[Improvement of the mastication function of orthodontics combined with restoration in the treatment of deep overbite with severe lower anterior teeth attrition].

PURPOSE: To observe the effect of orthodontics combined with restoration on masticatory function in deep overbite patients with severe lower anterior teeth attrition. METHODS: From January 2018 to January 2022, a total of 164 deep overbite patients with severe lower anterior teeth attrition were collected and divided into two groups according to different treatment plans: control group(72 patients, with restoration treatment) and experimental group(92 patients, with orthodontics combined with restoration treatment). The chewing efficiency of the two groups was evaluated, temporomandibular joint dysfunction index (DI), muscle palpation index (PI) and cranio-mandibular index (CMI) were calculated. The satisfaction with facial esthetic, the Chinese version of Oral Health Impact Scale-14(OHIP-14) and the repair satisfaction score were evaluated, the occurrence of adverse events between the two groups was compared. SPSS 23.0 software package was used for statistical analysis. RESULTS: After treatment, the chewing efficiency of the experimental group was significantly improved compared to the control group, while the DI, PI, and CMI were significantly reduced compared to the control group(P＜0.05). Compared with the control group, the satisfaction degree with facial esthetic and restoration in the experimental group was significantly higher, while the OHIP-14 score was significantly lower after treatment(P＜0.05). The incidence of adverse events in the experimental group was significantly decreased compared with the control group (6.52% vs 25.00%, P＜0.05). CONCLUSIONS: Combination of orthodontics and restoration treatment can enhance the effectiveness of restoration treatment for deep overbite with severe lower anterior teeth attrition, improve the mastication function and temporomandibular joint balance,satisfaction and quality of life of patients, as well as reduce the risk of adverse events.

The effect and mechanism of patchouli alcohol on cognitive dysfunction in AD mice induced by Aß1-42 oligomers through AMPK/mTOR pathway.

Alzheimer's disease (AD) is a neurodegenerative brain disorder that progressively impairs long-term and working memory. The function and mechanism of PA(Patchouli alcohol) in improving AD in the external treatment of encephalopathy remain unclear. This study aimed to investigate the therapeutic effect of PA on AD using an Aß1-42 induced AD mouse model with LPS(Lipopolysaccharide) stimulation of BV2 microglial cells. Additionally, we aimed to explore the potential mechanism of PA in enhancing autophagy and reducing neuroinflammation through the AMPK (AMP-activated protein kinase)/mTOR (Mammaliam target of rapamycin) signaling pathway. The Morris water maze was used to assess cognitive function, and cortical and hippocampal tissues were collected for further analysis of the corresponding signaling pathways and inflammatory changes through biological experiments. Our research findings demonstrate that PA has a significant positive impact on cognitive and memory impairments in mice that have been induced with Aß1-42-induced AD. Additionally, PA was also found to revert the activation of microglia induced by LPS. These effects may be attributed to the reduction of neuroinflammation and enhancement of the AMPK/mTOR autophagy pathway. Therefore, PA may serve as an effective therapeutic option to prevent or delay the progression of AD-associated memory dysfunction.

Statin use and fall risk in adults: a cross-sectional survey and mendelian randomization analysis.

Background and Objective: The issue of falls poses a significant threat to the health of the elderly population. Although statins can cause myopathy, which implies that they may cause balance problems and increase the risk of falling, this has not been tested. Our objective was to assess whether the use of statins is linked to a higher risk of falls. Methods: A cross-sectional survey study and Mendelian randomization (MR) study were conducted to examine whether the use of statins was associated with an increased risk of falling and balance problems. The cross-sectional study included 2,656 participants from the US population (NHANES) who reported information on balance and falling problems in the past year and their use of statins. Univariate and multivariate logistic regression models were used to investigate the association between statin use and the likelihood of falling or experiencing balance problems. The MR study identified five Single Nucleotide Polymorphisms (SNPs) that predict statin use across five ancestry groups: Admixed African or African, East Asian, European, Hispanic, and South Asian. Additionally, SNPs predicting the risk of falls were acquired from the UK Biobank population. A two-sample MR analysis was performed to examine whether genetically predicted statin use increased the risk of falls. Results: The use of statins was found to be associated with an increased likelihood of balance and falling problems (balance problem, OR 1.25, 95%CI 1.02 to 1.55; falling problem, OR 1.27, 95%CI 1.03-1.27). Subgroup analysis revealed that patients under the age of 65 were more susceptible to these issues when taking statins (balance problem, OR 3.42, 95%CI 1.40 to 9.30; falling problem, OR 5.58, 95%CI 2.04-15.40). The MR analysis indicated that the use of statins, as genetically proxied, resulted in an increased risk of falling problems (OR 1.21, 95% CI 1.1-1.33). Conclusion: Our study found an association between the use of statins and an increased risk of balance problems and falls in adults over 40 years old, and the MR study result suggested statin use increased risk of falls. The risk was higher in participants under 65 years old compared to those over 65 years old.

