A study on the falls factors among the older adult with cognitive impairment based on large-sample data.

Introduction: This study explored the correlative factors of falls among the older adult with cognitive impairment, to provide distinct evidence for preventing falls in the older adult with cognitive impairment compared with the general older adult population. Methods: This study was based on a cross-sectional survey, with an older adult population of 124,124 was included. The data was sourced from the Elderly Care Unified Needs Assessment for Long-Term Care Insurance in Shanghai. Binary and multivariable logistic regression analyses were conducted sequentially on the correlative factors of falls. Multivariable logistic regression was performed on variables that were significant, stratified by cognitive function levels. Results: The incidence of fall in the past 90 days was 17.67% in this study. Specific variables such as gender (male), advanced age (≥80), residence with a elevator (or lift), mild or moderate disability, quality of sleep (acceptable/poor) were negatively correlated with falls, while higher education level, living alone, residence with indoor steps, unclean and untidy living environment, MCI or dementia, chronic diseases, restricted joints, impaired vision, and the use of diaper were positively correlative factors of falls. Comparing with older adult with normal cognitive functions, older adult with dementia faced a higher risk of falling due to accessibility barrier in the residence. For general older adults, less frequency of going outside and poor social interactions were positively correlated with falls, while for older adult with cognitive impairments, going outside moderately (sometimes) was found positively correlated with falls. Older adults with cognitive impairments have increased fall risks associated with chronic diseases, restricted joints, and the use of diaper. The risk of falling escalated with the greater number of chronic diseases. Discussion: For older adult with cognitive impairments, it is advisable to live with others. Additionally, creating an accessible living environment and maintaining the cleanness and tidiness can effectively reduce the risk of falls, particularly for those with MCI or dementia. Optimal outdoor activity plans should be developed separately based on the cognitive function of older adults. Older adult with dementia who have comorbidities should be paid special attention in fall prevention compared to the general older adult population.

Retinoic acid signalling inhibits myogenesis by blocking MYOD translation in pig skeletal muscle cells.

Vitamin A is an essential nutrient in animals, playing important roles in animal health. In the pig industry, proper supplementation of vitamin A in the feed can improve pork production performance, while deficiency or excessive intake can lead to growth retardation or disease. However, the specific molecular mechanisms through which vitamin A operates on pig skeletal muscle growth as well as muscle stem cell function remain unexplored. Therefore, in this study, we isolated the pig primary skeletal muscle stem cells (pMuSCs) and treated with retinoic acid (RA), the natural metabolite of vitamin A, and then examined the myogenic capacity of pMuSCs via immunostaining, real-time PCR, CCK8 and western-blot analysis. Unexpectedly, the RA caused a significant decrease in the proliferation and differentiation of pMuSCs. Mechanistically, the RA addition induced the activation of retinoic acid receptor gamma (RARγ), which inhibited the myogenesis through the blockage of protein translation of the master myogenic regulator myogenic differentiation 1 gene (MYOD). Specifically, RARγ inactivate AKT kinase (AKT) signalling and lead to dephosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (eIF4EBP1), which in turn repress the eukaryotic translation initiation factor 4E (eIF4E) complex and block mRNA translation of MYOD. Inhibition of AKT could rescue the myogenic defects of RA-treated pMuSCs. Our findings revealed that retinoid acid signalling inhibits the skeletal muscle stem cell proliferation and differentiation in pigs. Therefore, the vitamin A supplement in the feedstuff should be cautiously optimized to avoid the potential adverse consequences on muscle development associated with the excessive levels of retinoic acid.

A large cross sectional study on diaper utilization and beneficial role in outdoor activity and emotions among incontinence elderly people.

This study was designed based on a cross-sectional investigation conducted Shanghai, China. Demographic characteristics, diaper utilization, Activities of Daily Living (ADL) and emotion were collected by Unified Needs Assessment Form for Elderly Care Questionnaire. Cognition function was assessed by Mini-mental State Examination (MMSE) scale. Multivariate logistic regression was used for statistical analysis. The diaper utilization rate was 31.2%. Female, higher level of education, poorer ADL and cognition, more severe incontinence and financial dependence on others were facilitating factors for diaper usage (P < 0.05). The possibility of using diaper differed according to the intimacy of caregivers. Among incontinent individuals with relatively good ADL and cognition level, diaper utilization can significantly decrease the risk of going out only once a month (OR: 2.63 vs 4.05), and going out less than once a month (OR: 5.32 vs 6.53). Incontinence people who going out at least once a week had a lower risk of some negative emotion. Significantly, diaper utilization further decreased this risk. In conclusion, for incontinence elderly people with relatively independent ability, proper use of diaper may improve the frequency of outdoor activity and emotion. Nevertheless, diaper utilization should be decided based on elderly people's own will.

