Mechanistic insights into phosphoactivation of SLAC1 in guard cell signaling.

Stomata in leaves regulate gas (carbon dioxide and water vapor) exchange and water transpiration between plants and the atmosphere. SLow Anion Channel 1 (SLAC1) mediates anion efflux from guard cells and plays a crucial role in controlling stomatal aperture. It serves as a central hub for multiple signaling pathways in response to environmental stimuli, with its activity regulated through phosphorylation via various plant protein kinases. However, the molecular mechanism underlying SLAC1 phosphoactivation has remained elusive. Through a combination of protein sequence analyses, AlphaFold-based modeling and electrophysiological studies, we unveiled that the highly conserved motifs on the N- and C-terminal segments of SLAC1 form a cytosolic regulatory domain (CRD) that interacts with the transmembrane domain(TMD), thereby maintaining the channel in an autoinhibited state. Mutations in these conserved motifs destabilize the CRD, releasing autoinhibition in SLAC1 and enabling its transition into an activated state. Our further studies demonstrated that SLAC1 activation undergoes an autoinhibition-release process and subsequent structural changes in the pore helices. These findings provide mechanistic insights into the activation mechanism of SLAC1 and shed light on understanding how SLAC1 controls stomatal closure in response to environmental stimuli.

The safety and efficacy of transfusing red blood cells stored for different durations: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this work was to resolve the uncertainty of whether transfusion of fresher red blood cells (RBCs) is better or not with regard to the safety and efficacy. METHODS: This systematic review was performed in accordance with our protocol registered on PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022379183). RESULTS: After a literature search, 13,247 records were identified, and 26 randomized controlled trials (RCTs) involving 53,859 participants were eligible and included in this review. The results in our review suggested that there was no significant effect of fresher vs older RBCs on mortality (relative risk [RR] = 1.04; 95% CI, 0.99-1.09; P = .39; I2 = 0%), transfusion reactions (RR = 0.87; 95% CI, 0.57-1.33; P = .64; I2 = 0%). However, the transfusion of fresher RBCs might increase the risk of nosocomial infection (RR = 1.11; 95% CI, 1.02-1.20; P = .02; I2 = 0%), whereas there was no significant difference in the fresh vs old subgroup (RR = 0.87; 95% CI, 0.68 to 1.12; P = .28; I2 = 0%). CONCLUSION: Our study updated and reinforced the evidence of previously published systematic reviews that support the safety and efficiency of current practice of issuing the oldest available RBCs in the blood bank inventory.

Central nervous system involvement in chronic lymphocytic leukemia: a case report and review of literature.

BACKGROUND: Central nervous system involvement in chronic lymphocytic leukemia rarely occurs, and there is no standard therapy for central nervous system involvement in chronic lymphocytic leukemia. This article aims to analyze the diagnosis and treatment of central nervous system involvement in chronic lymphocytic leukemia. CASE PRESENTATION: It reports two cases of central nervous system involvement in chronic lymphocytic leukemia describing the clinical course, therapy, and prognosis. Case 1 is a 67-year-old Asian male patient, he experienced complications with central nervous system involvement after developing resistance to ibrutinib, bendamustine, and rituximab (BR) chemotherapies. The central nervous system lesion was controlled with high-dose methotrexate combined with pomalidomide, but Richter transformation occurred several months later. Case 2 is a 62-year-old Asian female patient, she had central nervous system involvement at initial diagnosis, and bone marrow and central nervous system lesions were controlled by ibrutinib therapy. CONCLUSION: Central nervous system involvement in chronic lymphocytic leukemia is rare and can be diagnosed on the basis of clinical features, cerebrospinal fluid testing, and radiographic evaluation. Ibrutinib, pomalidomide, and other drugs that can cross the blood-brain barrier may be effective for treating central nervous system involvement in chronic lymphocytic leukemia.

The Effect of Preoperative Anemia on the Odds of Allogeneic Blood Transfusion and Patient Outcomes in Colorectal Neoplasm Patients.

