Cynarin alleviates acetaminophen-induced acute liver injury through the activation of Keap1/Nrf2-mediated lipid peroxidation defense via the AMPK/SIRT3 signaling pathway.

Overdose of Acetaminophen (APAP) is a major contributor to acute liver injury (ALI), a complex pathological process with limited effective treatments. Emerging evidence links lipid peroxidation to APAP-induced ALI. Cynarin (Cyn), a hydroxycinnamic acid derivative, exhibits liver protective effects, but whether it mitigates APAP-induced ALI is unclear. Our aim was to verify the protective impact of Cyn on APAP-induced ALI and elucidate the molecular mechanisms governing this process. Herein, the regulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) interaction was determined to be a novel mechanism underlying this protective impact of Cyn against APAP-induced ALI. Nrf2 deficiency increased the severity of APAP-induced ALI and lipid peroxidation and counteracted the protective effect of Cyn against this pathology. Additionally, Cyn promoted the dissociation of Nrf2 from Keap1, enhancing the nuclear translocation of Nrf2 and the transcription of downstream antioxidant proteins, thereby inhibiting lipid peroxidation. Molecular docking demonstrated that Cyn bound competitively to Keap1, and overexpression of Keap1 reversed Nrf2-activated anti-lipid peroxidation. Additionally, Cyn activated the adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)3 signaling pathway, which exhibits a protective effect on APAP-induced ALI. These findings propose that Cyn alleviates APAP-induced ALI by enhancing the Keap1/Nrf2-mediated lipid peroxidation defense via activation of the AMPK/SIRT3 signaling pathway.

LncRNA SNHG11 reprograms glutaminolysis in hepatic stellate cells via Wnt/ß-catenin/GLS axis.

Long non-coding RNAs (lncRNAs) have been identified as decisive regulators of liver fibrosis. Hepatic stellate cells (HSCs), major hepatic cells contributing to liver fibrosis, undergo metabolic reprogramming for transdifferentiation and activation maintenance. As a crucial part of metabolic reprogramming, glutaminolysis fuels the tricyclic acid (TCA) cycle that renders HSCs addicted to glutamine. However, how lncRNAs reprogram glutamine metabolism in HSCs is unknown. For this research, we characterized the pro-fibrogenic function of small nucleolar host gene 11 (SNHG11). Our data showed that in carbon tetrachloride (CCl4, 7 µL/g, intraperitoneally) treated C57BL/6J mice, SNHG11 expression was highly up-regulated in fibrotic livers and activated primary HSCs. SNHG11 knockdown attenuated the accumulation of fibrotic markers α-SMA and Col1A1 in liver fibrosis tissues and activated HSCs. Western blot and qRT-PCR assays demonstrated that glutaminase (GLS), the rate-limiting enzyme for glutaminolysis, was a downstream target of SNHG11. Furthermore, SNHG11 upregulated glutaminolysis in HSCs through the activation of the Wnt/ß-catenin signaling pathway. The results highlighted that SNHG11 is a glutaminolysis-regulated lncRNA that promotes liver fibrosis. A novel insight into the metabolic mechanism that reprograms glutaminolysis in HSCs could be exploited as anti-fibrotic targets.

Prevalence of Gastrointestinal Parasites in Zoo Animals and Phylogenetic Characterization of Toxascaris leonina (Linstow, 1902) and Baylisascaris transfuga (Rudolphi, 1819) in Jiangsu Province, Eastern China.

The burden of gastrointestinal parasites in zoo animals has serious implications for their welfare and the health of veterinarians and visitors. Zhuyuwan Zoo is located in the eastern suburb of Yangzhou city in eastern China, in which over 40 species of zoo animals are kept. In order to understand the infection status of GI parasites in Zhuyuwan Zoo, a total of 104 fresh fecal samples collected randomly from birds (n = 19), primates (n = 19), and non-primate mammals (n = 66) were analyzed using the saturated saline flotation technique and nylon sifter elutriation and sieving method for eggs/oocysts, respectively. Two Ascaris species were molecularly characterized. The results showed that the overall prevalence of parasitic infection was 42.3% (44/104). The parasitic infection rate in birds, primates, and non-primate mammals were 26.3% (5/19), 31.6% (6/19), and 50.0% (33/66), respectively. A total of 11 species of parasites were identified, namely, Trichostrongylidae, Capillaria sp., Trichuris spp., Strongyloides spp., Amidostomum sp., Toxascaris leonina, Baylisascaris transfuga, Parascaris equorum, Paramphistomum spp., Fasciola spp., and Eimeria spp. Paramphistomum spp. eggs were first detected from the captive Père David's deer, and Fasciola spp. eggs were first reported from sika deer in zoo in China. A sequence analysis of ITS-2 and cox1 showed that the eggs isolated from the African lion (Panthera leo Linnaeus, 1758) were T. leonina, and the eggs from the brown bear (Ursus arctos Linnaeus, 1758) were B. transfuga. The public health threat posed by these potential zoonotic parasitic agents requires attention. These results lay a theoretical foundation for prevention and control of wild animal parasitic diseases at zoos in China.