MIS-Net: A deep learning-based multi-class segmentation model for CT images.

The accuracy of traditional CT image segmentation algorithms is hindered by issues such as low contrast and high noise in the images. While numerous scholars have introduced deep learning-based CT image segmentation algorithms, they still face challenges, particularly in achieving high edge accuracy and addressing pixel classification errors. To tackle these issues, this study proposes the MIS-Net (Medical Images Segment Net) model, a deep learning-based approach. The MIS-Net model incorporates multi-scale atrous convolution into the encoding and decoding structure with symmetry, enabling the comprehensive extraction of multi-scale features from CT images. This enhancement aims to improve the accuracy of lung and liver edge segmentation. In the evaluation using the COVID-19 CT Lung and Infection Segmentation dataset, the left and right lung segmentation results demonstrate that MIS-Net achieves a Dice Similarity Coefficient (DSC) of 97.61. Similarly, in the Liver Tumor Segmentation Challenge 2017 public dataset, the DSC of MIS-Net reaches 98.78.

Interleukin 28A aggravates Con A-induced acute liver injury by promoting the recruitment of M1 macrophages.

Immune-mediated acute hepatic injury is characterized by the destruction of a large number of hepatocytes and severe liver function damage. Interleukin-28A (IL-28A), a member of the IL-10 family, is notable for its antiviral properties. However, despite advances in our understanding of IL-28A, its role in immune-mediated acute injury remains unclear. The present study investigated the role of IL-28A in concanavalin A (Con A)-induced acute immune liver injury. After Con A injection in mice, IL-28A level significantly increased. IL-28A deficiency was found to protect mice from acute liver injury, prolong survival time, and reduce serum aspartate aminotransferase and alanine aminotransferase levels. In contrast, recombinant IL-28A aggravated liver injury in mice. The proportion of activated M1 macrophages was significantly lower in the IL-28A-deficiency group than in the wild-type mouse group. In adoptive transfer experiments, M1 macrophages from WT could exacerbate mice acute liver injury symptoms in the IL-28A deficiency group. Furthermore, the expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-12, IL-6, and IL-1ß, by M1 macrophages decreased significantly in the IL-28A-deficiency group. Western blotting demonstrated that IL-28A deficiency could limit M1 macrophage polarization by modulating the nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), and interferon regulatory factor (IRF) signaling pathways. In summary, IL-28A deletion plays an important protective role in the Con A-induced acute liver injury model and IL-28A deficiency inhibits the activation of M1 macrophages by inhibiting the NF-κB, MAPK, and IRF signaling pathways. These results provide a potential new target for the treatment of immune-related hepatic injury.

Zn2+ Binding Increases Parallel Structure in the Aß(16-22) Oligomer by Disrupting Salt Bridge in Antiparallel Structure.

The aggregation of monomeric amyloid ß protein (Aß) into oligomers and amyloid plaque in the brain is associated with Alzheimer's disease. The hydrophobic central core Aß16-22 has been widely studied due to its essential role in the fibrillization of full-length Aß peptides. Compared to the homogeneous antiparallel structure of Aß16-22 at the late stage, the early-stage prefibrillar aggregates contain varying proportions of different ß structures. In this work, we studied the appearance probabilities of various self-assembly structures of Aß16-22 and the effects of Zn2+ on these probabilities by replica exchange molecular dynamics simulations. It was found that at room temperature, Aß16-22 can readily form assembled ß-sheet structures in pure water, where a typical antiparallel arrangement dominates (24.8% of all sampled trimer structures). The addition of Zn2+ to the Aß16-22 solution will dramatically decrease the appearance probability of antiparallel trimer structures to 12.5% by disrupting the formation of the Lys16-Glu22 salt bridge. Meanwhile, the probabilities of hybrid antiparallel/parallel structures increase. Our simulation results not only reveal the competition between antiparallel and parallel structures in the Aß16-22 oligomers but also show that Zn2+ can affect the oligomer structures. The results also provide insights into the role of metal ions in the self-assembly of short peptides.

