ELONGATED HYPOTCOTYL5 and SPINE BASE SIZE1 together mediate light-regulated spine expansion in cucumber.

Plant trichome development is influenced by diverse developmental and environmental signals, but the molecular mechanisms involved are not well understood in most plant species. Fruit spines (trichomes) are an important trait in cucumber (Cucumis sativus L.), as they affect both fruit smoothness and commercial quality. Spine Base Size1 (CsSBS1) has been identified as essential for regulating fruit spine size in cucumber. Here, we discovered that CsSBS1 controls a season-dependent phenotype of spine base size in wild-type plants. Decreased light intensity led to reduced expression of CsSBS1 and smaller spine base size in wild-type plants, but not in the mutants with CsSBS1 deletion. Additionally, knockout of CsSBS1 resulted in smaller fruit spine base size and eliminated the light-induced expansion of spines. Overexpression of CsSBS1 increased spine base size and rescued the decrease in spine base size under low light conditions. Further analysis revealed that ELONGATED HYPOTCOTYL5 (HY5), a major transcription factor involved in light signaling pathways, directly binds to the promoter of CsSBS1 and activates its expression. Knockout of CsHY5 led to smaller fruit spine base size and abolished the light-induced expansion of spines. Taken together, our study findings have clarified a CsHY5-CsSBS1 regulatory module that mediates light-regulated spine expansion in cucumber. This finding offers a strategy for cucumber breeders to develop fruit with stable appearance quality under changing light conditions.

Dynamic changes in macrophage morphology during the progression of choroidal neovascularization in a laser-induced choroidal neovascularization mouse model.

BACKGROUND: Neovascular age-related macular degeneration (AMD) is responsible for the majority of severe vision loss cases and is mainly caused by choroidal neovascularization (CNV). This condition persists or recurs in a subset of patients and regresses after 5 or more years of anti-vascular endothelial growth factor (VEGF) treatment. The precise mechanisms of CNV continue to be elucidated. According to our previous studies, macrophages play a critical role in CNV. Herein, we aimed to determine the morphological changes in macrophages in CNV to help us understand the dynamic changes. METHODS: Mice were subjected to laser injury to induce CNV, and lesion expansion and macrophage transformation were examined by immunofluorescence and confocal analysis. Several strategies were used to verify the dynamic changes in macrophages. Immunofluorescence and confocal assays were performed on choroidal flat mounts to evaluate the morphology and phenotype of macrophages in different CNV phases, and the results were further verified by western blotting and RT-PCR. RESULTS: The location of infiltrated macrophages changed after laser injury in the CNV mouse model, and macrophage morphology also dynamically changed. Branching macrophages gradually shifted to become round with the progression of CNV, which was certified to be an M2 phenotypic shift. CONCLUSIONS: Dynamic changes in macrophage morphology were observed during CNV formation, and the round-shaped M2 phenotype could promote neovascularization. In general, the changes in morphology we observed in this study can help us to understand the critical role of macrophages in CNV progression and exploit a potential treatment option for CNV indicated by a shift in macrophage polarity.

Chrysophanol alleviates acute lung injury caused by Klebsiella pneumoniae infection by inhibiting pro-inflammatory cytokine production.

Acute lung injury (ALI) caused by acute bacterial infection remains a common life-threatening lung disease. An increased inflammatory response is the basis for the occurrence and development of ALI. Most antibiotics can only reduce the bacterial load but do not protect from lung damage because of an excessive immune response. Chrysophanol (chrysophanic acid, Chr), as a natural anthraquinone extracted from Rheum palmatum L., has various biological functions, including anti-inflammatory, anti-cancer activities, and ameliorative effects on cardiovascular diseases. Considering these properties, we investigated the effect of Chr in Klebsiella pneumoniae (KP)-induced ALI mice and its potential mechanism. Our results showed that Chr had protective effects against KP-infected mice, including increased survival rate, decreased bacterial burden, reduced recruitment of immune cells, and reduced reactive oxygen species level of lung macrophages. Chr reduced the expression of inflammatory cytokines by inhibiting the toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-κB) signaling pathway and inflammasome activation and strengthening autophagy. Overactivation of the TLR4/NF-κB signaling pathway by the activator Neoseptin 3 led to Chr losing control of inflammatory cytokines in cells, resulting in increased cell death. Similarly, overactivation of the c-Jun N-terminal kinase signaling pathway using the activator anisomycin resulted in Chr losing its inhibitory effect on NOD-like receptor thermal protein domain associated protein 3 (NFRP3) inflammasome activation, and cell viability was reduced. In addition, autophagy was blocked by siBeclin1, so Chr could not reduce inflammatory factors, and cell viability was markedly inhibited. Collectively, this work unravels the molecular mechanism underpinning Chr-alleviated ALI via inhibiting pro-inflammatory cytokines. Thus, Chr is a potential therapeutic agent for KP-induced ALI.