Unveiling potential roles of earthworms in mitigating the presence of virulence factor genes in terrestrial ecosystems.

Earthworms can redistribute soil microbiota, and thus might affect the profile of virulence factor genes (VFGs) which are carried by pathogens in soils. Nevertheless, the knowledge of VFG profile in the earthworm guts and its interaction with earthworm gut microbiome is still lacking. Herein, we characterized earthworm gut and soil microbiome and VFG profiles in natural and agricultural ecosystems at a national scale using metagenomics. VFG profiles in the earthworm guts significantly differed from those in the surrounding soils, which was mainly driven by variations of bacterial communities. Furthermore, the total abundance of different types of VFGs in the earthworm guts was about 20-fold lower than that in the soils due to the dramatic decline (also by approximately 20-fold) of VFG-carrying bacterial pathogens in the earthworm guts. Additionally, five VFGs related to nutritional/metabolic factors and stress survival were identified as keystones merely in the microbe-VFG network in the earthworm guts, implying their pivotal roles in facilitating pathogen colonization in earthworm gut microhabitats. These findings suggest the potential roles of earthworms in reducing risks related to the presence of VFGs in soils, providing novel insights into earthworm-based bioremediation of VFG contamination in terrestrial ecosystems.

Cation Vacancies Enable Anion Redox in Li Cathodes.

Conventional Li-ion battery intercalation cathodes leverage charge compensation that is formally associated with redox on the transition metal. Employing the anions in the charge compensation mechanism, so-called anion redox, can yield higher capacities beyond the traditional limitations of intercalation chemistry. Here, we aim to understand the structural considerations that enable anion oxidation and focus on processes that result in structural changes, such as the formation of persulfide bonds. Using a Li-rich metal sulfide as a model system, we present both first-principles simulations and experimental data that show that cation vacancies are required for anion oxidation. First-principles simulations show that the oxidation of sulfide to persulfide only occurs when a neighboring vacancy is present. To experimentally probe the role of vacancies in anion redox processes, we introduce vacancies into the Li2TiS3 phase while maintaining a high valency of Ti. When the cation sublattice is fully occupied and no vacancies can be formed through transition metal oxidation, the material is electrochemically inert. Upon introduction of vacancies, the material can support high degrees of anion redox, even in the absence of transition metal oxidation. The model system offers fundamental insights to deepen our understanding of structure-property relationships that govern reversible anion redox in sulfides and demonstrates that cation vacancies are required for anion oxidation, in which persulfides are formed.

Discovery of a Ni2+-dependent heterohexameric metformin hydrolase.

The biguanide drug metformin is a first-line blood glucose-lowering medication for type 2 diabetes, leading to its presence in the global environment. However, little is known about the fate of metformin by microbial catabolism. Here, we characterize a Ni2+-dependent heterohexameric enzyme (MetCaCb) from the ureohydrolase superfamily, catalyzing the hydrolysis of metformin into guanylurea and dimethylamine. Either subunit alone is catalytically inactive, but together they work as an active enzyme highly specific for metformin. The crystal structure of the MetCaCb complex shows the coordination of the binuclear metal cluster only in MetCa, with MetCb as a protein binder of its active cognate. An in-silico search and functional assay discover a group of MetCaCb-like protein pairs exhibiting metformin hydrolase activity in the environment. Our findings not only establish the genetic and biochemical foundation for metformin catabolism but also provide additional insights into the adaption of the ancient enzymes toward newly occurred substrate.

Taurocholic acid represents an earlier and more sensitive biomarker and promotes cholestatic hepatotoxicity in ANIT-treated rats.

