The ER stress sensor inositol-requiring enzyme 1α in Kupffer cells promotes hepatic ischemia-reperfusion injury.

Hepatic ischemia/reperfusion (I/R) injury is an inflammation-mediated process arising from ischemia/reperfusion-elicited stress in multiple cell types, causing liver damage during surgical procedures and often resulting in liver failure. Endoplasmic reticulum (ER) stress triggers the activation of the unfolded protein response (UPR) and is implicated in tissue injuries, including hepatic I/R injury. However, the cellular mechanism that links the UPR signaling to local inflammatory responses during hepatic I/R injury remains largely obscure. Here, we report that IRE1α, a critical ER-resident transmembrane signal transducer of the UPR, plays an important role in promoting Kupffer-cell-mediated liver inflammation and hepatic I/R injury. Utilizing a mouse model in which IRE1α is specifically ablated in myeloid cells, we found that abrogation of IRE1α markedly attenuated necrosis and cell death in the liver, accompanied by reduced neutrophil infiltration and liver inflammation following hepatic I/R injury. Mechanistic investigations in mice as well as in primary Kupffer cells revealed that loss of IRE1α in Kupffer cells not only blunted the activation of the NLRP3 inflammasome and IL-1ß production, but also suppressed the expression of the inducible nitric oxide synthase (iNos) and proinflammatory cytokines. Moreover, pharmacological inhibition of IRE1α's RNase activity was able to attenuate inflammasome activation and iNos expression in Kupffer cells, leading to alleviation of hepatic I/R injury. Collectively, these results demonstrate that Kupffer cell IRE1α mediates local inflammatory damage during hepatic I/R injury. Our findings suggest that IRE1α RNase activity may serve as a promising target for therapeutic treatment of ischemia/reperfusion-associated liver inflammation and dysfunction.

Association between serum soluble α-klotho and bone mineral density (BMD) in middle-aged and older adults in the United States: a population-based cross-sectional study.

BACKGROUND: Osteoporosis is a degenerative disease defined by low bone mineral density, has a high prevalence, and causes fractures at multiple sites throughout the body, greatly affecting the quality of patients. α-Klotho is an endocrine factor involved in the regulation of various metabolic processes in humans, and its role in bone metabolism has attracted widespread attention. The relationship between α-klotho and bone mineral density has not been uniformly recognized, and no large-scale correlation analysis has been conducted in the middle-aged and elderly population. OBJECTIVE: To determine the relationship between α-klotho and bone mineral density in middle-aged and elderly people. METHODS: Population data of 3120 individuals aged 40-79 years were obtained from the NHANES database for the period 2011-2016. Regression analysis was performed using a general linear model with serum α-klotho as the independent variable and total bone mineral density, thoracic bone mineral density, lumbar bone mineral density, pelvic bone mineral density, and trunk bone mineral density as the dependent variables, respectively. The generalized additive model was also used for smoothing curve fitting and threshold effect analysis. RESULTS: Serum α-klotho was positively correlated with total bone mineral density at lg (Klotho) < 2.97 and with thoracic bone mineral density at lg (Klotho) > 2.69 (ß = 0.05, p = 0.0006), and negatively correlated (ß = -0.27, p = 0.0341) with lumbar bone mineral density at lg (Klotho) < 2.69. It also positively correlated with trunk bone mineral density (ß = 0.027, p = 0.03657) and had no segmental effect but did not correlate with pelvic bone mineral density. The positive association of serum α-klotho with those aged 40-49 years, female, non-Hispanic White, and without hypertension was clearer. In the population with diabetes, a significantly positive association between total (ß = 0.15, p = 0.01), thoracic (ß = 0.23, p = 0.0404), and lumbar (ß = 0.22, p = 0.0424) bone mineral density and α-klotho was observed. CONCLUSIONS: α-Klotho has different relationships with total, thoracic, lumbar, and trunk bone mineral density. Among them, the positive correlation between α-klotho and trunk bone mineral density is more valuable for predicting osteoporosis. The significant effect of α-klotho on bone mineral density in diabetes patients suggests its potential as a predictive marker of diabetes progression.

Potential and applications of capillary electrophoresis for analyzing traditional Chinese medicine: a critical review.

Capillary electrophoresis (CE) presents a promising possibility for analyzing traditional Chinese medicine (TCM) due to its low reagent consumption, high analysis speed, and enhanced efficiency. Herein we review the employment of CE for analyzing the effective components in TCM and identifying TCM via a fingerprint. Furthermore, we discuss the application of state-of-the-art capillary electrophoresis modes for screening enzyme inhibitors and investigating the interactions between TCM and plasma proteins. The review concludes with recommendations for future studies and improvements in this field of research. The general development trend identified in this review indicates that the application of CE has significantly improved TCM assay performance.