Acinetobacter baumannii among Patients Receiving Glucocorticoid Aerosol Therapy during Invasive Mechanical Ventilation, China.

Acinetobacter baumannii is a nosocomial pathogen associated with severe illness and death. Glucocorticoid aerosol is a common inhalation therapy in patients receiving invasive mechanical ventilation. We conducted a prospective cohort study to analyze the association between glucocorticoid aerosol therapy and A. baumannii isolation from ventilator patients in China. Of 497 enrolled patients, 262 (52.7%) received glucocorticoid aerosol, and A. baumannii was isolated from 159 (32.0%). Glucocorticoid aerosol therapy was an independent risk factor for A. baumannii isolation (hazard ratio 1.5, 95% CI 1.02-2.28; p = 0.038). Patients receiving glucocorticoid aerosol had a higher cumulative hazard for A. baumannii isolation and analysis showed that glucocorticoid aerosol therapy increased A. baumannii isolation in most subpopulations. Glucocorticoid aerosol was not a direct risk factor for 30-day mortality, but A. baumannii isolation was independently associated with 30-day mortality in ventilator patients. Physicians should consider potential A. baumannii infection when prescribing glucocorticoid aerosol therapy.

The impact of rifampicin on the pharmacokinetics of fuzuloparib in healthy Chinese male volunteers.

AIMS: This clinical study was conducted to evaluate the impact of rifampicin on the pharmacokinetics of fuzuloparib. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy male subjects took a single 50 mg dose of fuzuloparib on two separate occasions: the first was on Day 1 as monotherapy, and the second was on Day 12 after oral administration of rifampicin 600 mg once daily for 8 days. Series of blood samples were obtained before and after fuzuloparib administration at different time points: pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours post-dose. All samples were examined using liquid chromatography with tandem mass spectrometry. PK parameters were estimated by using a non-compartmental method with Phoenix WinNonlin software. Safety was assessed by monitoring for changes in vital signs and laboratory tests, physical examinations, and incidences of adverse events (AEs). RESULTS: A total of 16 Chinese male subjects were enrolled. Of these, 16 and 15 cases were evaluable for PK analysis following administration with fuzuloparib alone and pretreatment with rifampicin, respectively. Pretreatment with rifampicin resulted in a statistically significant reduction in the systemic exposure to fuzuloparib. The treatment ratio and 90% confidence intervals (CIs) for AUC0-∞ and Cmax were 0.10 (0.095-0.115) and 0.32 (0.281-0.365), respectively. A single administration of fuzuloparib after multiple oral dosing of rifampicin was well-tolerated, without severe AEs. CONCLUSION: The exposure of fuzuloparib was dramatically decreased when pretreated with rifampicin. Strong CYP3A4 inducers should be avoided during fuzuloparib treatment.

The experience of family caregivers of patients receiving home nasogastric tube feeding in China: A descriptive qualitative study.

BACKGROUND: The value of caregivers with respect to ensuring safety during home nasogastric tube (NGT) feeding is increasingly acknowledged. However, little attention has been given to the experience of caregivers. METHODS: A qualitative descriptive design using semi-structured interviews via purposive sampling at a comprehensive hospital in China was employed. Family caregivers of patients with home NGT feeding were recruited. Interviews were recorded, transcribed verbatim and analysed qualitatively using inductive content analysis. RESULTS: Thirteen family caregivers of patients with home NGT feeding were interviewed. Four main themes were generated: negative experience (uncertainty and ambivalence, transition gaps between hospitals and home care services), new role: adapting to the lifestyle (participating in decision-making, being responsible for everything, adjusting own life to NGT feeding), perceived benefit of caregiving (personal growth, development of positive attitudes and achievements) and expectations (expectations from continuity health system services, expectations from social support). CONCLUSIONS: The present study highlights the vulnerability and perceived benefits embedded in the role of a family caregiver. Improving communication and standardising practices between home and hospitals should be considered.