BACKGROUND: The optimal preoperative hemoglobin (Hb) value of colorectal neoplasm patients is still being debated. This study aimed at determining the effect of preoperative anemia on patient outcomes and allogeneic blood transfusion (ABT). METHODS: This retrospective cohort study enrolled colorectal neoplasm patients, that underwent surgery, from January 1, 2012, to December 31, 2021. The primary outcomes were the association between anemia and average length of stay (ALOS) and the odds of ABT. The secondary outcomes were the risk factors of the primary outcomes. Univariate and multivariate logistic regression analyses were applied to identify the association and risk factors. RESULTS: A total of 14,352 inpatients were included in the study, of whom 3,035 experienced (21.15%) mild anemia, 1,500 (10.45%) moderate anemia, and 104 (0.72%) severe anemia. Overall, 1,418 (9.88%) patients received ABT during the hospitalization, and 546 (3.80%) patients received perioperative ABT. In the multivariate logistic regression analysis, compared with the no anemic group, the odds ratio [OR] of ABT during the hospitalization for patients with mild/moderate/severe anemia were 5.915, 95% confidence interval [CI]: 4.717 - 7.418; 104.777, 95% CI: 84.345 - 130.160; and 13,361.442, 95% CI: 816.004 - 218,783.511, respectively, and the OR of periopera¬tive ABT were 4.332, 95% CI: 3.245 - 5.785; 27.492, 95% CI: 20.974 - 36.037; and 20.912, 95% CI: 11.832 - 36.959, respectively. Besides, the ALOS was longer, ß were 0.619, 95% CI: 0.346 - 0.892; 1.188, 95% CI: 0.821 - 1.554; and 1.395, 95% CI: 0.107 - 2.684, respectively. CONCLUSIONS: Anemia is a common phenomenon in colorectal neoplasm surgical patients, and even mild anemia could be a deleterious predictor on the outcomes of colorectal neoplasm patients that underwent surgery.

Low-Polarization, Broad-Spectrum Semiconductor Optical Amplifiers.

Polarization-insensitive semiconductor optical amplifiers (SOAs) in all-optical networks can improve the signal-light quality and transmission rate. Herein, to reduce the gain sensitivity to polarization, a multi-quantum-well SOA in the 1550 nm band is designed, simulated, and developed. The active region mainly comprises the quaternary compound InGaAlAs, as differences in the potential barriers and wells of the components cause lattice mismatch. Consequently, a strained quantum well is generated, providing the SOA with gain insensitivity to the polarization state of light. In simulations, the SOA with ridge widths of 4 µm, 5 µm, and 6 µm is investigated. A 3 dB gain bandwidth of >140 nm is achieved with a 4 µm ridge width, whereas a 6 µm ridge width provides more output power and gain. The saturated output power is 150 mW (21.76 dB gain) at an input power of 0 dBm but increases to 233 mW (13.67 dB gain) at an input power of 10 dBm. The polarization sensitivity is <3 dBm at -20 dBm. This design, which achieves low polarization sensitivity, a wide gain bandwidth, and high gain, will be applicable in a wide range of fields following further optimization.

Caerin 1.9-Titanium Plates Aid Implant Healing and Inhibit Bacterial Growth in New Zealand Rabbit Mandibles.

OBJECTIVES: With rising rates of maxillofacial fracture, postoperative infection following rigid internal fixation is an important issue that requires immediate resolution. It is important to explore an alternative antibacterial method apart from conventional antibiotics. A controlled experiment was conducted to evaluate the effectiveness of a caerin 1.9 peptide-coated titanium plate in reducing mandibular infection in New Zealand (NZ) rabbits, aiming to minimise the risk of post-metallic implantation infection. METHODS: Twenty-two NZ rabbits were randomly divided into 3 groups. The experiment group received caerin 1.9 peptide-coated titanium plates and mixed oral bacteria exposure. The control group received normal titanium plates with mixed oral bacteria exposure. The untreated group served as a control to prove that bacteria in the mouth can cause infection. Weight, temperature, hepatic function, and C-reactive protein levels were measured. Wound and bone conditions were evaluated. Further analysis included local infection, anatomic conditions, histology, and bacterial load. RESULTS: No significant differences were found in temperature, weight, blood alanine aminotransferase, and C-reactive protein levels amongst the 3 groups. The experiment group showed the lowest amount of bacterial RNA in wounds. Additionally, the experiment group had higher peripheral lymphocyte counts compared to the control group and lower neutrophil counts on the third and seventh day postoperatively. Histologic analysis revealed lower levels of inflammatory cell infiltration, bleeding, and areas of necrosis in the experimental group compared with the controls. CONCLUSIONS: A caerin 1.9-coated titanium plate is able to inhibit bacterial growth in a NZ rabbit mandibular mixed bacteria infection model and is worth further investigation.

