Neurological risks arising from the bioaccumulation of heavy metal contaminants: A focus on mercury.

This study investigated the concentrations of heavy metals in the water sources of the upstream region of the Huangpu River, the Yangtze River Estuary, and various areas in Shanghai, as well as the heavy metal concentrations in the blood of Shanghai residents. It aimed to analyze the heavy metal elements absorbed by the human body and the resulting pathological effects. The results revealed that surface water primarily contains five heavy metals: copper (Cu), lead (Pb), zinc (Zn), arsenic (As), and mercury (Hg), while water sediments primarily contain seven heavy metals: Cu, cadmium (Cd), Pb, chromium (Cr), Zn, As, and Hg. The main heavy metals present in the human body are Pb, Hg, As, and Cd. By reviewing previous articles, it was found that heavy metal concentrations in human blood are higher than those in surface water, suggesting uncertainties in the heavy metal content of surface water and its tendency to settle at the bottom. Furthermore, a comparison of heavy metal content in sediments revealed that Hg is the most readily absorbed heavy metal by the human body and is also a toxic environmental pollutant. Within the cell, Hg is highly toxic to mitochondria and may cause oxidative stress and neurodegenerative disease. This study concludes that water sediments serve as the major source of pollution in the human body and pose significant health risks, thereby necessitating the implementation of effective preventive measures.

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1flox/+;Wwtr1flox/+, Pkd1Oc-cKO, Wwtr1Oc-cKO, and Pkd1/Wwtr1Oc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1Oc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKO or Pkd1Oc-cKO mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Pkd1/Wwtr1Oc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Moreover, we found that Pkd1/Wwtr1Oc-cKO mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1Oc-cKO mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.

Antibody-drug conjugates: Recent advances in payloads.

Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing, show great clinical therapeutic value. The ADCs' payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field. An ideal ADC payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common ADC payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development. However, due to clinical limitations of traditional ADC payloads, such as inadequate efficacy and the development of acquired drug resistance, novel highly efficient payloads with diverse targets and reduced side effects are being developed. This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies, co-crystal structures, and designing strategies, and further discusses the future research directions of ADC payloads. This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy, low toxicity, adequate stability, and abilities to overcome drug resistance.

Genetic interactions between Polycystin-1 and TAZ in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and TAZ have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1flox/+;TAZflox/+, single Pkd1Oc-cKO, single TAZOc-cKO, and double Pkd1/TAZOc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and TAZ in bone in vivo, double Pkd1/TAZOc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either single TAZOc-cKO or Pkd1Oc-cKO mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in double Pkd1/TAZOc-cKO mice compared to either single Pkd1Oc-cKO or TAZOc-cKO mice. Double Pkd1/TAZOc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to single Pkd1Oc-cKO or TAZOc-cKO mice. Moreover, we found that double Pkd1/TAZOc-cKO mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic MS2 had marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, double Pkd1/TAZOc-cKO mice were resistant to the anabolic effects of MS2 that activates the polycystin signaling complex. These findings suggest that PC1 and TAZ form an anabolic mechanotransduction signaling complex that responds to mechanical loading and serve as a potential novel therapeutic target for treating osteoporosis.

Use of social health insurance for hospital care by internal migrants in China-Evidence from the 2018 China migrants dynamic survey.

Background: China's welfare system including social health insurance has been closely linked to its unique household registration system, despite high population mobility over the past few decades. This study aimed to determine the pattern of health insurance usage from internal migrants in mainland China for hospital care. Methods: Data were extracted from the 2018 China Migrants Dynamic Survey. The respondents who enrolled in a social health insurance program and reported illness or injury over the past year were eligible for this study (n = 15,302). Two groups of outcome indicators were calculated assessing the use (incidence and settlement location) of insurance funds for hospital care and the burden of hospital expenditure (total hospital expenditure, out-of-pocket payments, and share of insurance reimbursement), respectively. Logit regression and Heckman's sample selection models were established to determine the predictors of insurance fund usage and the burden of hospital expenditure, respectively. Results: Most respondents enrolled in a social health insurance program outside of their residential location (70.72%). About 28.90% were admitted to a hospital over the past year. Of those hospitalized, 72.98% were admitted to a hospital at their migration destination, and 69.96% obtained reimbursement from health insurance, covering on average 47% of total hospital expenditure. Those who had a local insurance fund aligned with residency (AOR = 2.642, 95% CI = 2.108-3.310, p < 0.001) and enrolled in employment-based insurance (AOR = 1.761, 95% CI = 1.348-2.301, p < 0.001) were more likely to use insurance funds for hospital care, and paid less out-of-pocket (ß = -0.183 for local funds, p = 0.017; ß = -0.171 for employment-based insurance, p = 0.005) than others. A higher share of insurance reimbursement as a proportion of hospital expenditure was found in the employment-based insurance enrollees (ß = 0.147, p < 0.001). Insurance claim settlement at the residential location was associated with lower total hospital expenditure (ß = -0.126, p = 0.012) and out-of-pocket payments (ß = -0.262, p < 0.001), and higher share of insurance reimbursement (ß = 0.066, p < 0.001) for hospital expenditure. Conclusion: Low levels of health insurance benefits for hospital care are evident for internal migrants in mainland China, which are associated with the funding arrangements linked to household registration and inequality across different funds.

