DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans.

Mitochondrial dysfunction underlies numerous age-related pathologies. In an effort to uncover how the detrimental effects of mitochondrial dysfunction might be alleviated, we examined how the nematode C. elegans not only adapts to disruption of the mitochondrial electron transport chain, but in many instances responds with extended lifespan. Studies have shown various retrograde responses are activated in these animals, including the well-studied ATFS-1-dependent mitochondrial unfolded protein response (UPRmt). Such processes fall under the greater rubric of cellular surveillance mechanisms. Here we identify a novel p38 signaling cascade that is required to extend life when the mitochondrial electron transport chain is disrupted in worms, and which is blocked by disruption of the Mitochondrial-associated Degradation (MAD) pathway. This novel cascade is defined by DLK-1 (MAP3K), SEK-3 (MAP2K), PMK-3 (MAPK) and the reporter gene Ptbb-6::GFP. Inhibition of known mitochondrial retrograde responses does not alter induction of Ptbb-6::GFP, instead induction of this reporter often occurs in counterpoint to activation of SKN-1, which we show is under the control of ATFS-1. In those mitochondrial bioenergetic mutants which activate Ptbb-6::GFP, we find that dlk-1, sek-3 and pmk-3 are all required for their life extension.

Survival analysis of early intention of antenatal care among women in Bangladesh.

This study focuses on the importance of early and regular Antenatal Care (ANC) visits in reducing maternal and child mortality rates in Bangladesh, a country where such health indicators are a concern. The research utilized data from the Bangladesh Demographic and Health Survey (BDHS) conducted in 2017-18 and employed the Cox proportional hazard model to identify factors influencing women's intention of ANC services. The results revealed that 40.4% of women engaged in at least one ANC activity during the first trimester, which, although higher than in other countries, falls below the global average. Notably, women between the aged of 25 and 29 years took 15% less time for their first ANC visit compared to their younger counterparts, suggesting higher awareness and preparedness in this age group. Education, both for women and their partners, had a significant influence on the intention to visit ANC early. Women in the poor wealth quantile exhibited lower odds of seeking timely ANC, whereas those with a planned pregnancy were more likely to do so. Moreover, access to mass media decreased the timing of ANC visits by 26% compared to women who were not exposed. Moreover, living in rural areas was linked to a 17% delay in the timing of the first ANC visit compared to urban areas. These findings underscore the importance of addressing these determinants to improve the timeliness and accessibility of ANC services, thereby enhancing maternal and child health outcomes in Bangladesh.

Determinants of household adoption of clean energy with its rural-urban disparities in Bangladesh.

This study aims to investigate factors influencing the adoption of clean energy among households in Bangladesh, using Blinder-Oaxaca decomposition and extended probit regression model with data from the 2019 Bangladesh multiple indicator cluster survey. Small households, primarily Muslim and urban dwellers, who speak the Bengali language and are Internet and mobile users, were likelier to adopt cleaner fuels than their counterparts. On the contrary, households residing in the Barisal, Khulna, Rajshahi, and Rangpur divisions, belonging to poor and middle-class households, with household heads aged 15-64 and without formal education, were less likely to adopt cleaner fuels than their counterparts. The concentration curve revealed socioeconomic inequality in the adoption of clean energy, particularly favouring richer households in urban and rural areas. Further analysis using the Blinder-Oaxaca decomposition showed that urban residents showed a higher probability of adopting clean energy, with a significant difference of 0.508 compared to rural areas. Regarding the endowment effect, poor wealth quintile contributed the most, followed by the ownership of rented dwellings and the middle wealth quintile. The Bengali differential effect made the largest contribution to this aspect of the disparity, followed by the exposure of the Internet and the influence of the Dhaka and Chattogram divisions. The detailed analysis provides valuable insights for policymakers and practitioners on the issue of disparities in the adoption of clean energy between urban and rural areas in Bangladesh.

Risk factors associated with elevated intraocular pressure: a population-based study in a rural community of Bangladesh.

