGROUND:Pakistan has a high burden of newborn mortality, which would be significantly preventable through appropriate routine immunization. The purpose of this study was to measure the basic timely childhood immunization coverage and to identify determinants of factors influencing childhood immunization coverage in Sindh, Pakistan. METHODS:Data from Maternal and Child Health Program Indicator Survey 2013-2014 which was conducted in Sindh province of Pakistan was used. Outcome measure was full coverage of the basic immunization schedule from child's vaccination card. The association of receiving basic immunization with demographic factors, socioeconomic status, mother and child health information sources, and perinatal care factors were tested by binary logistic regression. RESULTS:Among 2,253 children, 1,156 (51.3%) received age-based full basic immunization. The basic immunization rates were 69.1% for under five weeks old, 38.3% for six to nine weeks, 18.8% for 10-13 weeks, 44.0% for 14 weeks-eight months, 60.4% for nine to 11 months, and 59.1% for over one year. Child's age, number of living children, parents' education level, wealth, the source of mother and child health information, number of antenatal care, and assistance during delivery were associated with completing basic immunization. CONCLUSIONS:The overall full basic immunization coverage in Pakistan was still low. Policy makers should identify children at risk of low immunization coverage and obstacles of receiving antenatal care, implement educational interventions targeting on less educated parents, and conduct mass immunization campaigns for timely and complete immunization.

The radix of Scutellaria baicalensis (SB) is a herb widely used in traditional Chinese medicine to treat metabolic diseases. Several main components, including baicalin and wogonoside, possess anti-dyslipidemia, anti-obesity and anti-diabetic effects. We hypothesized that co-administration of SB extract and metformin exerts a better effect on obesity-induced insulin resistance and lipid metabolism than treatment with metformin alone. We compared the effect of metformin (100 mg/10 mL/kg/day) alone with co-administration of metformin (100 mg/5 mL/kg/day) and SB extract (200 mg/5 mL/kg/day) on Otsuka Long Evans Tokushima Fatty rats, a useful model of type II diabetes with obesity, and used Long-Evans Tokushima Otsuka rats as a control. Weight, fasting glucose, oral glucose tolerance test, intraperitoneal insulin tolerance test, and serum total cholesterol were measured after 12 weeks of drug administration. We observed a synergetic effect of metformin and SB on lowering cholesterol level by excretion of bile acid through feces. We found that this accompanied activation of FXR, CYP7A1 and LDLR genes and repression of HMGCR in the liver. Although there were no significant changes in BSH-active gut microbiota due to high variability, functional prediction with 16S sequences showed increased primary and secondary bile acid biosynthesis in the combination treatment group. Further study is needed to find the specific strains of bacteria which contribute to FXR-related cholesterol and bile acid regulations.

Seed storage proteins (SSPs) such as glutelin, prolamin and globulin are abundant components in some of the most widely consumed food cereals in the world. Synthesized in the rough endoplasmic reticulum (ER), SSPs are translocated to the protein bodies. Prolamins are located at the spherical protein body I derived from the ER, whereas glutelins and globulin are accumulated in the irregularly shaped protein bodies derived from vacuoles. Our previous studies have shown that the individual suppression of glutelins, 13-kDa prolamins and globulin caused the compensative accumulation of other SSPs. Herein, to investigate the phenotypic and molecular features of SSP deficiency transgenic rice plants suppressing all glutelins, prolamins and globulin were generated using RNA interference (RNAi). The results revealed that glutelin A, cysteine-rich 13-kDa prolamin and globulin proteins were less accumulated but that glutelin B and ER chaperones, such as binding protein 1 (BiP1) and protein disulfide isomerase-like 1-1 (PDIL1-1), were highly accumulated at the transcript and protein levels in seeds of the transformants compared to those in the wild-type seeds. Further, the transcription of starch synthesis-related genes was reduced in immature seeds at two weeks after flowering, and the starch granules were loosely packaged with various sphere sizes in seed endosperms of the transformants, resulting in a floury phenotype. Interestingly, the rates of sprouting and reducing sugar accumulation during germination were found to be delayed in the transformants compared to the wild-type. In all, our results provide new insight into the role of SSPs in the formation of intracellular organelles and in germination.