MicroRNA-146b protects kidney injury during urinary tract infections by modulating macrophage polarization.

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) can lead to severe kidney injury. However, the molecular mechanisms underlying the pathological process of kidney injury are still incompletely understood. In the present study, we demonstrate that microRNA-146b (miR-146b) deficiency aggravates kidney injury during UTIs caused by UPEC. In a mouse kidney infection model utilizing urosepsis isolate CFT073, we found that miR-146b expression significantly increased in the early stages of UPEC infection. Also, miR-146b-deficient mice displayed exacerbated inflammation in the kidney injury with severe M1 macrophage infiltration. Additionally, the results showed that miR-146b targeted interferon regulatory factor 5-regulated M1 macrophage polarization during UTIs. The results suggested that miR-146b contributed significantly to the control of kidney damage during UTIs, highlighting that miR-146b might be used as a novel therapeutic target for treating kidney injury during UTIs. IMPORTANCE Kidney injury during acute urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) is an important public health problem. However, how kidney injury develops during UPEC infection is still unclear. Although antibiotic therapy is currently an effective treatment for UTI, it cannot avoid kidney injury. MicroRNAs have gained extensive attention as essential molecules capable of regulating the autoimmune response. Among these, microRNA-146b (miR-146b) is involved in regulating inflammatory responses. In the present study, we demonstrated that miR-146b played an essential role in the development of kidney injury during UTIs caused by UPEC. The results showed that miR-146b may suppress M1 macrophage polarization and alleviate acute kidney injury. Furthermore, the miR-146b activator, agomir, in order to upregulate miR-146b, was effective in treating kidney damage by inhibiting the activation of M1 macrophages. In conclusion, our findings elucidated the mechanisms by which miR-146b alleviated kidney injury induced by UTIs, shed new light on the relationship between microRNA and bacterial infection, and provided a novel therapeutic target for treating this common bacterial infection.

Cornuside improves murine autoimmune hepatitis through inhibition of inflammatory responses.

BACKGROUND: Autoimmune hepatitis (AIH) poses an important public health concern worldwide, with few therapeutic options available. Cornuside, a primary cornel iridoid glycoside present in Cornus officinalis Sieb. et Zucc., is a well-known traditional Chinese medicine that possesses anti-inflammatory, antioxidant and anti-apoptotic properties. However, the effects of cornuside on autoimmune diseases including AIH is still not defined, neither is clear on the mechanisms of cornuside in the suppression of inflammatory responses. PURPOSE: The study was aimed to investigate the therapeutic effects of cornuside on AIH using murine models. STUDY DESIGN: A murine model of AIH induced by concanavalin A (Con A) was used to examine the pharmacological activity of cornuside in suppressing the inflammatory responses in vivo. METHODS: C57BL/6J mice were intravenously with different doses of cornuside and challenged with 18 mg/kg Con A 3 h later. Network pharmacological analysis was performed to identify the potential target genes and signaling pathways by cornuside in AIH. Next serum and liver tissues were collected 12 h after Con A injection to analyze the levels of markers for hepatic injury, apoptosis, oxidative stress, immune responses, and inflammation. RESULTS: Network pharmacological analysis revealed that cornuside may modulate oxidative stress and apoptosis in AIH. Compared with the Con A group, cornuside pretreatment significantly reduced the serum levels of alanine aminotransferase and aspartate aminotransferase, improving histopathological damage and apoptosis in the livers. In addition, cornuside decreased the levels of malondialdehyde, myeloperoxidase, but increased superoxide dismutase levels, suggesting the relieving of oxidative stress. Furthermore, cornuside suppressed the activation of T and natural killer T cells, whereas the proportion of myeloid-derived suppressor cells was significantly increased. The production of proinflammatory cytokines, including interleukin (IL)-6, IL-12, IL-1ß, and tumor necrosis factor-alpha (TNF-α), was also clearly decreased. Finally, western blot analysis displayed that cornuside inhibited the phosphorylation of extracellular receptor kinase (ERK) and c-Jun N-terminal kinase (JNK). CONCLUSIONS: We demonstrated that cornuside has protective effects for Con A-induced immune-mediated hepatitis by suppressing the oxidative stress, apoptosis, and the inflammatory responses through the ERK and JNK signaling pathways, as well as by modulating the activation and recruitment of immune cells.