OBJECTIVE: High intraocular pressure (IOP) is one of the major modifiable risk factors for glaucoma. The objective was to examine socio-demographic and clinical factors related to IOP. METHODS AND ANALYSIS: This study was conducted among 3097 adults residing in a rural area of Bangladesh, with all participants undergoing clinical and ophthalmological evaluations. The measurement of IOP was carried out using of a rebound Tonometer called Icare pro. Multiple logistic regression analysis was employed to identify variables associated to IOP levels of 21 mm Hg or above. Adjusted OR (aOR) and 95% CI were reported. RESULTS: This study found that, in total, 9% of the study population had high IOP in one or both eyes. Elevated IOP was significantly associated with respondents who were service holders (aOR 2.52; 95% CI 1.48 to 4.31), had a lower education level (aOR 1.55, 95% CI 1.07 to 2.23), used biomass fuel (aOR 2.00; 95% CI 1.09 to 3.67), belonged to a higher socioeconomic position (aOR 1.55, 95% CI 1.07 to 2.23) and had obesity (aOR 2.00; 95% CI 1.07 to 3.73), hypertension (aOR 1.32; 95% CI 1.01 to 1.73) or history of diabetes (aOR 2.44; 95% CI 1.67 to 3.55), after adjusting for covariates including age, sex, marital status, light source and tobacco consumption, in a multiple regression analysis. CONCLUSION: Chronic diseases, such as hypertension and diabetes, obesity and sociodemographic characteristics such as high socioeconomic status and use of biomass fuels, have all been linked to elevated IOP. Patients with chronic diseases should undergo for IOP testing regularly.

The role of MAP4K3 in lifespan regulation of Caenorhabditis elegans.

The TOR pathway is a kinase signaling pathway that regulates cellular growth and proliferation in response to nutrients and growth factors. TOR signaling is also important in lifespan regulation - when this pathway is inhibited, either naturally, by genetic mutation, or by pharmacological means, lifespan is extended. MAP4K3 is a Ser/Thr kinase that has recently been found to be involved in TOR activation. Unexpectedly, the effect of this protein is not mediated via Rheb, the more widely known TOR activation pathway. Given the role of TOR in growth and lifespan control, we looked at how inhibiting MAP4K3 in Caenorhabditis elegans affects lifespan. We used both feeding RNAi and genetic mutants to look at the effect of MAP4K3 deficiency. Our results show a small but significant increase in mean lifespan in MAP4K3 deficient worms. MAP4K3 thus represents a new target in the TOR pathway that can be targeted for pharmacological intervention to control lifespan.

HspB1 Overexpression Improves Life Span and Stress Resistance in an Invertebrate Model.

To explore the role of the small heat shock protein beta 1 (HspB1, also known as Hsp25 in rodents and Hsp27 in humans) in longevity, we created a Caenorhabiditis elegans model with a high level of ubiquitous expression of the naked mole-rat HspB1 protein. The worms showed increased life span under multiple conditions and also increased resistance to heat stress. RNAi experiments suggest that HspB1-induced life extension is dependent on the transcription factors skn-1 (Nrf2) and hsf-1 (Hsf1). RNAseq from HspB1 worms showed an enrichment in several skn-1 target genes, including collagen proteins and lysosomal genes. Expression of HspB1 also improved functional outcomes regulated by SKN-1, specifically oxidative stress resistance and pharyngeal integrity. This work is the first to link a small heat shock protein with collagen function, suggesting a novel role for HspB1 as a hub between canonical heat response signaling and SKN-1 transcription.

Mitochondrial metabolites extend lifespan.

Disruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long-lived respiratory mutants generate elevated amounts of α-ketoacids. These compounds are structurally related to α-ketoglutarate, suggesting they may be biologically relevant. Here, we show that provision of several such metabolites to wild-type worms is sufficient to extend their life. At least one mode of action is through stabilization of hypoxia-inducible factor-1 (HIF-1). We also find that an α-ketoglutarate mimetic, 2,4-pyridinedicarboxylic acid (2,4-PDA), is alone sufficient to increase the lifespan of wild-type worms and this effect is blocked by removal of HIF-1. HIF-1 is constitutively active in isp-1(qm150) Mit mutants, and accordingly, 2,4-PDA does not further increase their lifespan. Incubation of mouse 3T3-L1 fibroblasts with life-prolonging α-ketoacids also results in HIF-1α stabilization. We propose that metabolites that build up following mitochondrial respiratory dysfunction form a novel mode of cell signaling that acts to regulate lifespan.

TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants.

While numerous life-extending manipulations have been discovered in the nematode Caenorhabditis elegans, one that remains most enigmatic is disruption of oxidative phosphorylation. In order to unravel how such an ostensibly deleterious manipulation can extend lifespan, we sought to identify the ensemble of nuclear transcription factors that are activated in response to defective mitochondrial electron transport chain (ETC) function. Using a feeding RNAi approach, we targeted over 400 transcription factors and identified 15 that, when reduced in function, reproducibly and differentially altered the development, stress response, and/or fecundity of isp-1(qm150) Mit mutants relative to wild-type animals. Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1, NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4--were also essential for isp-1 life extension. When we tested the involvement of these seven transcription factors in the life extension of two other Mit mutants, namely clk-1(qm30) and tpk-1(qm162), TAF-4 and HIF-1 were consistently required. Our findings suggest that the Mit phenotype is under the control of multiple transcriptional responses, and that TAF-4 and HIF-1 may be part of a general signaling axis that specifies Mit mutant life extension.

Pomegranate extract induces cell cycle arrest and alters cellular phenotype of human pancreatic cancer cells.

BACKGROUND: Pomegranate extract (PE) is a standardized whole-fruit extract of pomegranate, a fruit with known anticancer properties. MATERIALS AND METHODS: PANC-1 and AsPC-1 human pancreatic cancer cells were used as in vitro models to test the effects of PE. RESULTS: PE treatment induced cell cycle arrest and inhibited cell proliferation in PANC-1 cells. PE treatment increased the proportion of cells lacking CD44 and CD24 expression, which are associated with increased tumor-initiating ability, demonstrating that PE altered cell phenotype. PE was more effective in inhibiting the proliferation of PANC-1 cells than the clinically used dose of paclitaxel. Similar results were obtained in the AsPC-1 cell line. Individual pomegranate phytochemicals were only modestly effective in inhibiting cell proliferation, suggesting that unidentified phytochemicals are responsible for the inhibitory effect of PE. CONCLUSION: These data suggest that PE is a promising candidate for further preclinical testing for treatment of human pancreatic cancer.

Pomegranate extract inhibits the proliferation and viability of MMTV-Wnt-1 mouse mammary cancer stem cells in vitro.

Pomegranate (Punica granatum L.) is known to possess anticancer activities. The effects of a standardized extract of pomegranate (PE) on a mouse mammary cancer cell line (designated WA4) derived from mouse MMTV-Wnt-1 mammary tumors were examined in this study. The WA4 cell line has been previously characterized as containing a majority of cells possessing stem cell characteristics. PE inhibited the proliferation of WA4 cells in a time- and concentration-dependent manner. This was due to an arrest of cell cycle progression in the G0/G1 phase. PE was also cytotoxic to quiescent WA4 cells in a concentration-dependent manner at concentrations >10 microg/ml. PE treatment of WA4 cells resulted in an increase in caspase-3 enzyme activity in a time- and concentration-dependent manner, indicating that the cytotoxic effect of PE was due to the induction of apoptosis. We tested the effect of several individual phytochemicals derived from PE on WA4 cells. Ellagic acid, ursolic acid and luteolin caused a time- and concentration-dependent reduction of cell proliferation and viability, suggesting that they contribute to the inhibitory effect of PE, while caffeic acid had no effect. Cancer stem cells, which are highly resistant to conventional chemotherapeutic agents, are thought to be the origin of both primary and secondary breast tumors, and thus are a critical target in both breast cancer therapy and prevention. These data suggest that PE, which is a proven and safe dietary supplement, has promise as an treatment against breast cancer by preventing proliferation of cancer stem cells.