Bile acid homeostasis is crucial for the normal physiological functioning of the liver. Disruptions in bile acid profiles are closely linked to the occurrence of cholestatic liver injury. As part of our diagnostic and therapeutic approach, we aimed to investigate the disturbance in bile acid profiles during cholestasis and its correlation with cholestatic liver injury. Before the occurrence of liver injury, alterations in bile acid profiles were detected in both plasma and liver between 8 and 16 h, persisting up to 96 h. TCA, TCDCA, and TUDCA in the plasma, as well as TCA, TUDCA, TCDCA, TDCA, TLCA, and THDCA in the liver, emerged as early sensitive and potential markers for diagnosing ANIT-induced cholestasis at 8-16 h. The distinguishing features of ANIT-induced liver injury were as follows: T-BAs exceeding G-BAs and serum biochemical indicators surpassing free bile acids. Notably, plasma T-BAs, particularly TCA, exhibited higher sensitivity to cholestatic hepatotoxicity compared with serum enzyme activity and liver histopathology. Further investigation revealed that TCA exacerbated ANIT-induced liver injury by elevating liver function enzyme activity, inflammation, and bile duct proliferation and promoting the migration of bile duct epithelial cell. Nevertheless, no morphological changes or alterations in transaminase activity indicative of liver damage were observed in the rats treated with TCA alone. Additionally, there were no changes in bile acid profiles or inflammatory responses under physiological conditions with maintained bile acid homeostasis. In summary, our findings suggest that taurine-conjugated bile acids in both plasma and liver, particularly TCA, can serve as early and sensitive markers for predicting intrahepatic cholestatic drugs and can act as potent exacerbators of cholestatic liver injury progression. However, exogenous TCA does not induce liver injury under physiological conditions where bile acid homeostasis is maintained.

The anti-aging effects of Chlorella polysaccharide extract in Caenorhabditis elegans.

Chlorella has a variety of biological activities, and it is worth further exploring its pharmacological effects. In this study, we investigated the antioxidant and anti-ageing activities of Chlorella polysaccharide extract (CPE). Further studies revealed that CPE exhibited anti-ageing, and antioxidant activities in vivo, including an extended Caenorhabditis elegans stress resistance, decreased deposition of lipofuscin, and reduced effects of amyloid ß protein on mobility, decreased levels of reactive oxygen species and increased activity of antioxidant enzymes. Moreover, it dramatically increased the expression of anti-stress and longevity genes and reduced the expression of ageing-related genes; therefore, it was hypothesised that the mechanism of the age-delaying effect of CPE was related to the insulin signalling pathway. In summary, CPE could delay ageing and provide a new avenue for the application and development of CPE.

In Vivo Imaging of Immune Rejection of MIN6 Cells Transplanted in C3H Mice.

Recently, we successfully utilized noninvasive magnetic resonance and bioluminescence imaging to track MIN6 cells subcutaneously transplanted in immunocompromised nude mice for up to 64 days. In this study, we further used bioluminescence imaging to investigate the immune rejection of MIN6 cells in immunocompetent C3H mice. A total of 5 × 106 luciferase-transfected MIN6 cells were implanted into the subcutaneous space of each nude or C3H mouse. After transplantation, hypoglycemia and persistent bioluminescence signals were observed in eight of eight (100%) nude mice and five of nine (56%) C3H mice (p < 0.05). We then presensitized a group of C3H mice with C57BL/6 spleen cells just prior to transplantation (n = 14). Interestingly, none of them had hypoglycemia or persistent bioluminescence signals (p < 0.01 vs. C3H mice without presensitization). Histological examination of the grafts revealed a lack or minimal presence of insulin-positive cells in recipients without hypoglycemia and persistent bioluminescence signals. In contrast, recipients with hypoglycemia and persistent bioluminescence signals showed a significant presence of insulin-positive cells in their grafts. Our results indicate that rejection of MIN6 cells occurred in C3H mice and could be enhanced by presensitization with C57BL/6 spleen cells and that bioluminescence imaging is a useful noninvasive tool for detecting rejection of subcutaneously transplanted MIN6 cells.

PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-ß signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-ß upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.

Esophageal squamous cell carcinoma metastases to kidney and renal hilar lymph nodes through epithelial-mesenchymal transition: a case report and literature review.