Health-related quality of life of young academics: A cross-sectional survey of universities in Wuhan, China.

Objective: This study aimed to assess the health-related quality of life (HRQoL) of young academics in Wuhan, China, and its determinants. Methods: A multistage stratified cluster sampling strategy was employed to recruit study participants (young academics <40 years old) from 12 universities in Wuhan. A total of 301 respondents returned a self-complete questionnaire that contained the EQ-5D-5L. Multivariate linear and Tobit regression models were established to determine the sociodemographic and job predictors of the visual analogue scale (VAS) score and the EQ-5D utility index, respectively. Results: The study participants reported a mean VAS value of 79.42 (SD = 10.51) and a mean EQ-5D utility index of 0.915 (SD = 0.090). Anxiety/depression was the most frequently reported problem (65.12%), followed by pain/discomfort (43.52%). Transitioning towards a full professorship in national key universities (p < 0.001), lower income (p < 0.05) and too much pressure for academic promotion (p < 0.001) were significant predictors of lower HRQoL; whereas, maintaining routines in physical activities (p < 0.001), sleep (p < 0.001) and meals (p < 0.001), a good relationship with colleagues and family members (p < 0.001), and social activities (p < 0.01) were significant predictors of higher HRQoL. Conclusion: Low HRQoL of young academics in China is evident, as indicated by the 7.08 and 0.049 gap in VAS and utility index, respectively, compared to the general population at the same age. Work and career pressures are associated with the low HRQoL of young academics. The findings of this study highlight the importance of work-life balance in promoting HRQoL of young academics in universities in China.

Does social participation decrease the risk of frailty? Impacts of diversity in frequency and types of social participation on frailty in middle-aged and older populations.

BACKGROUND: Social participation (SP) may be an effective measure for decreasing frailty risks. This study investigated whether frequency and type of SP is associated with decreased frailty risk among Chinese middle-aged and older populations. METHODS: Data were derived from the China Health and Retirement Longitudinal Study (CHARLS). Frailty was assessed using the Rockwood's Cumulative Deficit Frailty Index. SP was measured according to frequency (none, occasional, weekly and daily) and type (interacting with friends [IWF]; playing mah-jong, chess, and cards or visiting community clubs [MCCC], going to community-organized dancing, fitness, qigong and so on [DFQ]; participating in community-related organizations [CRO]; voluntary or charitable work [VOC]; using the Internet [INT]). Smooth curves were used to describe the trend for frailty scores across survey waves. The fixed-effect model (N = 9,422) was applied to explore the association between the frequency/type of SP and frailty level. For baseline non-frail respondents (N = 6,073), the time-varying Cox regression model was used to calculate relative risk of frailty in different SP groups. RESULTS: Weekly (ß = - 0.006; 95%CI: [- 0.009, - 0.003]) and daily (ß = - 0.009; 95% CI: [- 0.012, - 0.007]) SP is associated with lower frailty scores using the fixed-effect models. Time-varying Cox regressions present lower risks of frailty in daily SP group (HR = 0.76; 95% CI: [0.69, 0.84]). SP types that can significantly decrease frailty risk include IWF, MCCC and DFQ. Daily IWF and daily DFQ decreases frailty risk in those aged < 65 years, female and urban respondents, but not in those aged ≥ 65 years, male and rural respondents. The impact of daily MCCC is significant in all subgroups, whereas that of lower-frequent MCCC is not significant in those aged ≥ 65 years, male and rural respondents. CONCLUSION: This study demonstrated that enhancing participation in social activities could decrease frailty risk among middle-aged and older populations, especially communicative activities, intellectually demanding/engaging activities and community-organized physical activities. The results suggested very accurate, operable, and valuable intervening measures for promoting healthy ageing.

In Silico Screening and In Vivo Evaluation of Potential CACNA2D1 Antagonists as Intraocular Pressure-Reducing Agents in Glaucoma Therapy.

