(-)-Epicatechin ameliorates type 2 diabetes mellitus by reshaping the gut microbiota and Gut-Liver axis in GK rats.

As one of the most abundant plant polyphenols in the human diet, (-)-epicatechin (EC) can improve insulin sensitivity and regulate glucose homeostasis. However, the primary mechanisms involved in EC anti-T2DM benefits remain unclear. The present study explored the effects of EC on the gut microbiota and liver transcriptome in type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats for the first time. The findings showed that EC protected glucose homeostasis, alleviated systemic oxidative stress, relieved liver damage, and increased serum insulin. Further investigation showed that EC reshaped gut microbiota structure, including inhibiting the proliferation of lipopolysaccharide (LPS)-producing bacteria and reducing serum LPS. In addition, transcriptome analysis revealed that the insulin signaling pathway may be the core pathway of the EC anti-T2DM effect. Therefore, EC may modulate the gut microbiota and liver insulin signaling pathways by the gut-liver axis to alleviate T2DM. As a diet supplement, EC has promising potential in T2DM prevention and treatment.

Association between postoperative changes in natremia and outcomes in patients undergoing elective craniotomy.

Postoperative dysnatremias, characterized by imbalances in serum sodium levels, have been linked to increased resource utilization and mortality in surgical and intensive care patients. The management of dysnatremias may involve medical interventions based on changes in sodium levels. In this study, we aimed to investigate the impact of postoperative changes in natremia on outcomes specifically in patients undergoing craniotomy.We conducted a retrospective analysis of patient records from the Department of Neurosurgery at West China Hospital, Sichuan University, covering the period from January 2011 to March 2021. We compared the highest and lowest sodium values in the first 14 postoperative days with the baseline values to define four categories for analysis: no change < 5 mmol/L; decrease > 5 mmol/L; increase > 5 mmol/L; both increase and decrease > 5 mmol/L. The primary outcome measure was 30-day mortality.A total of 12,713 patients were included in the study, and the overall postoperative mortality rate at 30 days was 2.1% (264 patients). The increase in sodium levels carried a particularly high risk, with a tenfold increase (OR 10.21; 95% CI 7.25-14.39) compared to patients with minimal or no change. Decreases in sodium levels were associated with an increase in mortality (OR 1.60; 95% CI 1.11-2.23).Moreover, the study revealed that postoperative sodium decrease was correlated with various complications, such as deep venous thrombosis, pneumonia, intracranial infection, urinary infection, seizures, myocardial infarction, and prolonged hospital length of stay. On the other hand, postoperative sodium increases were associated with acute kidney injury, deep venous thrombosis, pneumonia, intracranial infection, urinary infection, surgical site infection, seizures, myocardial infarction, and prolonged hospital length of stay.Changes in postoperative sodium levels were associated with increased complications, prolonged length of hospital stay, and 30-day mortality. Moreover, the severity of sodium change values correlated with higher mortality rates.

HSPA8 Activates Wnt/ß-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.

BRAF V600E attracts wide attention in the treatment of colorectal cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/ß-catenin signaling is broadly activated and participates in the refractoriness of BRAF V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated autophagy (CMA), is identified as a potential therapeutic target for advanced BRAF V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release ß-catenin into the nucleus and thus activates the Wnt/ß-catenin pathway, contributing to metastasis and progression of BRAF V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRAF inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/ß-catenin axis in the development of refractory BRAF V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.

Association of postoperative hypernatremia with outcomes after elective craniotomy.