BACKGROUND: Esophageal cancer (EC) metastasized to the kidney is extremely rare clinically. Here, we present a case of metachronous renal metastasis of esophageal squamous cell carcinoma (ESCC) through epithelial-mesenchymal transition (EMT). CASE PRESENTATION: A 60-year-old patient, male, complained of left waist pain for 5 days, 11 months after radical esophagectomy. Laboratory tests revealed haematuria. Both CT and PET-CT scan showed retroperitoneal lymph nodes and left renal masses. Subsequently the patient received a left nephrectomy and lymph nodes resection, and squamous cell carcinoma of kidney and renal hilar lymph nodes was diagnosed, combined with morphology, medical history and immunophenotype, it was presumed to be metastasis of ESCC through the EMT pathway. CONCLUSIONS: The renal metastasis of squamous cell carcinoma should be considered in patients with history of EC, although this is very rare. Histopathological examination combined with immunochemical detection is helpful in differential diagnosis.

Single-crystalline hole-transporting layers for efficient and stable organic light-emitting devices.

Efficient charge-carrier injection and transport in organic light-emitting devices (OLEDs) are essential to simultaneously achieving their high efficiency and long-term stability. However, the charge-transporting layers (CTLs) deposited by various vapor or solution processes are usually in amorphous forms, and their low charge-carrier mobilities, defect-induced high trap densities and inhomogeneous thickness with rough surface morphologies have been obstacles towards high-performance devices. Here, organic single-crystalline (SC) films were employed as the hole-transporting layers (HTLs) instead of the conventional amorphous films to fabricate highly efficient and stable OLEDs. The high-mobility and ultrasmooth morphology of the SC-HTLs facilitate superior interfacial characteristics of both HTL/electrode and HTL/emissive layer interfaces, resulting in a high Haacke's figure of merit (FoM) of the ultrathin top electrode and low series-resistance joule-heat loss ratio of the SC-OLEDs. Moreover, the thick and compact SC-HTL can function as a barrier layer against moisture and oxygen permeation. As a result, the SC-OLEDs show much improved efficiency and stability compared to the OLEDs based on amorphous or polycrystalline HTLs, suggesting a new strategy to developing advanced OLEDs with high efficiency and high stability.

Effect of endoscopic full-thickness resection assisted by distal serosal turnover with floss traction for gastric submucosal masses.

BACKGROUND: Complex and high-risk surgical complications pose pressing challenges in the clinical implementation and advancement of endoscopic full-thickness resection (EFTR). Successful perforation repair under endoscopy, thereby avoiding surgical intervention and postoperative complications such as peritonitis, are pivotal for effective EFTR. AIM: To investigate the effectiveness and safety of EFTR assisted by distal serosal inversion under floss traction in gastric submucosal tumors. METHODS: A retrospective analysis of patients with gastric and duodenal submucosal tumors treated with EFTR assisted by the distal serosa inversion under dental floss traction from January 2023 to January 2024 was conducted. The total operation time, tumor dissection time, wound closure time, intraoperative bleeding volume, length of hospital stay and incidence of complications were analyzed. RESULTS: There were 93 patients, aged 55.1 ± 12.1 years. Complete tumor resection was achieved in all cases, resulting in a 100% success rate. The average total operation time was 67.4 ± 27.0 min, with tumor dissection taking 43.6 ± 20.4 min. Wound closure times varied, with gastric body closure time of 24.5 ± 14.1 min and gastric fundus closure time of 16.6 ± 8.7 min, showing a significant difference (P < 0.05). Intraoperative blood loss was 2.3 ± 4.0 mL, and average length of hospital stay was 5.7 ± 1.9 d. There was no secondary perforation after suturing in all cases. The incidence of delayed bleeding was 2.2%, and the incidence of abdominal infection was 3.2%. No patient required other surgical intervention during and after the operation. CONCLUSION: Distal serosal inversion under dental-floss-assisted EFTR significantly reduced wound closure time and intraoperative blood loss, making it a viable approach for gastric submucosal tumors.

Factors affecting the expression and stability of full-length and truncated SRSF3 proteins in human cancer cells.