Tuina Intervention in Sodium Monoiodoacetate Injection-Induced Rat Model of Knee Osteoarthritis.

Knee osteoarthritis (KOA), a common degenerative joint disorder, is characterized by chronic pain and disability, which can progress to irreparable structural damage of the joint. Investigations into the link between articular cartilage, muscles, synovium, and other tissues surrounding the knee joint in KOA are of great importance. Currently, managing KOA includes lifestyle modifications, exercise, medication, and surgical interventions; however, the elucidation of the intricate mechanisms underlying KOA-related pain is still lacking. Consequently, KOA pain remains a key clinical challenge and a therapeutic priority. Tuina has been found to have a regulatory effect on the motor, immune, and endocrine systems, prompting the exploration of whether Tuina could alleviate KOA symptoms, caused by the upregulation of inflammatory factors, and further, if the inflammatory factors in skeletal muscle can augment the progression of KOA. We randomized 32 male Sprague Dawley (SD) rats (180-220 g) into four groups of eight animals each: antiPD-L1+Tuina (group A), model (group B), Tuina (group C), and sham surgery (group D). For groups A, B, and C, we injected 25 µL of sodium monoiodoacetate (MIA) solution (4 mg MIA diluted in 25 µL of sterile saline solution) into the right knee joint cavity, and for group D, the same amount of sterile physiological saline was injected. All the groups were evaluated using the least to most stressful tests (paw mechanical withdrawal threshold, paw withdrawal thermal latency, swelling of the right knee joint, Lequesne MG score, skin temperature) before injection and 2, 9, and 16 days after injection.

A nomogram for predicting prognosis in patients with transjugular intrahepatic portosystemic shunt creation based on deep learning-derived spleen volume-to-platelet ratio.

OBJECTIVES: The objective of our study was to develop a nomogram to predict post-transjugular intrahepatic portosystemic shunt (TIPS) survival in patients with cirrhosis based on CT images. METHODS: This retrospective cohort study included patients who had received TIPS operation at the Wenzhou Medical University First Affiliated Hospital between November 2013 and April 2017. To predict prognosis, a nomogram and Web-based probability were developed to assess the overall survival (OS) rates at 1, 3, and 5 years based on multivariate analyses. With deep learning algorithm, the automated measurement of liver and spleen volumes can be realized. We assessed the predictive accuracy and discriminative ability of the nomogram using the concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). RESULTS: Age, total bilirubin, and spleen volume-to-platelet ratio (SVPR) were identified as the independent risk factors for OS. The nomogram was constructed based on the above risk factors. The C-index (0.80, 0.74, 0.70), ROC curve (area under curve: 0.828, 0.761, 0.729), calibration curve, and DCA showed that nomogram good at predictive value, stability, and clinical benefit in the prediction of 1-, 3-, 5-year OS in patients with TIPS creation. CONCLUSIONS: We constructed a nomogram for predicting prognosis in patients with TIPS creation based on risk factors. The nomogram can help clinicians in identifying patients with poor prognosis, eventually facilitating earlier treatment and selecting suitable patients before TIPS. ADVANCES IN KNOWLEDGE: This study developed the first nomogram based on SVPR to predict the prognosis of patients treated with TIPS. The nomogram could help clinician in non-invasive decision-making.

Evaluation and comparison of efficacy and safety of tirzepatide and semaglutide in patients with type 2 diabetes mellitus: A Bayesian network meta-analysis.