Decisions made at the household level, for example, to seek antenatal care or breastfeed, can have a direct impact on the health of mothers and newborns. The SMART Community-based Initiatives program in Egypt worked with community development associations to encourage better household decision-making by training community health workers to disseminate information and encourage healthy practices during home visits, group sessions, and community activities with pregnant women, mothers of young children, and their families. A quasi-experimental design was used to evaluate the program, with household surveys conducted before and after the intervention in intervention and comparison areas. Survey questions asked about women's knowledge and behaviors related to maternal and newborn care and child nutrition and, at the endline, exposure to SMART activities. Exposure to program activities was high in intervention areas of Upper Egypt: 91% of respondents reported receiving home visits and 84% attended group sessions. In Lower Egypt, these figures were 58% and 48%, respectively. Knowledge of danger signs related to pregnancy, delivery, and newborn illness increased significantly more in intervention than comparison areas in both regions (with one exception in Lower Egypt), after controlling for child's age and woman's education; this pattern also occurred for two of five behaviors (antenatal care visits and consumption of iron-folate tablets). Findings suggest that there may have been a significant dose-response relationship between exposure to SMART activities and certain knowledge and behavioral indicators, especially in Upper Egypt. The findings demonstrate the ability of civil society organizations with minimal health programming experience to increase knowledge and promote healthy behaviors among pregnant women and new mothers. The SMART approach offers a promising strategy to fill gaps in health education and counseling and strengthen community support for behavior change.

T cell protein tyrosine phosphatase N2 (PTPN2) is a phosphotyrosine-specific nonreceptor phosphatase and is ubiquitously expressed in tissues. Although PTPN2 functions as an important regulator in different signaling pathways, it is still unclear what is specific target protein of PTPN2 and how is regulated in lipopolysaccharide (LPS)-induced inflammatory signaling pathway. Here, we found that PTPN2 deficiency downregulated the expression of LPS-mediated pro-inflammtory cytokine genes. Conversely, overexpression of PTPN2 in Raw264.7 cells enhanced the expression and secretion of those cytokines. The activation of MAPK and NF-κB signaling pathways by LPS was reduced in PTPN2-knockdowned cells and ectopic expression of PTPN2 reversed these effects. Furthermore, we found that PTNP2 directly interacted with Src and removed the inhibitory Tyr527 phosphorylation of Src to enhance the activatory phosphorylation of Tyr416 residue. These results suggested that PTPN2 is a positive regulator of LPS-induced inflammatory response by enhancing the activity of Src through targeting the inhibitory phosphor-tyrosine527 of Src.

Activity-guided separation of antioxidant response element (ARE)-inducing constituents from the rhizomes of Atractylodis Rhizoma Alba was performed by the combination of centrifugal partition chromatography (CPC) and an ARE luciferase reporter assay. From 3 g of the active n-hexane fraction, one polyacetylene, (6E,12E)-tetradeca-6,12-dien-8,10-diyne-1,3-diyl diacetate (47.3 mg), and two sesquiterpenes, atractylenolide I (40.9 mg), and selina-4(14),7(11)-dien-8-one (6.0 mg) were successfully isolated by CPC with n-hexane–ethyl acetate–methanol–water (8:2:8:2, v/v). The chemical structures of the isolated compounds were determined by 1H- and 13C-NMR and ESI-MS. Among the isolated compounds, (6E,12E)-tetradeca-6,12-diene-8,10-diyne-1,3-diol diacetate and selina-4(14),7(11)-dien-8-one increased ARE activity 32.9-fold and 16.6-fold, respectively, without significant cytotoxicity, when 5 µM sulforaphane enhanced ARE activity 27.1-fold. However, atractylenolide I did not increase ARE activity at 100 µM, and showed cytotoxicity at concentrations over 10 µM.

Nine flavonoids were isolated and identified from a chloroform-soluble fraction of the roots of Scutellaria baicalensis through a bioactivity-guided fractionation using a proprotein convertase subtilisin/kexin type 9 (PCSK9) monitoring assay in HepG2 cells. All structures were established by interpreting the corresponding spectroscopic data and comparing measured values from those in the literature. All compounds were assessed for their ability to inhibit PCSK9 mRNA expression; compounds 1 (3,7,2′-trihydroxy-5-methoxy-flavanone) and 4 (skullcapflavone II) were found to suppress PCSK9 mRNA via SREBP-1. Furthermore, compound 1 was found to increase low-density lipoprotein receptor protein expression. Also, synthesis of compound 1 as a racemic mixture form (1a) was completed for the first time. Natural compound 1 and synthetic racemic 1a were evaluated for their inhibitory activities against PCSK9 mRNA expression and the results confirmed the stereochemistry of 1 was important.