Alternative splicing plays a crucial role in increasing the diversity of mRNAs expressed in the genome. Serine/arginine-rich splicing factor 3 (SRSF3) is responsible for regulating the alternative splicing of its own mRNA and ensuring that its expression is balanced to maintain homeostasis. Moreover, the exon skipping of SRSF3 leads to the production of a truncated protein instead of a frameshift mutation that generates a premature termination codon (PTC). However, the precise regulatory mechanism involved in the splicing of SRSF3 remains unclear. In this study, we first established a platform for coexpressing full-length SRSF3 (SRSF3-FL) and SRSF3-PTC and further identified a specific antibody against the SRSF3-FL and truncated SRSF3 (SRSF3-TR) proteins. Next, we found that exogenously overexpressing SRSF3-FL or SRSF3-PTC failed to reverse the effects of digoxin, caffeine, or both in combination on this molecule and its targets. Endoplasmic reticulum-related pathways, transcription factors, and chemicals such as palmitic acid and phosphate were found to be involved in the regulation of SRSF3 expression. The downregulation of SRSF3-FL by palmitic acid and phosphate was mediated via different regulatory mechanisms in HeLa cells. In summary, we provide new insights into the altered expression of the SRSF3-FL and SRSF3-TR proteins for the identification of the functions of SRSF3 in cells.

TBC1D10B promotes tumor progression in colon cancer via PAK4­mediated promotion of the PI3K/AKT/mTOR pathway.

This study aimed to explore the expression, function, and mechanisms of TBC1D10B in colon cancer, as well as its potential applications in the diagnosis and treatment of the disease.The expression levels of TBC1D10B in colon cancer were assessed by analyzing the TCGA and CCLE databases. Immunohistochemistry analysis was conducted using tumor and adjacent non-tumor tissues from 68 colon cancer patients. Lentiviral infection techniques were employed to silence and overexpress TBC1D10B in colon cancer cells. The effects on cell proliferation, migration, and invasion were evaluated using CCK-8, EDU, wound healing, and Transwell invasion assays. Additionally, GSEA enrichment analysis was used to explore the association of TBC1D10B with biological pathways related to colon cancer. TBC1D10B was significantly upregulated in colon cancer and closely associated with patient prognosis. Silencing of TBC1D10B notably inhibited proliferation, migration, and invasion of colon cancer cells and promoted apoptosis. Conversely, overexpression of TBC1D10B enhanced these cellular functions. GSEA analysis revealed that TBC1D10B is enriched in the AKT/PI3K/mTOR signaling pathway and highly correlated with PAK4. The high expression of TBC1D10B in colon cancer is associated with poor prognosis. It influences cancer progression by regulating the proliferation, migration, and invasion capabilities of colon cancer cells, potentially acting through the AKT/PI3K/mTOR signaling pathway. These findings provide new targets and therapeutic strategies for the treatment of colon cancer.

Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Studies have indicated that immune dysfunction plays a central role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emergence of immune dysfunction in sepsis. The major manifestations of DCs in the septic state are abnormal functions and depletion in numbers, which are linked to higher mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most widely studied pathway of number reduction in DCs. In the past few years, there has been a surge in studies focusing on regulated cell death (RCD). This emerging field encompasses various forms of cell death, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death (ADCD). Regulation of DC's RCD can serve as a possible therapeutic focus for the treatment of sepsis. Throughout time, numerous tactics have been devised and effectively implemented to improve abnormal immune response during sepsis progression, including modifying the functions of DCs and inhibiting DC cell death. In this review, we provide an overview of the functional impairment and RCD of DCs in septic states. Also, we highlight recent advances in targeting DCs to regulate host immune response following septic challenge.

Prevalence and risk factors for chronic kidney disease among older adult patients with schizophrenia in Taiwan.

OBJECTIVES: There is an increasing incidence and prevalence of patients with chronic kidney disease (CKD) worldwide. Little is known the prevalence of CKD among older patients with schizophrenia. The purpose of this study was to investigate the prevalence of CKD and its risk factors in older adults with schizophrenia. METHODS: In this cross-sectional study, a convenience sample of 240 patients with schizophrenia age 50 or older were recruited. In addition to demographic and clinical data, participants' estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation based on age, sex, ethnicity, and serum creatinine level determined from a blood sample taken from participants. RESULTS: The overall prevalence of CKD was 11.3%. Those with CKD group were older, had a longer duration of psychiatric illness, a higher body mass index (BMI), and diagnoses of hypertension compared to those in the non-CKD group. Independent of other risk factors, older age and BMI were significantly associated with CKD. CONCLUSIONS: This study found that the overall prevalence of CKD in older patients with schizophrenia was 11.3%. Risk factors for CKD in this population were older age and higher BMI. In addition to early identification and early treatment of CKD in older patients with schizophrenia, clinicians should actively manage the risk factors identified in this study, such as higher BMI and older age.