Ivermectin induces apoptosis of esophageal squamous cell carcinoma via mitochondrial pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the most predominant primary malignant tumor among worldwide, especially in China. To date, the successful treatment remains a mainly clinical challenge, it is imperative to develop successful therapeutic agents. METHODS: The anti-proliferative effect of ivermectin on ESCC is investigated in cell model and in nude mice model. Cell apoptosis was assessed using flow cytometry, TUNEL assay and western blotting. Mitochondrial dysfunction was determined by reactive oxygen species accumulation, mitochondrial membrane potential and ATP levels. RESULTS: Our results determined that ivermectin significantly inhibited the proliferation of ESCC cells in vitro and in vivo. Furthermore, we found that ivermectin markedly mediated mitochondrial dysfunction and induced apoptosis of ESCC cells, which indicated the anti-proliferative effect of ivermectin on ESCC cells was implicated in mitochondrial apoptotic pathway. Mechanistically, ivermectin significantly triggered ROS accumulation and inhibited the activation of NF-κB signaling pathway and increased the ratio of Bax/Bcl-2. CONCLUSIONS: These finding indicated that ivermectin has significant anti-tumour potential for ESSC and may be a potential therapeutic candidate against ESCC.

Contribution of traditional Chinese medicine combined with conventional western medicine treatment for the novel coronavirus disease (COVID-19), current evidence with systematic review and meta-analysis.

This study provides current evidence for efficacy and safety of treating COVID-19 with combined traditional Chinese medicine (TCM) and conventional western medicine (CWM). Six databases were searched from January 1 to December 31, 2020. Randomized controlled trials (RCTs), case-control studies (CCTs), and cohort studies on TCM or TCM combined with CWM treatment for COVID-19 were included. The quality of included RCTs was assessed by Cochrane risk of bias tool, and the Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort studies and CCTs. Review Manager 5.4 software was used to perform meta-analysis. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 35 studies (3,808 patients) composing 19 RCTs and 16 observational studies were included. The results of meta-analysis revealed that comparing with CWM alone, integrated TCM and CWM had significant improvement in total effective rate, improvement rate of chest CT, the rate of disease progression, as well as improvement of fever, fatigue and cough. The overall quality of evidence was very low to moderate. In conclusion, TCM combined with CWM was a potential treatment option for increasing clinical effective rate, improving the clinical symptoms, and preventing disease progression in COVID-19 patients. High-quality clinical trials are required in the further.

Anthocyanin Extract from Purple Sweet Potato Exacerbate Mitophagy to Ameliorate Pyroptosis in Klebsiella pneumoniae Infection.

Given the rise of morbidity and mortality caused by Klebsiella pneumoniae (KP), the increasing number of strains resistant to antibiotics, and the emergence of hypervirulent Klebsiella pneumonia, treatment of KP infection becomes difficult; thus, novel drugs are necessary for treatment. Anthocyanins, or natural flavonoids, have an extensive effect against bacterial infection. However, few studies on anti-KP are identified. Here, we evaluated the therapeutic effect of purple sweet potato anthocyanins (PSPAs) on KP, containing 98.7% delphinidin 3-sambubioside. Results showed that KP-infected mice after PSPAs treatment manifested decreased mortality, weakened lung injury, dampened inflammatory responses, and reduced bacterial systemic dissemination in vivo. In Vitro, PSPAs significantly suppressed pyroptosis and restricted NLRP3 inflammasome activation in alveolar macrophages infected with KP. As for the mechanism, PSPAs promote mitophagy by recruiting Parkin to the mitochondria. PSPAs-conferred mitophagy increased mitochondrial membrane potential and decreased mitochondrial reactive oxygen species and mitochondrial DNA, resulting in impaired NLRP3 inflammasome activation. In addition, the promotion of mitophagy by PSPAs required the Nrf2 signaling pathway. Collectively, these findings suggest that PSPAs are a potential option for the treatment of KP infection.