Translocator protein (18 kDa) positron emission tomography imaging as a biomarker of neuroinflammation in epilepsy.

Increasing evidence indicate that neuroinflammation triggered by glial cells plays a significant role in epileptogenesis. To this effect, the overexpression of translocator protein 18 kDa (TSPO) in activated microglia and astrocytes has been identified as an inflammatory biomarker in epilepsy. It is now possible to quantify neuroinflammation using non-invasive positron emission tomography (PET) imaging of TSPO. With the advancement of radiotracers, TSPO PET has become an innovative tool in elucidating the "neuroinflammatory machinery" of drug-resistant epilepsy. Furthermore, TSPO PET has demonstrated potential in detecting MRI-negative epileptogenic zones (EZ) and provided an innovative perspective in epileptic medical treatment. This manuscript presents a comprehensive exploration of the neuroinflammatory mechanisms of epilepsy, alongside a thorough review of TSPO PET studies conducted in clinical and preclinical settings. The primary objective is to deepen our understanding of epilepsy progression and to establish TSPO PET as an effective monitoring tool for treatment efficacy.

Comparison of Accuracy and Operation Time in Robotic, Dynamic, and Static-Assisted Endodontic Microsurgery: An In Vitro Study.

INTRODUCTION: This study aimed to compare the accuracy and operation time (OT) of robotic-assisted endodontic microsurgery (RA-EMS), dynamic navigation-guided (DN-guided) EMS, and static navigation-guided (SN-guided) EMS. METHODS: Seventy-two teeth from three sets of standardized jaw models (TrueTooth, DELendo, Santa Barbara, CA) randomly assigned into 3 groups underwent osteotomy and root-end resection. Preoperative plans and postoperative cone-beam computed tomography images were imported into an accuracy analysis system and aligned based on the anatomical structures to assess accuracy. The OT was recorded from the moment the foot pedal was pressed down until the bur reached the target depth. Statistical analyses were conducted using Kruskal-Wallis and Scheirer-Ray-Hare tests, with significance set at P < .05. RESULTS: RA-EMS exhibited significantly higher accuracy than DN- and SN-guided EMS in terms of platform, angular, and resection angular deviations (P < .05). Additionally, RA-EMS exhibited significantly higher accuracy than DN-guided EMS in resection length deviation (P < .05). Significant differences were also observed in OTs between the 3 approaches, with SN-guided EMS showing the shortest OT, followed by RA-EMS and DN-guided EMS. Differences in jaw types within the DN-guided EMS group were observed in terms of angular deviation (P < .05). CONCLUSIONS: All 3 treatment approaches demonstrated acceptable clinical accuracy and OT. RA-EMS exhibited superior accuracy, suggesting its potential application prospects in endodontics. Further high-quality clinical studies are warranted.

Lower plasma linoleic acids as a risk factor for gout: an integrated analysis of population-based cohort and genetic data.

Background: Gout is a nutrition-related, highly prevalent inflammatory arthritis with undesirable effects on the quality of life. The relationships between circulating fatty acids (FAs) and gout remain poorly understood. Method: We included 268 174 participants with plasma FAs measured using nuclear magnetic resonance at the baseline (2006-2010) from the UK Biobank, of which 15 194 participants had repeated measures of FAs between 2012 and 2013. Cox proportional hazards models were used to assess the association of the baseline and longitudinal changes in relative levels of plasma FAs (% total FAs) with incident gout. Mendelian randomization (MR) analyses were conducted to assess the potential causality of the examined association. Results: Over a median follow-up of 12.8 years, 5160 incident cases of gout occurred. Baseline polyunsaturated fatty acids (PUFAs), n-6 PUFAs, and linoleic acids (LAs) were inversely associated with incident gout (all P-trend values < 0.0001). Baseline monounsaturated fatty acids (MUFAs), n-3 PUFAs, and docosahexaenoic acids (DHAs) were positively associated with incident gout (all P-trend values < 0.0001). Longitudinal increments of n-6 PUFAs and LAs were associated with a lower risk of subsequent gout, whereas an increment of n-3 PUFAs was associated with a higher risk. In two-sample MR analyses, genetically determined higher levels of PUFAs, n-6 PUFAs, and LAs were associated with a decreased risk of gout (all P values < 0.05). Conclusions: Our findings consistently indicate a causal relationship of elevated levels of n-6 PUFAs, especially LAs, with a reduced risk of gout.