Impaired distal renal potassium handling in streptozotocin-induced diabetic mice.

Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC.NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.

Trim14-IκBα Signaling Regulates Chronic Inflammatory Pain in Rats and Osteoarthritis Patients.

Chronic inflammatory pain is the highest priority for people with osteoarthritis when seeking medical attention. Despite the availability of NSAIDs and glucocorticoids, central sensitization and peripheral sensitization make pain increasingly difficult to control. Previous studies have identified the ubiquitination system as an important role in the chronic inflammatory pain. Our study displayed that the E3 ubiquitin ligase tripartite motif-containing 14 (Trim14) was abnormally elevated in the serum of patients with osteoarthritis and pain, and the degree of pain was positively correlated with the degree of Trim14 elevation. Furthermore, CFA-induced inflammatory pain rat model showed that Trim14 was significantly increased in the L3-5 spinal dorsal horn (SDH) and dorsal root ganglion (DRG), and in turn the inhibitor of nuclear factor Kappa-B isoform α (IκBα) was decreased after Trim14 elevation. After intrathecal injection of Trim14 siRNA to inhibit Trim14 expression, IκBα expression was reversed and increased, and the pain behaviors and anxiety behaviors of rats were significantly relieved. Overall, these findings suggested that Trim14 may contribute to chronic inflammatory pain by degrading IκBα, and that Trim14 may become a novel therapeutic target for chronic inflammatory pain.

SOFA in sepsis: with or without GCS.

PURPOSE: Sepsis is a global public health burden. The sequential organ failure assessment (SOFA) is the most commonly used scoring system for diagnosing sepsis and assessing severity. Due to the widespread use of endotracheal intubation and sedative medications in sepsis, the accuracy of the Glasgow Coma Score (GCS) is the lowest in SOFA. We designed this multicenter, cross-sectional study to investigate the predictive efficiency of SOFA with or without GCS on ICU mortality in patients with sepsis. METHODS: First, 3048 patients with sepsis admitted to Peking Union Medical College Hospital (PUMCH) were enrolled in this survey. The data were collected from June 8, 2013 to October 12, 2022. Second, 18,108 patients with sepsis in the eICU database were enrolled. Third, 2397 septic patients with respiratory system ≥ 3 points in SOFA in the eICU database were included. We investigated the predictive efficiency of SOFA with or without GCS on ICU mortality in patients with sepsis in various ICUs of PUMCH, and then we validated the results in the eICU database. MAIN RESULTS: In data of ICUs in PUMCH, the predictive efficiency of SOFA without GCS (AUROC [95% CI], 24 h, 0.724 [0.688, 0.760], 48 h, 0.734 [0.699, 0.769], 72 h, 0.748 [0.713, 0.783], 168 h, 0.781 [0.747, 0.815]) was higher than that of SOFA with GCS (AUROC [95% CI], 24 h, 0.708 [0.672, 0.744], 48 h, 0.721 [0.685, 0.757], 72 h, 0.735 [0.700, 0.757], 168 h, 0.770 [0.736, 0.804]) on ICU mortality in patients with sepsis, and the difference was statistically significant (P value, 24 h, 0.001, 48 h, 0.003, 72 h, 0.004, 168 h, 0.005). In septic patients with respiratory system ≥ 3 points in SOFA in the eICU database, although the difference was not statistically significant (P value, 24 h, 0.148, 48 h, 0.178, 72 h, 0.132, 168 h, 0.790), SOFA without GCS (AUROC [95% CI], 24 h, 0.601 [0.576, 0.626], 48 h, 0.625 [0.601, 0.649], 72 h, 0.639 [0.615, 0.663], 168 h, 0.653 [0.629, 0.677]) had a higher predictive efficiency on ICU mortality than SOFA with GCS (AUROC [95% CI], 24 h, 0.591 [0.566, 0.616], 48 h, 0.616 [0.592, 0.640], 72 h, 0.628 [0.604, 0.652], 168 h, 0.651 [0.627, 0.675]). CONCLUSIONS: In severe sepsis, it is realistic and feasible to discontinue the routine GCS for SOFA in patients with a respiratory system ≥ 3 points, and even better predict ICU mortality.