BACKGROUND: As new antidiabetic drugs, tirzepatide (Tir) and semaglutide (Sem) are progressively applied in clinical practice. However, their efficacy and safety profiles have not been comprehensively assessed. Therefore, a Bayesian network meta-analysis was used to evaluate and compare the efficacy and safety of Tir and Sem in treating type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were systematically searched from inception to April 3rd, 2023. Randomized clinical trials (RCTs) comparing the efficacy and safety of Tir and Sem with placebo or the other antidiabetic drugs in treating T2DM were included. The efficacy outcomes included changes in glycated hemoglobin (HbA1c), body weight (BW), body mass index (BMI), and the proportion of participants with HbA1c< 7 %. The safety outcome was the proportion of participants experiencing gastrointestinal adverse events (GIAEs). RESULTS: A total of 38 studies involving 34,166 participants were included. Compared to 1 mg of subcutaneous Sem (Sem SC), 5 mg, 10 mg and 15 mg of Tir demonstrated superior efficacy in reducing HbA1c (mean difference (MD), [95 % CI], -0.22 [-0.40, -0.03] %, -0.42 [-0.60, -0.24] % and -0.53 [-0.71, -0.35] %, respectively) and BW (MD [95 % CI], -1.48 [-2.53, -0.43] kg, -4.00 [-5.05, -2.95] kg and -5.71 [-6.73, -4.68] kg, respectively). Conversely, 7 mg and 14 mg of oral Sem (Sem PO) displayed inferior efficacy in reducing HbA1c (MD [95 % CI], 0.47 [0.26, 0.68] % and 0.35 [0.16, 0.54] %, respectively) and BW (MD [95 % CI], 2.36 [1.24, 3.48] kg and 1.11 [0.10, 2.13] kg). However, 20 mg and 40 mg of Sem PO were non-inferior in reducing HbA1c (MD [95 % CI], 0.13 [-0.29, 0.55] % and 0.01 [-0.38, 0.40] %, respectively) and BW (MD [95 % CI], -0.41 [-2.71, 1.90] kg and -1.32 [-3.58, 0.92] kg). In terms of safety, compared to 1 mg of Sem SC, 5 mg, 10 mg and 15 mg of Tir did not significantly increase the incidence of GIAEs (odd ratio (OR) [95 % CI], 0.70 [0.42, 1.10], 0.87 [0.52, 1.36] and 0.99 [0.60, 1.54], respectively), while 7 mg of Sem PO showed a lower incidence of GIAEs (OR [95 % CI], 0.48 [0.25, 0.83]). Compared to insulin, 0.5 mg of Sem SC, 1 mg of Sem SC, 5 mg of Tir, 10 mg of Tir and 15 mg of Tir displayed better efficacy in lowering HbA1c (MD [95 % CI], -0.40 [-0.63, -0.18] %, -0.69 [-0.90, -0.48] %, -0.91 [-1.10, -0.72] %, -1.11 [-1.30, -0.92] % and -1.22 [-1.41, -1.03] %, respectively) and BW (MD [95 % CI], -5.34[-6.60, -4.09] kg, -6.70 [-7.90,-5.51] kg, -8.18 [-9.27, -7.10] kg, -10.70 [-11.79, -9.61] kg and -12.41 [-13.49,-11.33] kg, respectively). According to the surface under the cumulative ranking curve (SUCRA) value, among all the included interventions, 15 mg of Tir exhibited the most potent effect in reducing HbA1c (99.81 %) and BW (99.98 %), followed by 10 mg of Tir (96.83 % and 95.72 %), 5 mg of Tir (92.88 % and 86.04 %), 1 mg of Sem SC (85.85 % and 74.97 %), 40 mg of Sem PO (83.66 % and 84.31 %), 20 mg of Sem PO (76.98 % and 77.12 %), 300 mg of Can (49.93 % and 60.89 %), insulin (36.38 % and 0.22 %) and 100 mg of Sit (12.28 % and 18.51 %) respectively. Meanwhile, 5 mg, 10 mg, and 15 mg of Tir (48.32 %, 30.96 %, and 21.07 %, respectively), 0.5 mg and 1 mg of Sem SC (33.54 % and 24.77 %, respectively) significantly increased the incidence of GIAEs. CONCLUSION: Both Tir and Sem demonstrated favorable antidiabetic effects and were particularly suitable for T2DM patients who were obese or overweight. Despite a high incidence of GIAEs, their safety profile was deemed acceptable. Tir was the best option among all the included interventions.