STUDY OBJECTIVE: Hypernatremia is a treatable biochemical disorder associated with significant morbidity and mortality in patients undergoing surgery. However, its impact on patients who undergo elective craniotomy is not well understood. This study aimed to investigate the prognostic implications of postoperative hypernatremia on the 30-day mortality of patients undergoing elective craniotomy. DESIGN: Retrospective cohort study. SETTING: The Department of Neurosurgery of a high-volume center. PATIENTS: Adult patients undergoing elective craniotomy except those with pituitary tumors, intracerebral hemorrhage, subarachnoid hemorrhage, or traumatic brain injury. INTERVENTIONS: None. MEASUREMENTS: Perioperative laboratory data were collected for all study participants, including sodium levels, neutrophil count, serum albumin, lymphocyte count, and blood glucose. These measurements were obtained as part of routine clinical care and provided valuable information for data analysis. MAIN RESULTS: Of the 10,223 identified elective craniotomy patients who met our inclusion and exclusion criteria, 14.9% (1519) developed postoperative hypernatremia. This population's overall postoperative 30-day mortality rate was 1.7% (175). After performing an adjusted logistic regression analysis, we found that the odds of 30-day mortality increased gradually with increasing severity of hypernatremia: 2.9 deaths (OR, 3.79; 95% CI, 2.46-5.85) in patients with mild hypernatremia, 13.9 deaths (OR, 17.73; 95% CI, 11.17-28.12) in those with moderate hypernatremia, and 38.3 deaths (OR, 67.00; 95% CI, 40.44-111.00) in those with severe hypernatremia. CONCLUSIONS: Hypernatremia is common after elective craniotomy, and its presence is associated with increased mortality and complications, particularly in cases of severe hypernatremia. These results emphasize the significance of risk evaluation in neurosurgical patients and propose the advantages of closely monitoring serum sodium levels in high-risk individuals. Future randomized controlled trials could provide more insight into the effect of treating postoperative hypernatremia in these patients.

Preoperative hematocrit levels and postoperative mortality in patients undergoing craniotomy for brain tumors.

Background: Abnormal hematocrit values, including anemia and polycythemia, are common in patients undergoing craniotomy, but the extent to which preoperative anemia or polycythemia independently increases the risk of mortality is unclear. This retrospective cohort study aimed to examine the association between preoperative anemia and polycythemia and postoperative mortality in patients who underwent craniotomy for brain tumor resection. Methods: We retrospectively analyzed data from 12,170 patients diagnosed with a brain tumor who underwent cranial surgery at West China Hospital between January 2011 and March 2021. The preoperative hematocrit value was defined as the last hematocrit value within 7 days before the operation, and patients were grouped according to the severity of their anemia or polycythemia. We assessed the primary outcome of 30-day postoperative mortality using logistic regression analysis adjusted for potential confounding factors. Results: Multivariable logistic regression analysis reported that the 30-day mortality risk was raised with increasing severity of both anemia and polycythemia. Odds ratios for mild, moderate, and severe anemia were 1.12 (95% CI: 0.79-1.60), 1.66 (95% CI: 1.06-2.58), and 2.24 (95% CI: 0.99-5.06), respectively. Odds ratios for mild, moderate, and severe polycythemia were 1.40 (95% CI: 0.95-2.07), 2.81 (95% CI: 1.32-5.99), and 14.32 (95% CI: 3.84-53.44), respectively. Conclusions: This study demonstrated that moderate to severe anemia and polycythemia are independently associated with increased postoperative mortality in patients undergoing craniotomy for brain tumor resection. These findings underscore the importance of identifying and managing abnormal hematocrit values before craniotomy surgery.

Obesity Paradox for Postoperative Mortality in Young Chinese Patients Undergoing Craniotomy for Brain Tumor Resection.

BACKGROUND: There is little evidence regarding the association of body mass index (BMI) with postoperative mortality after craniotomy, especially in the Asian population. Our study aimed to explore the association between BMI and postoperative 30-day mortality in Chinese patients undergoing craniotomy for brain tumor resection. METHODS: This large retrospective cohort study, Supplemental Digital Content 9, http://links.lww.com/JNA/A634 collected data from 7519 patients who underwent craniotomy for brain tumor resection. On the basis of the World Health Organization obesity criteria for Asians, included patients were categorized as underweight (<18.5 kg/m2), normal weight (18.5 to 22.9 kg/m2), overweight (23to 24.9 kg/m2), obese I (25 to 29.9 kg/m2), and obese II (≥30 kg/m2). We used a multivariable logistic regression model to explore the association between different BMI categories and 30-day postoperative mortality. In addition, we also conducted stratified analyses based on age and sex. RESULTS: Overweight (adjusted odds ratio 0.63, 95% CI 0.40-0.99) and obese I (adjusted odds ratio 0.44, 95% CI 0.28-0.72) were associated with decreased 30-day postoperative mortality compared with normal-weight counterparts. Such associations were prominent among younger (age younger than 65 y) patients but not older patients, and there was an interaction between age and overweight versus normal weight on mortality (P for interaction=0.04). CONCLUSIONS: We found that among Chinese patients undergoing craniotomy for brain tumors, there was a J-shaped association between BMI and postoperative 30-day mortality, with lowest mortality at 27 kg/m². Moreover, in young patients, overweight and obese I were both associated with decreased risk of 30-day mortality.