Hearing aids utilization, effect factors, and its benefit in the association between hearing and cognition decline: A longitudinal follow-up in Shanghai, China.

OBJECTIVE: To explore the rate and effect factors of hearing aids utilization in Chinese community elderly people, as well as the benefit role of hearing aids in the association of hearing loss and cognition decline. METHODS: This study was designed based on a longitudinal 7-years follow-up conducted in Shanghai (China). Demographic characteristics, hearing level, hearing aids utilization and Activities of Daily Living (ADL) of participants were collected by Unified Needs Assessment Form for Elderly Care Questionnaire. Cognition function was assessed by Mini-mental State Examination (MMSE) scale. Multivariate logistic regression and linear regression were used for statistical analysis. RESULTS: Hearing aids utilization rate in Chinese community elderly people is below 10 %. Participants with older age (≥80 years old), higher education (7-12 years and >12 years), who can manage money more independently were more likely to use hearing aids (P < 0.05). Whether hearing aids are used or not, hearing level is significantly associated with cognition in elderly people, but participants with hearing aids showed a slower cognitive decline speed. CONCLUSION: Hearing aids utilization may slow down the cognition descent via assisting hearing in daily life, so strategies need to be concerned in order to protect hearing function in all elderly and improve the use of hearing aids in HL elderly.

Identification of a cuproptosis-related lncRNA prognostic signature in lung adenocarcinoma

Purpose Cuproptosis-related long non-coding RNA (lncRNA) diseases are associated with the occurrence and development of tumors. This study aimed to investigate whether cuproptosis-related lncRNA can predict the prognosis of patients with lung adenocarcinoma (LUAD). Methods Cuproptosis-related lncRNA prognosis (CLPS) model was successfully constructed through cox regression and lasso regression analyses. Then, the prognostic value of CLPS model was tested through the survival analysis, the ROC curve and the nomogram. Finally, the correlation of CLPS model with tumor immunity and tumor mutation burden was analyzed, and the potential susceptibility of drugs for LUAD were predicted. Results CLPS model for LUAD (AC090948.1, CRIM1-DT, AC026356.2, AC004832.5, AL161431.1) was successfully constructed, which has an independent prognostic value. Furthermore, the risk score of CLPS model was correlated with tumor immune characteristics and immune escape, which can predict the sensitivity of drugs including Cisplatin, Etoposide, Gemcitabine, and Erlotinib. Conclusions In conclusion, it was found that CLPS model was associated with tumor immunity and tumor mutation load, which also predicted four potentially sensitive drugs for LUAD patients at different risks (AU)

Primary pulmonary angiosarcoma mimicking diffuse pulmonary hemorrhage: A case report.

Pulmonary angiosarcomas are usually secondary tumors, and a primary angiosarcoma of the lung is extremely rare. The present study reports a case of an elderly patient diagnosed with primary pulmonary angiosarcoma (PPA). A 78-year-old man presented with a 3-month history of cough and blood in phlegm. A computed tomography scan of the chest indicated pulmonary infection with ground-glass opacity in the right upper lobe. The patient underwent lobectomy of the right upper lobe as his clinical symptoms did not significantly improve after anti-infection treatment. The postoperative pathological examination confirmed a diagnosis of PPA. He developed left lung and pelvic metastases 1 month after surgery. After four cycles of liposomal doxorubicin therapy, the patient achieved partial remission. The patient remained in sustained remission after 6 months of follow-up. The present case report is intended to provide diagnostic insight into PPA. In addition, the findings indicate that timely diagnosis and treatment of PPA are very important due to its increased risk of local recurrence and distant metastasis.

A cross-sectional study on the need for and utilization of assistive walking devices by people age 55 and older in Shanghai.