Bioactivity-guided fractionation for the stems of leaves of Larrea nitida Cav., using interleukin-6 (IL-6) inhibitory assay in human mast cells (HMC-1), led to the isolation of three new compounds with an unprecedented skeleton in nature (1–3) and three known compounds (4–6). Their structures were elucidated through extensive spectroscopic analysis. The three new compounds were elucidated as two new spiroketones, nitidaones A (1), and B (2) and one new biphenyl analog, nitidaol (3). The known compounds were identified as nordihydroguaiaretic acid (4), 7,3′,4′-tri-O-methylquercetin (5) and ayanin (6). All the isolates were tested for their inhibitory activity against IL-6 production in HMC-1 cells. Of them, compounds 1, 3–6 showed potent anti-inflammatory activity, with IC50 values of 12.8, 17.5, 14.9, 22.9, and 17.8 µM, respectively.

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The authors wish to make the following correction to their paper [1].[...]

Atractylodin is one of the major constituents of the rhizome of Atractylodes lancea, which is widely used in Korean traditional medicine as a remedy for the treatment of gastritis and gastric ulcers. Despite of a major constituent of widely used botanical to treat inflammatory responses little is known about anti-inflammatory effect of atractylodin in the human mast cell (HMC-1). Hence, we evaluated the effect of atractylodin on the release of IL-6, the involvement of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) and mitogen-activated protein kinases (MAPKs) in phorbol-12-myristate-13-acetate and A23187-induced HMC-1. In addition, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), phospholipase C (PLC) gamma 1, and AKT phosphorylation relevant to NPM-ALK signal pathway were assessed. IL-6 levels in the HMC-1 stimulated by phorbol-12-myristate-13-acetate and A23187 were apparently decreased by the treatment of atractylodin. Concurrently, atractylodin not only inhibited the phosphorylation of NPM-ALK, but also suppressed the phosphorylation of JAK2, STAT3, PLC gamma 1, and AKT. Furthermore, the activated mitogen-activated protein kinases (MAPKs) by phorbol-12-myristate-13-acetate and A23187 were inhibited by atractylodin. These results suggested that atractylodin might have a potential regulatory effect on inflammatory mediator expression through blockade of both the phosphorylation of MAPKs and the NPM-ALK signaling pathway.

The anti-inflammatory effects and molecular mechanism of 6,8-diprenyl-7,4′-dihydroxyflavanone (DDF), one of the flavanones found in Sophora tonkinensis, were assessed in vitro through macrophage-mediated inflammation in the present study. The anti-inflammatory effects of DDF were not previously reported. DDF inhibited the production of nitric oxide and the expression of tumor necrosis factor α, interleukin-1β, and interleukin-6. Furthermore, the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases (ERKs) in lipopolysaccharide-stimulated macrophages was suppressed by treatment with DDF. Therefore, DDF demonstrated potentially anti-inflammatory effects via the blockade of NF-κB and ERK activation in macrophages.

Introduction: In 2016, UNAIDS set ambitious targets to reduce global HIV infections by 75% by 2020 and 90% by 2030, based on the 2.1 million new infections reported in 2010. However, by 2022, new HIV infections had only decreased by 38%, from 2.1 million in 2010 to 1.3 million in 2022, raising concerns about reaching the 2030 goal. Female sex workers (FSWs) in subSaharan Africa face a disproportionately high risk of HIV acquisition, contributing 5%–20% of all new infections in several countries in the region. This analysis investigates HIV seroconversion and associated factors among FSWs, offering insights into critical interventions for preventing HIV transmission in this population and advancing the goal of ending the HIV pandemic by 2030. Methods: We conducted a retrospective cohort study involving 17,977 FSWs who initially tested HIV negative upon enrollment in the Sauti project between October 2016 and September 2018. HIV incidence rates were calculated by dividing the number of new HIV cases by observed person-time within the cohort. Cox regression analysis identified factors associated with seroconversion. Results: The study revealed an HIV incidence rate of 8.6 per 100 person-years among FSWs [95% confidence interval (CI): 8.1–9.1]. Factors independently associated with HIV seroconversion included age 35 years or older [adjusted hazard ratio (aHR): 2.53; 95% CI: 2.03–3.14], unprotected sex (aHR: 1.27; 95% CI: 1.13–1.42), STI symptoms (aHR: 1.99; 95% CI: 1.67–2.38), and alcohol consumption before sex (aHR: 1.20; 95% CI: 1.07–1.34). Conclusion: Targeted interventions are vital in curbing HIV transmission among FSWs, with a focus on expanding access to primary HIV prevention services, particularly for older FSWs who face heightened risk. Tailored sexual health education programs are imperative to encourage consistent condom use and enable informed decision-making. Accessible and timely STI screening and treatment services are crucial to mitigate HIV transmission risk. Collaborative partnerships between healthcare providers, community organizations, and government agencies are essential in implementing these interventions among FSWs. [ABSTRACT FROM AUTHOR]