Comparative proteomic analysis of wall-forming bodies and oocyst wall reveals the molecular basis underlying oocyst wall formation in Eimeria necatrix.

BACKGROUND: The durable oocyst wall formed from the contents of wall-forming bodies (WFBs) protects Eimeria parasites from harsh conditions and enhances parasite transmission. Comprehending the contents of WFBs and proteins involved in oocyst wall formation is pivotal to understanding the mechanism of the oocyst wall formation and the search for novel targets to disrupt parasite transmission. METHODS: Total proteins extracted from WFBs and the oocyst wall of Eimeria necatrix were subjected to comparative proteomic analysis using tandem mass tag in conjunction with liquid chromatography tandem-mass spectrometry techniques. After functional clustering analysis of the identified proteins, three proteins, including E. necatrix disulfide isomerase (EnPDI), thioredoxin (EnTrx) and phosphoglycerate kinase (EnPGK), were selected for further study to confirm their potential roles in oocyst wall formation. RESULTS: A total of 3009 and 2973 proteins were identified from WFBs and the oocyst wall of E. necatrix, respectively. Among these proteins, 1102 were identified as differentially expressed proteins, of which 506 were upregulated and 596 downregulated in the oocyst wall compared to the WFBs. A total of 108 proteins, including compositional proteins of the oocyst wall, proteases, oxidoreductases, proteins involved in glycosylation, proteins involved in synthesis of the acid-fast lipid layer and proteins related to transport, were proposed to be involved in oocyst wall formation. The approximate molecular sizes of native EnPDI, EnTrx and EnPGK proteins were 55, 50 and 45 kDa, respectively. EnPDI was present in both type 1 and type 2 WFBs, EnTrx was present only in type 2 WFB2 and EnPGK was present only in type 1 WFBs, whereas all of them were localized to the outer layer of the oocyst wall, indicating that all of them participate in the formation of the oocyst wall. CONCLUSIONS: To the best of our knowledge, this is the first report on the proteomes of WFBs and the oocyst wall of E. necatrix. The data obtained from this study form a basis for deciphering the molecular mechanisms underlying oocyst wall formation of Eimeria parasites. They also provide valuable resources for future studies on the development of novel therapeutic agents and vaccines aimed at combating coccidian transmission.

Localization in vivo and in vitro confirms EnApiAP2 protein encoded by ENH_00027130 as a nuclear protein in Eimeria necatrix.

Introduction: Apicomplexan AP2 family of proteins (ApiAP2) are transcription factors (TFs) that regulate parasite growth and development, but little is known about the ApiAP2 TFs in Eimeria spp. ENH_00027130 sequence is predicted to encode a Eimeria necatrix ApiAP2 protein (EnApiAP2). Methods: The cDNAs encoding full-length and truncated EnApiAP2 protein were cloned and sequenced, respectively. Then, the two cDNAs were cloned into the pET28a(+) expression vector and expressed expressed in Escherichia coli BL21. The mouse polyclonal antibody (pAb) and monoclonal antibody (mAb) against recombinant EnApiAP2 (rEnApiAP2) and EnApiAP2tr (rEnApiAP2tr) were prepared and used to localize the native EnApiAP2 protein in E. necatrix, respectively. Finally, the recombinant pEGFP-C1-ΔNLS-EnApiAP2s (knockout of a nuclear localization sequence, NLS) and pEGFP-C1-EnApiAP2 plasmid were constructed and transfected into DF-1 cells, respectively, to further observe subcellular localization of EnApiAP2 protein. Results: The EnApiAP2 gene had a size of 5019 bp and encoded 1672 amino acids, containing a conserved AP2 domain with a secondary structure consisting of an α-helix and three antiparallel ß-strands. The rEnApiAP2 and rEnApiAP2tr were predominantly expressed in the form of inclusion bodies, and could be recognized by the 6×His tag mAb and the serum of convalescent chickens after infection with E. necatrix, respectively. The native EnApiAP2 protein was detected in sporozoites (SZ) and second generation merozoites (MZ-2) extracts, with a size of approximately 210 kDa. A quantitative real-time PCR (qPCR) analysis showed that the transcription level of EnApiAP2 was significantly higher in SZ than in MZ-2, third generation merozoites (MZ-3) and gametocytes (P<0.01). EnApiAP2 protein was localized in the nuclei of SZ, MZ-2 and MZ-3 of E. necatrix. The protein of EnApiAP2 was localized in the nucleus of the DF-1 cells, whereas the ΔNLS-EnApiAP2 was expressed in the cytoplasm, which further confirmed that EnApiAP2 is nucleoprotein. Discussion: EnApiAP2 protein encoded by ENH_00027130 sequence was localized in the nucleus of E. necatrix parasites, and relied on the NLS for migration to DF-1 cell nucleus. The function of EnApiAP2 need further study.