We conducted a study to analyze the unmet needs of and risk factors for use of assistive walking devices by the elderly based on sample survey data from Shanghai, China from July to October 2019. Among a total sample size of 11,193 people age 55 and older, 1,947 people (17.39%) needed assistive walking devices, 829 (42.58%) of whom needed but did not use those devices. Multivariate analysis indicated that residence, living alone or cohabitating, indoor handrails, the number of diseases, and IADL were factors influencing the unmet need for assistive walking devices (p < 0.05, respectively). People who lived in community health centers (p = 0.0104, OR = 1.956, 95% CI: 1.171-3.267) and those who lived only with their spouse (p = 0.0002, OR = 2.901, 95% CI: 1.641-5.126) were more likely to have an unmet need for assistive walking devices. People without indoor handrails (p = 0.0481, OR = 0.718, 95% CI: 0.517-0.997), those with 3 or more diseases (p = 0.0008, OR = 0.577, 95% CI: 0.418-0.796), and those with severely impaired IADL (p = 0.0002, OR = 0.139, 95% CI: 0.05-0.386) were less likely to have an unmet need for assistive walking devices. Self-perceived needs of the elderly, the diversity and performance of assistive devices, and the accessibility and affordability of assistive walking devices may lead to unmet needs.

Characteristics, scope of activity, and negative emotions in elderly women with urinary incontinence: Based on a longitudinal follow-up in Shanghai, China.

We conducted a study to assess the characteristics, scope of activity, and negative emotions in elderly women with urinary incontinence (UI) based on a longitudinal follow-up conducted in Shanghai, China from 2013 to 2019. A total of 3,531 elderly women were included in the final analysis, and 697 women who experienced UI during follow-up were included in the UI group. Subjects with UI were subdivided into those with partial UI (UI once a day or less) and UI (frequent UI). Two thousand eight hundred and thirty-four women who did not have UI during the same period served as the control group. The prevalence of UI was 19.74% in this study. Logistic regression analysis revealed that being older (> 80 years of age), having a high level of education (> 12 years; elderly people with a high level of education may pay more attention to their health and notice UI more readily), a low personal monthly income (≤ 3,000 RMB), more gravidity/parity, and having a chronic disease (chronic obstructive pulmonary disease (COPD), dementia, or Parkinson's disease) were risk factors for UI (p < 0.05). About 60% of women in the partial UI group engaged in daily activities outdoors, while this number decreased sharply to 3.6% in the UI group. Women in the UI group were more likely to have negative emotions, such as depression, anxiety, irritability, or feeling worthless (p < 0.001). Among elderly women with dementia, those with UI had defects in terms of judgment in everyday life, the ability of convey information, and the ability to understand information (p < 0.05). More attention needs to be paid to the adverse effects of UI on activities of daily living (ADL) and mental health in the future.

Role and mechanism of PIM family in the immune microenvironment of diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is a more common non-Hodgkin lymphoma (NHL). This study aims to explore the prognostic value of PIM kinase family in DLBCL and its relationship with the immune microenvironment, to provide a certain reference for the prognosis and treatment of DLBCL. METHODS: The prognostic value of PIM kinase family in DLBCL from the data set GSE10846 was verified through survival analysis and cox regression analysis. Mutations in PIM kinase family and its relationship with immune cell infiltration were explored with online cBioPortal, TIMER database, and single-gene GSEA analysis. Finally, the expression of PIM kinase family in tissues from DLBCL clinical samples was validated through immunohistochemical staining. RESULTS: The proteins of PIM kinase family were highly expressed in DLBCL patients, which are good prognostic factors for DLBCL patients. Then, PIM1-3 proteins were positively correlated with the immune infiltration of B cells, whose types of mutations also showed different degrees of correlation with B cells. PIM kinase family proteins also showed a high correlation with PDL1. In addition, PIM kinase family was also associated with the commonly mutated genes in DLBCL, such as MYD88, MYC, and BTK. CONCLUSION: PIM kinase family may be a potential therapeutic target for DLBCL patients.

Inducible nitric oxide synthase-expressing myeloid-derived suppressor cells regulated by interleukin 35 contribute to the pathogenesis of psoriasis.