Association between preoperative renin-angiotensin system inhibitor use and postoperative acute kidney injury risk in patients with hypertension
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PURPOSE: To determine whether preoperative renin-angiotensin system (RAS) inhibitor use within 7 days of noncardiac surgery is associated with a lower incidence of postoperative acute kidney injury (AKI) in hypertensive patients. MATERIALS AND METHODS: We retrospectively analyzed 12,545 hypertensive patients undergoing noncardiac surgery at the Third Xiangya Hospital of Central South University from February 2007 to November 2015. According to the use of RAS inhibitors within 7 days of surgery, the patients were divided into a RASI group and a non-RASI group. We used a multivariable logistic regression model and propensity score matching (PSM) analysis to examine the association between preoperative RAS inhibitor use and postoperative AKI incidence. RESULTS: Among the 12,545 hypertensive patients undergoing noncardiac surgery who met the inclusion/exclusion criteria, 18.74% received preoperative RAS inhibitor treatment within 7 days of surgery. After PSM, 2,192 patients in each group were matched successfully. The incidence of postoperative AKI in the RASI group was significantly lower than that in the non-RASI group (7.39% vs. 12.32%, p < 0.001). The multivariable logistic regression analysis and the PSM analysis demonstrated similar associations between preoperative RAS inhibitor use and postoperative AKI incidence. This association was modified by the presence of preoperative congestive heart failure (CHF) (p-value for the interaction: 0.027), and the observed association was not evident in patients without CHF (CHF: adjusted odds ratios (ORs): 0.47; 95% CI: 0.31 - 0.70 vs. no CHF: adjusted OR: 0.80; 95% CI: 0.62 - 1.03). CONCLUSION: The preoperative use of RAS inhibitors in hypertensive patients was associated with a lower incidence of AKI following noncardiac surgery, and this association was not significant in the subgroup population without CHF.
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Probiotics decrease depressive behaviors induced by constipation via activating the AKT signaling pathway.

Chronic constipation is often accompanied by emotional disorders such as depression and anxiety. The aim of this study was to determine whether administration of a multispecies probiotic can decrease depressive behaviors through the gut-brain axis and identify any underlying mechanisms. A mouse model of constipation induced by loperamide (5 mg·kg-1,i.p.) was used. For that purpose, 36 ICR male mice were divided into three groups: control, constipation and probiotic groups. The probiotic group received treatment with a probiotic once per day for 14 days via a gavage. All other groups were given an equal volume of normal saline. The fecal parameters and intestinal transit ratio were recorded. The forced swimming test and tail suspension test were used to detect changes in depressive behaviors. Total superoxide dismutase (T-SOD) activity and malondialdehyde (MDA) levels were measured by assay kits. We also detected neuronal survival, as well as phosphorylated Ser/Thr protein kinase (p-AKT), Bcl-2, Bcl-2 associated X protein (Bax) and cleaved caspase-3 levels in the hippocampus. The results showed that administration of a probiotic could ameliorate depressive behaviors and relieve neuronal cell injury in the hippocampal CA3 regions. Moreover, probiotic treatment decreased MDA levels and increased SOD activity. Furthermore, probiotic administration increased p-AKT and Bcl-2 levels in the hippocampus of the constipated mice, while decreasing the concentrations of Bax and cleaved caspase-3, so as to inhibit the neural apoptosis. In the present study, we confirm that probiotics can alleviate depression induced by constipation through protecting neuronal health via activation of the AKT signaling pathway.

Specific Influences of Early Acoustic Environments on Cochlear Hair Cells in Postnatal Mice.

The auditory function develops and matures after birth in many mammalian species. After hearing onset, environmental sounds exert profound and long-term effects on auditory functions. However, the effects of the acoustic environment on the functional development of the peripheral auditory system, especially the cochlear sensory hair cells, are still unclear. In the present study, we exposed mouse pups to frequency-enriched acoustic environments in postnatal days 0-14. The results indicated that the acoustic environment significantly decreased the threshold of the auditory brainstem response in a frequency-specific manner. Compared with controls, no difference was found in the number and alignment of inner and outer hair cells or in the length of hair bundles after acoustic overstimulation. The expression and function of prestin, the motor protein of outer hair cells (OHCs), were specifically increased in OHCs activated by acoustic stimulation at postnatal days 7-11. We analyzed the postnatal maturation of ribbon synapses in the hair cell areas. After acoustic stimulation, the number of ribbon synapses was closer to the mature stage than to the controls. Taken together, these data indicate that early acoustic exposure could promote the functional maturation of cochlear hair cells and the development of hearing.

Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) involves the pathogenesis of atherosclerosis (AS) and increased plasma MIF levels in diabetes mellitus (DM) patients are associated with AS. Here, we have been suggested that MIF could be a critical contributor for the pathological process of diabetes-associated AS by using adenovirus-mediated RNA interference. First, streptozotocin (STZ)-induced diabetic animal model was constructed in 114 apolipoprotein E-deficient mice (apoE-/- mice) fed on a regular chow diet. Then, the animals were randomly divided into three groups: Adenovirus-mediated MIF interference (Ad-MIFi), Ad-enhanced green fluorescent protein (EGFP) and normal saline (NS) group (n ≈ 33/group). Non-diabetic apoE-/- mice (n = 35) were served as controls. Ad-MIFi, Ad-EGFP and NS were, respectively, injected into the tail vein of mice from Ad-MIFi, Ad-EGFP and NS group, which were injected repeatedly 4 weeks later. Physical, biochemical, morphological and molecular parameters were measured. The results showed that diabetic apoE-/- mice had significantly aggravated atherosclerotic lesions. MIF gene interference attenuated atherosclerotic lesions and stabilized atheromatous plaque, accompanied by the decreased macrophages and lipids deposition and inflammatory cytokines production, improved glucose intolerance and plasma cholesterol level, the decreased ratio of matrix matalloproteinase-2/tissue inhibitor of metalloproteinase-1 and plaque instability index. An increased expression of MIF and its ligand CD74 was also detected in the diabetic patients with coronary artery disease. The results suggest that MIF gene interference is able to inhibit atherosclerotic lesions and increase plaque stability in diabetic apoE-/-mice. MIF inhibition could be a novel and promising approach to the treatment of DM-associated AS.

Progress of One-Dimensional SiC Nanomaterials: Design, Fabrication and Sensing Applications.

One-dimensional silicon carbide (SiC) nanomaterials hold great promise for a series of applications, such as nanoelectronic devices, sensors, supercapacitors, and catalyst carriers, attributed to their unique electrical, mechanical, and physicochemical properties. Recent progress in their design and fabrication has led to a deep understanding of the structural evolution and structure-property correlation. Several unique attributes, such as high electron mobility, offer SiC nanomaterials an opportunity in the design of SiC-based sensors with high sensitivity. In this review, a brief introduction to the structure and properties of SiC is first presented, and the latest progress in design and fabrication of one-dimensional SiC nanomaterials is summarized. Then, the sensing applications of one-dimensional SiC nanomaterials are reviewed. Finally, our perspectives on the important research direction and future opportunities of one-dimensional SiC nanomaterial for sensors are proposed.

Anthocyanin Extracted from Purple Sweet Potato Alleviates Dextran Sulfate Sodium-Induced Colitis in Mice by Suppressing Pyroptosis and Altering Intestinal Flora Structure.

The objective of this study was to examine the impact and underlying mechanisms of pelargonidin-3-galactoside (Pg3gal) produced from purple sweet potatoes on colonic inflammation induced by dextran sulfate sodium (DSS) in a murine model of ulcerative colitis (UC). C57BL/6J mice were categorized into four groups (n = 6 per group): DSS+Pg3gal, control, control+Pg3gal, and DSS. Colitis was induced by providing free access to 3% DSS for 10 days. The DSS+Pg3gal model mice received DSS concurrently with intragastric Pg3gal (25 mg/kg). The health of the mice was carefully monitored on a regular basis, and scores for the Disease Activity Index (DAI) were documented. A histological assessment was conducted using hematoxylin and eosin staining to evaluate the extent of mucosal injury present. The expression levels of IL-6, NLRP3, ASC, cleaved-Caspase-1, TNF-α, N-GSDMS, and cleaved-IL-1ß proteins were evaluated by Western blot analysis. The process of 16S rRNA sequencing was carried out to examine the composition and relative abundance of gut microbiotas within the intestines of the mice. The DAI results revealed that Pg3gal significantly attenuated the DSS-induced UC in mice. In addition, it successfully alleviated the decline in colon size, improved the condition of colonic tissue, and significantly inhibited the production of proinflammatory cytokines, such as IL-6, IL-1ß, and TNF-α, in the colon tissues. Additionally, Pg3gal modulated the DSS-induced imbalanced gut microbiota, as evidenced by decreased Proteobacteria and Deferribacteres and simultaneous elevation in Firmicutes, Bacteroidetes, and Verrucomicrobia. In summary, Pg3gal alleviated DSS-induced UC by inhibiting pyroptosis in intestinal epithelial cells and enhancing the structural integrity of the gut microbiota.