Prevalence and risk factors associated with gastrointestinal parasites in goats (Capra hircus) and sheep (Ovis aries) from three provinces of China.

Gastrointestinal (GI) parasites in small ruminants, especially goats and sheep, have caused significant socio-economic and public health challenges worldwide. The aim of the present study was to investigate the diversity and prevalence of GI parasites in goats and sheep in Jiangsu, Shaanxi and Hunan provinces of China, and to assess whether the age of animals, sampling season and feeding mode influence the distribution and infection of GI parasites. A total of 1,081 fecal samples collected from goats (n = 835) and sheep (n = 246) were detected by saturated saline flotation technique and nylon sifter elutriation and sieving method for eggs/oocysts, respectively. Based on the morphological observation of eggs and oocysts, one tapeworm, five nematodes, three trematodes and nineteen coccidia were identified, of which seven helminths belong to zoonotic parasites. The infection rate of parasites was 83.4% (902/1081) in total samples, 91.6% (765/835) in goats, and 55.7% (137/246) in sheep. The infection rate of coccidia was 71.0% (767/1081), and that of helminths was 56.2% (607/1081). The dominant species was E. alijeri (67.3%, 562/835) in goats, E. parva (30.1%, 74/246) in sheep. The highest prevalent helminths were Trichostrongylidae spp. in goats (58.3%, 487/835), and Moniezia spp. in sheep (22.76%, 56/246). Of 902 positive samples, 825 (91.5%, 825/902) contained multiple (2-10) parasites. The feeding mode, sampling season and regions were relevant risk factors which have significant influence on the occurrence of GI parasites in goats and sheep. The risk coefficient of parasite infection in autumn was 2.49 times higher than spring (Odds ratio = 2.49, 95% CI = 1.51-4.09, p < 0.001). Compared to raising on the high beds, the goats and sheep raising on the ground had the higher risk of parasite infection (OR = 3.91, 95% CI = 2.07-7.40, p < 0.001). The risk coefficient of parasite infection in Shaanxi and Hunan was 3.78 and 1.25 times higher than that in Jiangsu (OR = 3.78, 95% CI = 2.01-7.12, p < 0.001; OR = 1.25, 95% CI = 1.21-1.29, p < 0.001). These data are significant for the development of prevention strategies to minimise economic losses from small ruminant production and to reduce the risk of water and food infecting humans as vectors of zoonotic parasitic diseases.

Corrigendum: Synergistic effects of nab-PTX and anti-PD-1 antibody combination against lung cancer by regulating Pi3K/AKT pathway through the Serpinc1 gene.

[This corrects the article DOI: 10.3389/fonc.2022.933646.].

Association of glycemic variability with death and severe consciousness disturbance among critically ill patients with cerebrovascular disease: analysis of the MIMIC-IV database.

BACKGROUND: The association of glycemic variability with severe consciousness disturbance and in-hospital all-cause mortality in critically ill patients with cerebrovascular disease (CVD) remains unclear, This study aimed to investigate the association of glycemic variability with cognitive impairment and in-hospital death. METHOD: We extracted all blood glucose measurements of patients diagnosed with CVD from the Medical Information Mart for Intensive Care IV (MIMIC-IV). Glycemic variability was defined as the coefficient of variation (CV), which was determined using the ratio of standard deviation and the mean blood glucose levels. Cox hazard regression models were applied to analyze the link between glycemic variability and outcomes. We also analyzed non-linear relationship between outcome indicators and glycemic variability using restricted cubic spline curves. RESULTS: The present study included 2967 patients diagnosed with cerebral infarction and 1842 patients diagnosed with non-traumatic cerebral hemorrhage. Log-transformed CV was significantly related to cognitive impairment and in-hospital mortality, as determined by Cox regression. Increasing log-transformed CV was approximately linearly with the risk of cognitive impairment and in-hospital mortality. CONCLUSION: High glycemic variability was found to be an independent risk factor for severe cognitive decline and in-hospital mortality in critically ill patients with CVD. Our study indicated that enhancing stability of glycemic variability may reduced adverse outcomes in patients with severe CVD.

Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics.

Sunitinib is the first-line drug for renal cell carcinoma (RCC) treatment. However, patients who received sunitinib treatment will ultimately develop drug resistance after 6-15 months, creating a huge obstacle to the current treatment of renal cell carcinoma. Therefore, it is urgent to clarify the mechanisms of sunitinib resistance and develop new strategies to overcome it. In this review, the mechanisms of sunitinib resistance in renal cell carcinoma have been summarized based on five topics: activation of bypass or alternative pathway, inadequate drug accumulation, tumour microenvironment, metabolic reprogramming and epigenetic regulation. Furthermore, present and potential biomarkers, as well as potential treatment strategies for overcoming sunitinib resistance in renal cell carcinoma, are also covered.

Canagliflozin reduces chemoresistance in hepatocellular carcinoma through PKM2-c-Myc complex-mediated glutamine starvation.

Cisplatin (CPT) is one of the standard treatments for hepatocellular carcinoma (HCC). However, its use is limits as a monotherapy due to drug resistance, and the underlying mechanism remains unclear. To solve this problem, we tried using canagliflozin (CANA), a clinical drug for diabetes, to reduce chemoresistance to CPT, and the result showed that CANA could vigorously inhibit cell proliferation and migration independent of the original target SGLT2. Mechanistically, CANA reduced aerobic glycolysis in HCC by targeting PKM2. The downregulated PKM2 directly bound to the transcription factor c-Myc in the cytoplasm to form a complex, which upregulated the level of phosphorylated c-Myc Thr58 and promoted the ubiquitination and degradation of c-Myc. Decreased c-Myc reduced the expression of GLS1, a key enzyme in glutamine metabolism, leading to impaired glutamine utilization. Finally, intracellular glutamine starvation induced ferroptosis and sensitized HCC to CPT. In conclusion, our study showed that CANA re-sensitized HCC to CPT by inducing ferroptosis through dual effects on glycolysis and glutamine metabolism. This is a novel mechanism to increase chemosensitivity, which may provide compatible chemotherapy drugs for HCC.

TUG1 protects against ferroptosis of hepatic stellate cells by upregulating PDK4-mediated glycolysis.

The induction of ferroptosis in hepatic stellate cells (HSCs) has shown promise in reversing liver fibrosis. And ferroptosis has been confirmed to be associated with glycolysis. The objective of this study is to determine whether ferroptosis inhibition in HSCs, induced by elevation of recombinant pyruvate dehydrogenase kinase isozyme 4 (PDK4)-mediated glycolysis, could mediate the pathogenesis of liver fibrosis. Liver fibrosis was induced using CCl4, the level of which was assessed through histochemical staining. Lentivirus was used to modulate the expression of specific genes. And underlying mechanisms were explored using primary HSCs extracted from normal mice. The results confirmed that Taurine up-regulated gene 1 (TUG1) expression was upregulated in liver fibrotic tissues and HSCs, showing a positive correlation with fibrosis. In addition, TUG1 attenuated ferroptosis in HSCs by promoting PDK4-mediated glycolysis, thereby promoting the progression of liver fibrosis. Moreover, TUG1 was observed to impact HSCs activation, exacerbating liver fibrosis to some extent. In conclusion, our study revealed that TUG1 expression was elevated in mouse models of liver fibrosis and activated HSCs, which inhibited ferroptosis in HSCs through PDK4-mediated glycolysis. This finding may open up a new therapeutic strategy for liver fibrosis.

Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway.

Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress is a systemic response triggered by the accumulation of unfolded or misfolded proteins in the ER. Ferroptosis and ER stress have been proven to contribute to the progression of APAP-induced acute liver injury (ALI). It was reported that salidroside protects against APAP-induced ALI, but the potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) to induce an ALI model. Salidroside was i.p. injected at a dose of 100 mg/kg 2 h prior to APAP administration. Mice were sacrificed 12 h after APAP injection and the liver and serum of the mice were obtained for histological and biochemistry analysis. AML12 cells were used in in vitro assays. The results indicated that salidroside mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) to attenuate ferroptosis, and simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated ER stress, thus alleviating APAP-induced ALI. However, PERK activator CCT020312 and overexpression of ATF4 inhibited the protective function of salidroside on CHAC1-mediated ferroptosis. Besides this, activation of the AMPK/SIRT1 signaling pathway by salidroside was demonstrated to have a protective effect against APAP-induced ALI. Interestingly, selective inhibition of SIRT1 ameliorated the protective effects of salidroside on ER stress and ferroptosis. Overall, salidroside plays a significant part in the mitigation of APAP-induced ALI by activating the AMPK/SIRT1 signaling to inhibit ER stress-mediated ferroptosis in the ATF4-CHAC1 axis.

Immune-related adverse events associated with nab-paclitaxel/paclitaxel combined with immune checkpoint inhibitors: a systematic review and network meta-analysis.

Objective: The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in cancer patients. However, the safety of these combination regimens remains conflicting in former researches. Therefore, in order to address this issue, we performed a systematic review and network meta-analysis (NMA) to evaluate and compare the safety profile. Methods: We performed a systematic review by searching randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science up to August 15, 2022. The primary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) immune-related adverse events (irAEs). Secondary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) irAEs of subgroups of ICIs. Results: There were 22 RCTs included in the NMA, involving a total of 15 963 patients diagnosed with any type of cancer. ICIs+nab-PTX was associated with a noticeably decreased risk of grade 3-5 pneumonitis (odds ratio [OR]=0.28, 95% credible interval [CrI]: 0.09,0.90) compared to ICI monotherapy; ICIs+PTX showed a lower risk of grade 1-5 hyperthyroidism (OR=0.46, 95% CrI: 0.22-0.96) and grade 1-5 hypothyroidism (OR=0.49, 95% CrI: 0.26-0.93) than ICIs. Compared with PD-1, PD-1+PTX was associated with a statistically significantly lower risk of grade 1-5 pneumonitis (OR=0.32, 95% CrI: 0.11-0.92). PD-L1 resulted in a noticeably lower risk of grade 1-5 hypothyroidism (OR=0.34, 95% CrI: 0.12-1.00) than PD-L1+PTX. Nearly all treatment regimens containing ICIs demonstrated significantly higher risks of irAEs compared to the standard chemotherapy groups. Conclusion: Nab-PTX/PTX+ICIs demonstrated an approach leading to decreased risk of irAEs compared with ICI monotherapy. This finding supports that ICIs+nab-PTX/PTX may be a safer treatment strategy. Moreover, we also found that the combination regimens containing ICIs had a higher risk of irAEs than standard chemotherapy. Additionally, ICIs+nab-PTX demonstrated a decreased risk of irAEs compared to ICIs+PTX. PD-1 inhibitors were associated with a higher risk of irAEs than PD-L1 inhibitors.

Anlotinib and fruquintinib co-administrated with warfarin increases the risk of bleeding: Studied from pharmacokinetic and pharmacodynamic perspectives.

BACKGROUND: Recent studies have reported a higher risk of bleeding among patients that are co-administrated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and anticoagulant, which raises our concern about the possible TKIs-warfarin pharmacokinetic and pharmacodynamic interaction that could be life-threatening to tumor patients who take warfarin for preventing deep vein thrombosis (DVT). METHODS: Influences of anlotinib and fruquintinib on the pharmacokinetic and dynamic behavior of warfarin were estimated. Influence on the activity of cytochrome P450 (CYP450) enzymes was detected in vitro through rat liver microsomes. Quantitative analysis of blood concentration in rats was finished by a validated UHPLC-MS/MS method. Furthermore, pharmacodynamic interactions were studied in rats by monitoring prothrombin time (PT) and activated partial thromboplastin time (APTT), while Inferior vena cava (IVC) stenosis-induced DVT model was built to further investigate the antithrombotic effect after co-administration. RESULTS: Anlotinib inhibited the activity of cyp2c6, cyp3a1/2 and cyp1a2 in rat liver microsomes in a dose-dependent manner, meanwhile enhanced the AUC0∼t and AUC0∼∞ of R-warfarin. However, fruquintinib showed no effects on pharmacokinetics of warfarin. Anlotinib and fruquintinib co-administrated with warfarin was found to exert more significant increase on PT and APTT values than that taking warfarin alone. In IVC stenosis-induced DVT model rats, the co-administration groups significantly reduced the length of thrombus compared with the single warfarin group. CONCLUSIONS: Anlotinib and fruquintinib enhanced the anticoagulated and antithrombotic effect of warfarin. The anlotinib-induced interaction may due to the inhibition of the metabolism of warfarin. The mechanism of the pharmacodynamic interaction between fruquintinib and warfarin should be further investigated.