Lactobacillus rhamnosus GG alleviates radiation-induced intestinal injury by modulating intestinal immunity and remodeling gut microbiota.

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 108 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.

A Dual-Stream Cross AGFormer-GPT Network for Traffic Flow Prediction Based on Large-Scale Road Sensor Data.

Traffic flow prediction can provide important reference data for managers to maintain traffic order, and can also be based on personal travel plans for optimal route selection. On account of the development of sensors and data collection technology, large-scale road network historical data can be effectively used, but their high non-linearity makes it meaningful to establish effective prediction models. In this regard, this paper proposes a dual-stream cross AGFormer-GPT network with prompt engineering for traffic flow prediction, which integrates traffic occupancy and speed as two prompts into traffic flow in the form of cross-attention, and uniquely mines spatial correlation and temporal correlation information through the dual-stream cross structure, effectively combining the advantages of the adaptive graph neural network and large language model to improve prediction accuracy. The experimental results on two PeMS road network data sets have verified that the model has improved by about 1.2% in traffic prediction accuracy under different road networks.

Liraglutide alleviates high-fat diet-induced kidney injury in mice by regulating the CaMKKß/AMPK pathway.

OBJECTIVE: Liraglutide, a glucagon-like peptide-1 receptor agonist, has been shown to regulate blood sugar and control body weight, but its ability to treat obesity-related nephropathy has been poorly studied. Therefore, this study was designed to observe the characteristics and potential mechanism of liraglutide against obesity-related kidney disease. METHODS: Thirty-six C57BL/6J male mice were randomly divided into six groups (n = 6 per group). Obesity-related nephropathy was induced in mice by continuous feeding of high-fat diet (HFD) for 12 weeks. After 12 weeks, liraglutide (0.6 mg/kg) and AMP-activated protein kinase (AMPK) agonists bortezomib (200 µg/kg) were injected for 12 weeks, respectively. Enzyme-linked immunosorbent assay was employed to detect the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine in serum, as well as urinary protein in urine. Besides, hematoxylin-eosin staining and periodic acid-Schiff staining were used to observe the pathological changes of kidney tissue; immunohistochemistry, western blot, and real-time quantitative PCR to assess the calmodulin-dependent protein kinase kinase beta (CaMKKß)/AMPK signaling pathway activation. RESULTS: Liraglutide significantly reduced serum lipid loading, improved kidney function, and relieved kidney histopathological damage and glycogen deposition in the mouse model of obesity-related kidney disease induced by HFD. In addition, liraglutide also significantly inhibited the CaMKKß/AMPK signaling pathway in kidney tissue of HFD-induced mice. However, bortezomib partially reversed the therapeutic effect of liraglutide on HDF-induced nephropathy in mice. CONCLUSIONS: Liraglutide has a therapeutic effect on obesity-related kidney disease, and such an effect may be achieved by inhibiting the CaMKKß/AMPK signaling pathway in kidney tissue.

[Growth decline characteristics of Picea schrenkiana at different altitudes in Yili River Basin, western Tian-shan Mountains, Xinjiang, China]. / 新疆天山西部伊犁河流域不同海拔雪岭云杉生长衰退特征.