Multimodal Nature of the Single-cell Primate Brain Atlas: Morphology, Transcriptome, Electrophysiology, and Connectivity.

Primates exhibit complex brain structures that augment cognitive function. The neocortex fulfills high-cognitive functions through billions of connected neurons. These neurons have distinct transcriptomic, morphological, and electrophysiological properties, and their connectivity principles vary. These features endow the primate brain atlas with a multimodal nature. The recent integration of next-generation sequencing with modified patch-clamp techniques is revolutionizing the way to census the primate neocortex, enabling a multimodal neuronal atlas to be established in great detail: (1) single-cell/single-nucleus RNA-seq technology establishes high-throughput transcriptomic references, covering all major transcriptomic cell types; (2) patch-seq links the morphological and electrophysiological features to the transcriptomic reference; (3) multicell patch-clamp delineates the principles of local connectivity. Here, we review the applications of these technologies in the primate neocortex and discuss the current advances and tentative gaps for a comprehensive understanding of the primate neocortex.

Crystal Face-Dependent Behavior of Single-Atom Pt: Construct of SA-FLP Dual Active Sites for Efficient NO2 Detection.

The strong potential of platinum single atom (PtSA) in gas sensor technology is primarily attributed to its high atomic economy. Nevertheless, it is imperative to conduct further exploration to understand the impact of PtSA on the active sites. In this study, the evolution of PtSA on (100)CeO2 and (111)CeO2 is examined, revealing notable disparities in the position and activity of surface PtSA on different crystal planes. The PtSA in (100)CeO2 surface can enhance the stability of Ce3+ and construct a frustrated Lewis pair (FLP) to form a double active site by combining the steric hindrance effect of oxygen vacancies, which increases the response value from 1.8 to 27 and reduce the response-recovery time from 140-192 s to 25-26 s toward five ppm NO2 at room temperature. Conversely, PtSA tends to bind to terminal oxygen on the surface of (111)CeO2 and become an independent reaction site. The response value of PtSA-(111)CeO2 surface only increased from 1.6 to 3.8. This research underscores the correlation between single atoms and crystal plane effects, laying the groundwork for designing and synthesizing ultra-stable and efficient gas sensors.

[Protective effect and mechanism of quercetin on acute liver injury induced by diquat poisoning in mice].