Association between triglyceride-glucose index and all-cause mortality in critically ill patients with ischemic stroke: analysis of the MIMIC-IV database.

BACKGROUND: The triglyceride-glucose (TyG) index was significantly associated with insulin resistance (IR). Several studies have validated the effect of TyG index on cerebrovascular disease. However, the value of TyG index in patients with severe stroke requiring ICU admission remains unclear. The aim of this study was to investigate the association between the TyG index and clinical prognosis of critically ill patients with ischemic stroke (IS). METHODS: This study identified patients with severe IS requiring ICU admission from the Medical Information Mart for Intensive Care (MIMIC-IV) database, and divided them into quartiles based on TyG index level. The outcomes included in-hospital mortality and ICU mortality. The association between the TyG index and clinical outcomes in critically ill patients with IS was elucidated using Cox proportional hazards regression analysis and restricted cubic splines. RESULTS: A total of 733 patients (55.8% male) were enrolled. The hospital mortality and intensive care unit (ICU) mortality reached 19.0% and 14.9%, respectively. Multivariate Cox proportional hazards analysis showed that the elevated TyG index was significantly related to all-cause death. After confounders adjusting, patients with an elevated TyG index had a significant association with hospital mortality (adjusted hazard ratio, 1.371; 95% confidence interval, 1.053-1.784; P = 0.013) and ICU mortality (adjusted hazard ratio, 1.653; 95% confidence interval, 1.244-2.197; P = 0.001). Restricted cubic splines revealed that a progressively increasing risk of all-cause mortality was related to an elevated TyG index. CONCLUSION: The TyG index has a significant association with hospital and ICU all-cause death in critically ill patients with IS. This finding demonstrates that the TyG index might be useful in identifying patients with IS at high risk of all-cause death.

Performance of Machine Learning Algorithms for Predicting Disease Activity in Inflammatory Bowel Disease.

This study aimed to explore the effectiveness of predicting disease activity in patients with inflammatory bowel disease (IBD), using machine learning (ML) models. A retrospective research was undertaken on IBD patients who were admitted into the First Affiliated Hospital of Wenzhou Medical University between September 2011 and September 2019. At first, data were randomly split into a 3:1 ratio of training to test set. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to reduce the dimension of variables. These variables were used to generate seven ML algorithms, namely random forests (RFs), adaptive boosting (AdaBoost), K-nearest neighbors (KNNs), support vector machines (SVMs), naïve Bayes (NB), ridge regression, and eXtreme gradient boosting (XGBoost) to train to predict disease activity in IBD patients. SHapley Additive exPlanation (SHAP) analysis was performed to rank variable importance. A total of 876 participants with IBD, consisting of 275 ulcerative colitis (UC) and 601 Crohn's disease (CD), were retrospectively enrolled in the study. Thirty-three variables were obtained from the clinical characteristics and laboratory tests of the participants. Finally, after LASSO analysis, 11 and 5 variables were screened out to construct ML models for CD and UC, respectively. All seven ML models performed well in predicting disease activity in the CD and UC test sets. Among these ML models, SVM was more effective in predicting disease activity in the CD group, whose AUC reached 0.975, sensitivity 0.947, specificity 0.920, and accuracy 0.933. AdaBoost performed best for the UC group, with an AUC of 0.911, sensitivity 0.844, specificity 0.875, and accuracy 0.855. ML algorithms were available and capable of predicting disease activity in IBD patients. Based on clinical and laboratory variables, ML algorithms demonstrate great promise in guiding physicians' decision-making.

Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model.

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01−1.0 µg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.