Picea schrenkiana is the dominant tree species in Ili River Basin located in the western Tianshan Mountains of Xinjiang. We investigated the growth decline characteristics of P. schrenkiana at different altitudes (1800, 2300 and 2800 m) based on tree-ring index (TRI) and percentage growth change (GC), aiming to understand the growth response of P. schrenkiana to drought events at different altitudes and the impacts of altitude on tree growth decline in this region. The results showed that P. schrenkiana experienced multiple decline events at low-altitude (1800 m). TRI and GC identified inconsistent occurrence time of the decline events. The variations of TRI indicated that P. schrenkiana at low-altitude experienced two large-scale declines during 1927-1933 and 2017-2014, respectively. The variations of GC identified four decline events, including 1891-1893, 1924-1926, 1973-1975, and 2004-2009. The radial growth of P. schrenkiana across altitudes from low to high was significantly affected by the Palmer drought severity index (PDSI) of the previous growing season. The impact of current PDSI on P. schrenkiana during the growing season initially enhanced but later decreased with increasing altitude. In the extreme drought year 1917, the magnitude of growth decline increased with altitude. At low-altitude (1800 m), the TRI was 0.65, which was 35% lower than the normal level. At mid-altitude (2300 m) and high-altitude (2800 m), it was 0.56 and 0.54, respectively, being 40% lower than the average level. The drought event in 1917 had a 2-year legacy effect on the growth of P. schrenkiana at all the altitudes, with the TRI in 1920 recovered to exceeding 0.9, being close to the normal level. The impact of altitude on drought-induced forest decline was significant. Tree growth in low-altitude areas was more vulnerable to drought events due to the relatively poorer water and temperature conditions at low-altitude, which could lead to multiple large-scale decline events. In mid- and high-altitude areas, where hydrothermal conditions were more favorable, trees could experience even more severe decline during extreme droughts.

Semiconductor Optical Amplifiers with Wide Gain Bandwidth and Enhanced Polarization Insensitivity Based on Tensile-Strained Quantum Wells.

The paper presents a wide-bandwidth, low-polarization semiconductor optical amplifier (SOA) based on strained quantum wells. By enhancing the material gain of quantum wells for TM modes, we have extended the gain bandwidth of the SOA while reducing its polarization sensitivity. Through a combination of tilted waveguide design and cavity surface optical thin film design, we have effectively reduced the cavity surface reflectance of the SOA, thus decreasing device transmission losses and noise figure. At a wavelength of 1550 nm and a drive current of 1.4 A, the output power can reach 188 mW, with a small signal gain of 36.4 dB and a 3 dB gain bandwidth of 128 nm. The linewidth broadening is only 1.032 times. The polarization-dependent gain of the SOA is below 1.4 dB, and the noise figure is below 5.5 dB. The device employs only I-line lithography technology, offering simple fabrication processes and low costs yet delivering outstanding and stable performance. The designed SOA achieves wide gain bandwidth, high gain, low polarization sensitivity, low linewidth broadening, and low noise, promising significant applications in the wide-bandwidth optical communication field across the S + C + L bands.

Linewidth Measurement of a Narrow-Linewidth Laser: Principles, Methods, and Systems.

Narrow-linewidth lasers mainly depend on the development of advanced laser linewidth measurement methods for related technological progress as key devices in satellite laser communications, precision measurements, ultra-high-speed optical communications, and other fields. This manuscript provides a theoretical analysis of linewidth characterization methods based on the beat frequency power spectrum and laser phase noise calculations, and elaborates on existing research of measurement technologies. In addition, to address the technical challenges of complex measurement systems that commonly rely on long optical fibers and significant phase noise jitter in the existing research, a short-delay self-heterodyne method based on coherent envelope spectrum demodulation was discussed in depth to reduce the phase jitter caused by 1/f noise. We assessed the performance parameters and testing conditions of different lasers, as well as the corresponding linewidth characterization methods, and analyzed the measurement accuracy and error sources of various methods.

Female reproductive factors, exogenous hormone use, and incident chronic kidney disease and end-stage renal disease.

CONTEXT: Younger women have a slower progressive loss of kidney function than age-matched men and the sex advantage diminishes after menopause, suggesting a role for female hormones in the development of kidney diseases. OBJECTIVE: To examine the relationships of numerous reproductive factors and exogenous hormone use with long-term risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in women. METHODS: A total of 260,108 women without prevalent CKD and ESRD were included. The relationships of various reproductive factors and exogenous hormone use with incident CKD and ESRD were assessed, with multivariable adjustment for potential confounders. RESULTS: During a median of ∼12.5 years of follow-up, 8,766 CKD and 554 ESRD cases were identified. Younger age at first live birth, hysterectomy or bilateral oophorectomy before 50 years old, menopausal before 45 years old, and menopausal hormone therapy (MHT) initiated before 50 years old was associated with a higher risk of CKD. The relationships of these factors with ESRD were generally consistent with those for CKD. Each 5-year increment in menopausal age was associated with an 11% lower risk of CKD (HR = 0.89; 95% CI: 0.87, 0.91) and a 13% lower risk of ESRD (HR = 0.87; 95% CI: 0.79, 0.95). Each 5-year delay in starting MHT was associated with a 13% lower risk of CKD (HR = 0.87; 95% CI: 0.84, 0.90) and a 15% lower risk of ESRD (HR = 0.85; 95% CI: 0.73, 0.99). CONCLUSION: Several reproductive characteristics reflecting shorter cumulative exposure to endogenous estrogen or premature exposure to exogenous hormones are associated with a greater risk of CKD and ESRD in women, supporting a potential role of female hormones in renal pathophysiology.