High Mitochondrial Genome Diversity and Intricate Population Structure of Bursaphelenchus xylophilus in Kyushu, Japan.

Mitogenomic diversity and genetic population structure of the pinewood nematode (PWN) Bursaphelenchus xylophilus inhabiting Kyushu, Japan were analyzed. A method for performing long PCR using single nematodes and sequencing nematode mitochondrial genomes individually is presented here. About 8 kb (∼55%) of the complete mitochondrial genome was successfully obtained from 285 individuals collected from 12 populations. The 158 single nucleotide polymorphisms detected corresponded to 30 haplotypes, clearly classified into two clades. Haplotype diversity was 0.83, evidencing a remarkable high diversity within Kyushu. The high genetic differentiation among the 12 populations (0.331) might be due to past invasion and expansion routes of PWN in northeastern and southeastern Kyushu. The distinct genetic composition of populations within the northwestern, central western, and southwestern Kyushu seems to be mostly related to the extinction of pine forests and long-range migration of PWN due to human activity. Overall, direct long PCR and sequencing of single nematode individuals are effective methods for investigating mitochondrial polymorphisms, and these are effective tools for PWN population genetics and other intraspecific studies.

Age-related Changes in Humanin Expression in the Ovarian Tissue of Rat.

OBJECTIVE: This study examined humanin expression in rat ovarian tissue, its cellular localization, and its correlation with rat age under physiological conditions. METHODS: A total of 40 Sprague-Dawley rats of various ages (2, 12, 30, and 60 days old and 1 year old) were grouped by age. Immunofluorescence and immunohistochemical techniques were used to observe humanin expression and cellular location in the ovarian tissues of rats from each age group. In addition, Western blotting and Real-time quantitative reverse transcription PCR (qRT-PCR) techniques were used to measure humanin expression level in the ovarian tissues of rats from each age group. RESULTS: The immunofluorescence and immunohistochemical results confirmed that humanin was expressed in rat ovarian tissues. In addition, cellular localization analysis showed that humanin was expressed in the cytoplasm of oocytes, interstitial cells, granulosa cells and theca cells in all levels of follicles after the primary follicles, and in the corpus luteum. The qRT-PCR results revealed that the level of humanin expression in the ovarian tissues of 12-day-old rats was non-significantly higher than that in the ovarian tissues of 2-day-old rats (P>0.05), whereas the levels of humanin expression in the ovarian tissues of 30-day-old, 60-day-old, and 1-year-old rats were significantly lower than that in the ovarian tissues of 2-day-old rats (P<0.05). The Western blotting results demonstrated that the levels of humanin protein expression in the ovarian tissues of 60-day-old and 1-year-old rats were significantly lower than those of 2-day-old rats (P<0.01), whereas there was no significant difference in the level of humanin protein expression between the ovarian tissues of 12-day-old and 30-day-old rats. CONCLUSION: This study confirmed that humanin is expressed in the cytoplasm of various cells in rat ovarian tissues. Moreover, the level of humanin expression was highest in the ovarian tissues of 12-day-old rats, and it subsequently decreased with age. The changes in the expression of humanin in the ovary of rats at different ages will lay the foundation for the role of humanin in ovarian aging. The effect of humanin on ovarian function is worthy of further study in the future.

CpG-Conjugated Silver Nanoparticles as a Multifunctional Nanomedicine to Promote Macrophage Efferocytosis and Repolarization for Atherosclerosis Therapy.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases, necessitating the development of novel therapeutic strategies to alleviate plaque burden. Macrophage efferocytosis, the process by which macrophages clear apoptotic and foam cells, plays a crucial role in plaque regression. However, this process is impaired in AS lesions due to the overexpression of CD47, which produces a "do not eat me" signal. In this study, we investigated the potential of CpG, a toll-like receptor 9 agonist, to enhance macrophage efferocytosis for AS therapy. We demonstrated that CpG treatment promoted the engulfment of CD47-positive apoptotic cells and foam cells by macrophages. Mechanistically, CpG induced a metabolic shift in macrophages characterized by enhanced fatty acid oxidation and de novo lipid biosynthesis, contributing to its pro-efferocytic effect. To enable in vivo application, we conjugated CpG on silver nanoparticles (AgNPs) to form CpG-AgNPs, which could protect CpG from biological degradation, promote its cellular uptake, and release CpG in response to intracellular glutathione. Combining the intrinsic antioxidative and anti-inflammatory abilities of AgNPs, such nanomedicine displayed multifunctionalities to simultaneously promote macrophage efferocytosis and repolarization. In an ApoE-/- mouse model, intravenous administration of CpG-AgNPs effectively targeted atherosclerotic plaques and exhibited potent therapeutic efficacy with excellent biocompatibility. Our study provides valuable insights into CpG-induced macrophage efferocytosis and highlights the potential of CpG-AgNPs as a promising therapeutic strategy for AS.

TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway.

OBJECTIVE: Cisplatin is the first-line treatment for breast cancer, but it faces challenges of drug resistance. This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer. METHODS: We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2 (TMED2) and breast cancer. Western blotting, real-time PCR, CCK-8, and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines. RESULTS: TMED2 was overexpressed in breast cancer and associated with poor prognosis. TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1 (KEAP1), relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2 (Nrf2), and increasing expression of downstream drug resistance related genes, such as heme oxygenase 1 (HO-1) and NAD (P) H quinone oxidoreductase 1 (NQO1). CONCLUSION: We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer. Our results provide theoretical guidance for future clinical applications.

Effects of Atmospheric Pressure Plasma in the Treatment of Experimental Periodontitis in Beagle Dogs.

OBJECTIVE: The specific objective of this study was to evaluate the effects of atmospheric pressure plasma (APP) in the treatment of experimental periodontitis in Beagle dogs. METHODS: The APP jet was diagnosed using optical emission spectroscopy and laser-induced fluorescence spectroscopy. Six Beagles received stainless steel ligatures to establish experimental periodontitis model. The teeth in the control group were subjected to conventional root surface debridement (RSD) and chlorhexidine irrigation. The APP group also started with RSD and was then subjected to plasma irradiation. Clinical analyses including plaque index, modified sulcus bleeding index, pocket depth and attachment loss (AL), as well as cone-beam computed tomography (CBCT) analysis, were performed at baseline, 4th week, 8th week and 12th week after treatment. RESULTS: The results showed that typical reactive oxygen and nitrogen species were found in the full spectrum and the gas temperature of APP was close to room temperature. The highest concentrations of hydroxide and oxygen were obtained at 5 mm away from the nozzle. In both groups, all values in clinical examinations were significantly lower (P<0.05) at 12th week after treatment than those at baseline. At the 12th week, the AL in clinical examinations and the bone loss in CBCT images in the APP group were significantly lower than those in the control group (P<0.05). The hematoxylin-eosin staining showed more renascent alveolar bone in the APP group than in the control group. CONCLUSION: These findings suggested that APP has profound potential for use as an adjunct approach for periodontitis treatment.

Biodegradation performance and biofouling control of a halophilic biocarriers-MBR in saline pharmaceutical (ampicillin-containing) wastewater treatment.

This work develops a halophilic biocarriers-MBR for saline pharmaceutical wastewater treatment. The system has effectively treated the ampicillin-containing saline wastewater for 32 days, when the ampicillin concentration is lower than 20 mg/L. The system can tolerate the saline organic wastewater with a reasonable biodegradability (removals of COD over 75%) when the ampicillin concentration is 50 mg/L. The system has a bad performance in biodegradation (COD removals around 60-70%) and fouled within 16 days at a high ampicillin concentration of 100 mg/L. At high transmembrane pressures over 30 KPa, some ampicillin molecules may permeate through the membrane causing decreases in the ampicillin removal. The concentrations of protein and carbohydrate in EPS and SMP have increased over time and with increasing the ampicillin concentration. The method of biofouling control in MBR for the ampicillin situations has been proposed based on monitoring the concentrations of EPS and SMP. The drying-assisted monitoring of membrane biofoulants has showed a better efficiency than the monitoring of transmembrane pressure for membrane anti-biofouling in the treatment of pharmaceutical saline wastewaters where a spectroscopic detection can be hardly applied. This work may benefit relative research works for the control of biodegradation performance and membrane biofouling to better treat saline pharmaceutical wastewaters.

Novel Automatic Epilepsy Detection Method Multi-weight Transition Network.

The automatic diagnosis of epilepsy using Electroencephalogram (EEG) signals had always been an important research direction. A novel automatic epilepsy detection method based on multi-weight transition network was proposed in this paper. The epileptic EEG signal was first transformed into complex network according to our proposed multi-weight transition network algorithm. Then, based on the statistical characteristics of the multi-weight transition network, the degree of network and the local entropy of network were extracted as features. Finally, the extracted features and support vector machines (SVM) were combined to classify epileptic seizure and non-seizure signals, and the classification performance was evaluated by k-fold cross validation. Seven different experimental cases were tested. The experimental results indicate that the algorithm had high classification accuracy for all cases.