Although psoriasis is classified as a T cell-mediated inflammatory disease, the contribution of myeloid cells to the pathogenesis of psoriasis is not fully understood. In the present study, we demonstrated that the expression of the anti-inflammatory cytokine interleukin-35 (IL-35) was significantly increased in patients with psoriasis with a marked increase in the number of myeloid-derived suppressor cells (MDSCs). Similar results were obtained in an imiquimod-induced psoriasis mouse model. IL-35 reduced the total number of MDSCs and their subtypes in the spleens and psoriatic skin lesions, ameliorating psoriasis. IL-35 also reduced the expression of inducible nitric oxide synthase in MDSCs, although it had no significant effect on interleukin-10 expression. Adoptive transfer of MDSCs from imiquimod-challenged mice aggravated the disease and weakened the effect of IL-35 in the recipient mice. In addition, mice transferred with MDSCs isolated from inducible nitric oxide synthase knockout mice had milder disease than those with wild-type MDSCs. Furthermore, wild-type MDSCs reversed the effects of IL-35, while MDSCs isolated from inducible nitric oxide synthase knockout mice did not affect IL-35 treatment. In summary, IL-35 may play a critical role in the regulation of iNOS-expressing MDSCs in the pathogenesis of psoriasis, highlighting IL-35 as a novel therapeutic strategy for patients with chronic psoriasis or other cutaneous inflammatory diseases.

Identification of a cuproptosis-related lncRNA prognostic signature in lung adenocarcinoma.

PURPOSE: Cuproptosis-related long non-coding RNA (lncRNA) diseases are associated with the occurrence and development of tumors. This study aimed to investigate whether cuproptosis-related lncRNA can predict the prognosis of patients with lung adenocarcinoma (LUAD). METHODS: Cuproptosis-related lncRNA prognosis (CLPS) model was successfully constructed through cox regression and lasso regression analyses. Then, the prognostic value of CLPS model was tested through the survival analysis, the ROC curve and the nomogram. Finally, the correlation of CLPS model with tumor immunity and tumor mutation burden was analyzed, and the potential susceptibility of drugs for LUAD were predicted. RESULTS: CLPS model for LUAD (AC090948.1, CRIM1-DT, AC026356.2, AC004832.5, AL161431.1) was successfully constructed, which has an independent prognostic value. Furthermore, the risk score of CLPS model was correlated with tumor immune characteristics and immune escape, which can predict the sensitivity of drugs including Cisplatin, Etoposide, Gemcitabine, and Erlotinib. CONCLUSIONS: In conclusion, it was found that CLPS model was associated with tumor immunity and tumor mutation load, which also predicted four potentially sensitive drugs for LUAD patients at different risks.

DAP12 deletion causes age-related motor function impairment but promotes functional recovery after sciatic nerve crush injury.

DNAX activating protein of 12 kDa (DAP12)-deficiency mice showed impaired differentiation of oligodendrocytes and reduced myelin in the central nervous system. Whether DAP12 is expressed by Schwann cells and its roles in the peripheral nervous system (PNS) remains unknown. In this study, expression of DAP12 was detected in Schwann cells in vivo and in vitro. The DAP12-knockout (KO) mice showed age-related motor deficits and thinner myelin in the sciatic nerve than WT mice but significantly faster clinical recovery after sciatic nerve crush injury. In sciatic nerves of DAP12 KO and WT mice, proteomic profiles analysis identified 158 differentially expressed proteins (DEPs) at 8-week-old, 29 DEPs at 54-week-old and 33 DEPs at two weeks after crush injury. Typically, of the DEPs at 54-week-old, up-regulated Lgmn and down-regulated RecK and Yap1 were associated with myelin loss in the sciatic nerve of DAP12 KO mice. Upregulation of nicotinamide nucleotide transhydrogenase and haptoglobin were associated with the accumulation of macrophages in the crushed sciatic nerve of DAP12 KO mice. After crush injury, there were significantly more M1 macrophages at one-week and more M2 macrophages at two-week in sciatic nerve of DAP12 KO mice than WT mice, indicating that DAP12 deletion promotes the phenotype conversion of macrophages from M1 to M2. Collectively, our findings suggest that DAP12 may exert dual roles in the PNS including promoting the physiological myelin formation and maintenance of Schwann cells but delaying nerve repair after injury by modulating the recruitment of macrophages and phenotype conversion.

Pyruvate Dehydrogenase Kinase 2 Accelerates Endotoxin Shock by Promoting Mitogen-Activated Protein Kinase Activation.

Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.