Establishing equivalent circuits of mounted, high-power VCSEL arrays for iToF cameras.

Solid-state indirect time-of-flight (iToF) cameras are crucial to numerous short-to-medium-range applications, owing to their advantages in terms of system integrability and long-term reliability. However, due to the low light intensity, the sensing range of iToF cameras is generally limited to a few meters, which hinders their wide applications. Further increasing the sensing range requires not only higher-power laser diodes but also well-designed driver circuits, which are based on prior knowledge of the laser diodes' equivalent circuits (ECs). However, experimental studies on ECs of a mounted, high-power vertical-cavity surface-emitting laser (VCSEL) array that comprehensively incorporates all parasitic components, especially parasitic stemming from printed circuit boards (PCBs), remain absent. In this Letter, an 850 nm VCSEL array with a 15.3 W peak power and a 581 MHz bandwidth is fabricated, and more importantly, its EC is experimentally established. Leveraging the accurate EC, a compact iToF camera with a sensing range up to 11.50 m is designed. In addition, a modified precision model is proposed to better evaluate the iToF camera's performance.

A new mechanism of thyroid hormone receptor ß agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.

Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor ß (THRß) agonist and the first approved drug for NASH treatment. It is well known that the THRß activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg-1·d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRß activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRß agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRß activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRß agonists in NASH treatment.

Celastrol mediates CAV1 to attenuate pro-tumorigenic effects of senescent cells.

BACKGROUND: Cellular senescence is an emerging hallmark of cancers, primarily fuels cancer progression by expressing senescence-associated secretory phenotype (SASP). Caveolin-1 (CAV1) is a key mediator of cell senescence. Previous studies from our group have evidenced that the expression of CAV1 is downregulated by Celastrol (CeT). PURPOSE: To investigate the impact of CeT on cellular senescence and its subsequent influence on post-senescence-driven invasion, migration, and stemness of clear cell renal cell carcinoma (ccRCC). STUDY DESIGN AND METHODS: The expression levels of CAV1, canonical senescence markers, and markers associated with epithelial-mesenchymal transition (EMT) and stemness in clinical samples were assessed through Pearson correlation analysis. Senescent cell models were induced using DOX, and their impact on migration, invasion, and stemness was evaluated. The effects of CeT treatment on senescent cells and their pro-tumorigenic effects were examined. Subsequently, the underlying mechanism of CeT were explored using lentivirus transfection and CRISPR/Cas9 technology to silence CAV1. RESULTS: In human ccRCC clinical samples, the expression of the canonical senescence markers p53, p21, and p16 are associated with ccRCC progression. Senescent cells facilitated migration, invasion, and enhanced stemness in both ccRCC cells and ccRCC tumor-bearing mice. As expected, CeT treatment reduced senescence markers (p16, p53, p21, SA-ß-gal) and SASP factors (IL6, IL8, CXCL12), alleviating cell cycle arrest. However, it did not restore the proliferation of senescent cells. Additionally, CeT suppressed senescence-driven migration, invasion, and stemness. Further investigations into the underlying mechanism demonstrated that CAV1 is a critical mediator of cell senescence and represents a potential target for CeT to attenuate cellular senescence. CONCLUSIONS: This study presents a pioneering investigation into the intricate interplay between cellular senescence and ccRCC progression. We unveil a novel mechanism of CeT to mitigate cellular senescence by downregulating CAV1, thereby inhibiting the migration, invasion and stemness of ccRCC driven by senescent cells. These findings provide valuable insights into the underlying mechanisms of CeT and its potential as a targeted therapeutic approach for alleviating the aggressive phenotypes associated with senescent cells in ccRCC.