Glaucoma is a leading cause of permanent vision loss and current drugs do not halt disease progression. Thus, new therapies targeting different drug targets with novel mechanisms of action are urgently needed. Previously, we identified CACNA2D1 as a novel modulator of intraocular pressure (IOP) and demonstrated that a topically applied CACNA2D1 antagonist-pregabalin (PRG)-lowered IOP in a dose-dependent manner. To further validate this novel IOP modulator as a drug target for IOP-lowering pharmaceutics, a homology model of CACNA2D1 was built and docked against the NCI library, which is one of the world's largest and most diverse compound libraries of natural products. Acivicin and zoledronic acid were identified using this method and together with PRG were tested for their plausible IOP-lowering effect on Dutch belted rabbits. Although they have inferior potency to PRG, both of the other compounds lower IOP, which in turn validates CACNA2D1 as a valuable drug target in treating glaucoma.

A Luminacin D Analog HL142 Inhibits Ovarian Tumor Growth and Metastasis by Reversing EMT and Attenuating the TGFß and FAK Pathways.

Epithelial to mesenchymal transition (EMT) is known to contribute to tumor metastasis and chemoresistance. Reversing EMT using small molecule inhibitors to target EMT associated gene expression represents an effective strategy for cancer treatment. The purpose of this study is to test whether a new luminacin D analog HL142 reverses EMT in ovarian cancer (OC) and has the therapeutic potential for OC. We chemically synthesized HL142 and tested its functions in OC cells in vitro and its efficacy in inhibiting ovarian tumor growth and metastasis in vivo using orthotopic OC mouse models. We first demonstrate that ASAP1 is co-amplified and interacts with the focal adhesion kinase (FAK) protein in serous ovarian carcinoma. HL142 inhibits ASAP1 and its interaction protein FAK in highly invasive OVCAR8 and moderately invasive OVCAR3 cells. HL142 inhibits EMT phenotypic switch, accompanied by upregulating epithelial marker E-cadherin and cytokeratin-7 and downregulating mesenchymal markers vimentin, ß-catenin, and snail2 in both cell lines. Functionally, HL142 inhibits proliferation, colony formation, migration, and invasion. HL142 also sensitizes cell responses to chemotherapy drug paclitaxel treatment and inhibits ovarian tumor growth and metastasis in orthotopic OC mouse models. We further show that HL142 attenuates the TGFß and FAK pathways in vitro using OC cells and in vivo using orthotopic mouse models.

Berberine, A Phytoalkaloid, Inhibits Inflammatory Response Induced by LPS through NF-Kappaß Pathway: Possible Involvement of the IKKα.

Berberine (BBR), a plant alkaloid, is known for its therapeutic properties of anticancer, cardioprotective, antidiabetic, hypolipidemic, neuroprotective, and hepatoprotective activities. The present study was to determine the molecular mechanism of BBR's pharmacological activity in human monocytic (THP-1) cells induced by arachidonic acid (AA) or lipopolysaccharide (LPS). The effect of BBR on AA/LPS activated proinflammatory markers including TNF-α, MCP-1, IL-8 and COX-2 was measured by ELISA or quantitative real-time PCR. Furthermore, the effect of BBR on LPS-induced NF-κB translocation was determined by immunoblotting and confocal microscopy. AA/ LPS-induced TNF-α, MCP-1, IL-6, IL-8, and COX-2 markers were markedly attenuated by BBR treatment in THP-1 cells by inhibiting NF-κB translocation into the nucleus. Molecular modeling studies suggested the direct interaction of BBR to IKKα at its ligand binding site, which led to the inhibition of the LPS-induced NF-κB translocation to the nucleus. Thus, the present study demonstrated the anti-inflammatory potential of BBR via NF-κB in activated monocytes, whose interplay is key in health and in the pathophysiology of atherosclerotic development in blood vessel walls. The present study findings suggest that BBR has the potential for treating various chronic inflammatory disorders.

Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development.

CDATA[Osteoporosis is a pathological loss of bone mass due to an imbalance in bone remodeling where osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation resulting in skeletal fragility and fractures. Anti-resorptive agents, such as bisphosphonates and SERMs, and anabolic drugs that stimulate bone formation, including PTH analogues and sclerostin inhibitors, are current treatments for osteoporosis. Despite their efficacy, severe side effects and loss of potency may limit the long term usage of a single drug. Sequential and combinational use of current drugs, such as switching from an anabolic to an anti-resorptive agent, may provide an alternative approach. Moreover, there are novel drugs being developed against emerging new targets such as Cathepsin K and 17ß-HSD2 that may have less side effects. This review will summarize the molecular mechanisms of osteoporosis, current drugs for osteoporosis treatment, and new drug development strategies.