OBJECTIVE: To investigate the protective effect of quercetin (QR) on acute liver injury induced by diquat (DQ) poisoning in mice and its mechanism. METHODS: Eighty healthy male C57BL/6 mice with SPF grade were randomly divided into control group, DQ model group, QR treatment group, and QR control group, with 20 mice in each group. The DQ poisoning model was established by a one-time intraperitoneal injection of DQ solution (40 mg/kg); the control and QR control groups received equivalent amounts of distilled water through intraperitoneal injection. Four hours after modeling, the QR treatment group and the QR control group received 0.5 mL QR solution (50 mg/kg) through gavage. Meanwhile, an equivalent amount of distilled water was given orally to the control group and the DQ model group. The treatments above were administered once daily for seven consecutive days. Afterwards, the mice were anesthetized, blood and liver tissues were collected for following tests: changes in the structure of mice liver tissue were observed using transmission electron microscopy; the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected using enzyme linked immunosorbent assay (ELISA); the levels of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured using the water-soluble tetrazolium-1 (WST-1) method, the thiobarbituric acid (TBA) method, and enzymatic methods, respectively; the protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Kelch-like ECH-associated protein 1 (Keap1), and activated caspase-9 in liver tissues were detected using Western blotting. RESULTS: Severe mitochondrial damage was observed in the liver tissues of mice in the DQ model group using transmission electron microscopy, yet mitochondrial damage in the QR treatment group showed significant alleviation. Compared to the control group, the DQ model group had significantly increased levels of MDA in liver tissue, serum AST, and ALT, yet had significantly decreased levels of GSH and SOD in liver tissue. In comparison to the DQ model group, the QR treatment group exhibited significant reductions in serum levels of ALT and AST, as well as MDA levels in liver tissue [ALT (U/L): 52.60±6.44 vs. 95.70±8.00, AST (U/L): 170.45±19.33 vs. 251.10±13.09, MDA (nmol/mg): 12.63±3.41 vs. 18.04±3.72], and notable increases in GSH and SOD levels in liver tissue [GSH (µmol/mg): 39.49±6.33 vs. 20.26±3.96, SOD (U/mg): 121.40±11.75 vs. 81.67±10.01], all the differences were statistically significant (all P < 0.01). Western blotting results indicated that the protein expressions of Nrf2 and HO-1 in liver tissues of the DQ model group were significantly decreased compared to the control group. On the other hand, the protein expressions of Keap1 and activated caspase-9 were conspicuously higher when compared to the control group. In comparison to the DQ model group, the QR treatment group showed a significant increase in the protein expressions of Nrf2 and HO-1 in liver tissues (Nrf2/ß-actin: 1.17±0.08 vs. 0.92±0.45, HO-1/ß-actin: 1.53±0.17 vs. 0.84±0.09). By contrast, there was a notable decrease in the protein expressions of Keap1 and activated caspase-9 (Keap1/ß-actin: 0.48±0.06 vs. 1.22±0.09, activated caspase-9/ß-actin: 1.17±0.12 vs. 1.59±0.30), the differences were statistically significant (all P < 0.01). CONCLUSIONS: QR may reduce acute liver injury induced by DQ poisoning in mice via activating Keap1/Nrf2 signaling pathway.

CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation.

The circular RNA (circRNA) family is a group of endogenous non-coding RNAs (ncRNAs) that have critical functions in multiple physiological and pathological processes, including inflammation, cancer, and cardiovascular diseases. However, their roles in regulating innate immune responses remain unclear. Here, we define Cell division cycle 42 (CDC42)-165aa, a protein encoded by circRNA circCDC42, which is overexpressed in Klebsiella pneumoniae (KP)-infected alveolar macrophages. High levels of CDC42-165aa induces the hyperactivation of Pyrin inflammasomes and aggravates alveolar macrophage pyroptosis, while the inhibition of CDC42-165aa reduces lung injury in mice after KP infection by inhibiting Pyrin inflammasome-mediated pyroptosis. Overall, these results demonstrate that CDC42-165aa stimulates Pyrin inflammasome by inhibiting CDC42 GTPase activation and provides a potential clinical target for pathogenic bacterial infection in clinical practice.

The impact of CYP3A5*3 on oral quetiapine: A population pharmacokinetic model in Chinese bipolar disorder patients.

BACKGROUND: There is great interindividual difference in the plasma concentration of quetiapine, and optimizing quetiapine therapy to achieve a balance between efficacy and safety is still a challenge. In our study, a population pharmacokinetic (PPK) model considering genetic information was developed with the expectation of comprehensively explaining this observation in Chinese patients with bipolar disorder. METHODS: Patients who were dispensed quetiapine and underwent the therapeutic drug monitoring (TDM) were included. The genotypes of CYP3A5*3, CYP2D6*10, and ABCB1 C3435T/G2677T were analyzed. Finally, a multivariable linear regression model was applied to describe the PPK of quetiapine considering the covariates weight, height and genotype information. RESULTS: A total of 175 TDM points from 107 patients were adopted for PPK model development. Resultantly, the CL/F of quetiapine in CYP3A5 expressers was 81.1 CL/h, whereas it was 43.6 CL/h in CYP3A5 nonexpressers. The interindividual variability in CL/F was 47.7 %. However, neither the ABCB1 nor CYP2D6 genotype was significantly associated with the predictor of quetiapine clearance in our study. LIMITATIONS: Only trough concentrations were collected, and the span between different points was relatively wide, impeding the application of the typical nonlinear compartment model for PPK analysis. In addition, this was a single-center study which limited the sample of wild-type CYP3A5 carriers. CONCLUSIONS: The currently established PPK model of quetiapine considering the contribution of the CYP3A5 genotype could efficiently predict the population and individual pharmacokinetic parameters of Chinese bipolar disorder patients, which could better guide the personalized therapy with quetiapine, thus to achieve the best clinical response.