Association between intraoperative steroid and postoperative mortality in patients undergoing craniotomy for brain tumor.

Background: Despite the widespread use of intraoperative steroids in various neurological surgeries to reduce cerebral edema and other adverse symptoms, there is sparse evidence in the literature for the optimal and safe usage of intraoperative steroid administration in patients undergoing craniotomy for brain tumors. We aimed to investigate the effects of intraoperative steroid administration on postoperative 30-day mortality in patients undergoing craniotomy for brain tumors. Methods: Adult patients who underwent craniotomy for brain tumors between January 2011 to January 2020 were included at West China Hospital, Sichuan University in this retrospective cohort study. Stratified analysis based on the type of brain tumor was conducted to explore the potential interaction. Results: This study included 8,663 patients undergoing craniotomy for brain tumors. In patients with benign brain tumors, intraoperative administration of steroids was associated with a higher risk of postoperative 30-day mortality (adjusted OR 1.98, 95% CI 1.09-3.57). However, in patients with malignant brain tumors, no significant association was found between intraoperative steroid administration and postoperative 30-day mortality (adjusted OR 0.86, 95% CI 0.55-1.35). Additionally, administration of intraoperative steroids was not associated with acute kidney injury (adjusted OR 1.11, 95% CI 0.71-1.73), pneumonia (adjusted OR 0.89, 95% CI 0.74-1.07), surgical site infection (adjusted OR 0.78, 95% CI 0.50-1.22) within 30 days, and stress hyperglycemia (adjusted OR 1.05, 95% CI 0.81-1.38) within 24 h after craniotomy for brain tumor. Conclusion: In patients undergoing craniotomy for benign brain tumors, intraoperative steroids were associated with 30-day mortality, but this association was not significant in patients with malignant brain tumors.

Unusual presentation of systemic lupus erythematosus as hemophagocytic lymphohistiocytosis in a female patient: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disorder, often resulting in the immune-mediated injury of multiple organ systems, including primary HLH and secondary HLH (sHLH). Among them, sHLH results from infections, malignant, or autoimmune conditions, which have quite poor outcomes even with aggressive management and are more common in adults. CASE SUMMARY: We report a rare case of a 36-year-old female manifested with sHLH on background with systemic lupus erythematosus (SLE). During hospitalization, the patient was characterized by recurrent high-grade fever, petechiae and ecchymoses of abdominal skin, and pulmonary infection. Whole exon gene sequencing revealed decreased activity of natural killer cells. She received systematic treatment with Methylprednisolone, Etoposide, and anti-infective drugs. Intravenous immunoglobulin and plasmapheresis were applied when the condition was extremely acute and progressive. The patient recovered and did not present any relapse of the HLH for one year of follow-up. CONCLUSION: The case showed sHLH, thrombotic microvascular, and infection in the whole course of the disease, which was rarely reported by now. The treatment of the patient emphasizes that early recognition and treatment of sHLH in SLE patients was of utmost importance to improve the prognosis and survival rate of patients.

Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant.

The single-nucleotide polymorphism (SNP) of p53, in particular the codon 72 variants, has recently been implicated as a critical regulator in tumor progression. However, the underlying mechanism remains elusive. Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation. Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant (but not p5372R) with phosphoserine aminotransferase 1 (PSAT1). Interestingly, p5372P-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) that otherwise bound to p5372P, leading to subsequent nuclear translocation of PGC-1α and activation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Depletion of PSAT1 restored p5372P-PGC-1α interaction and impeded the OXPHOS and TCA function, resulting in mitochondrial dysfunction and metastasis suppression. Notably, pharmacological targeting the PSAT1-p5372P interaction by aminooxyacetic acid (AOA) crippled the growth of liver cancer cells carrying the p5372P variant in both in vitro and patient-derived xenograft models. Moreover, AOA plus regorafenib, an FDA-proved drug for hepatocellular carcinoma and colorectal cancer, achieved a better anti-tumor effect on tumors carrying the p5372P variant. Therefore, our findings identified a gain of function of the p5372P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p5372P-PSAT1 perturbation.

Association of Postoperative Drift in Hemoglobin With Mortality After Brain Tumor Craniotomy.

BACKGROUND: Postoperative downward drift in hemoglobin (Hb) concentration may be associated with complications and death, even if nadir Hb remains more than the red blood cell transfusion threshold of 7 g/dL. OBJECTIVE: To assess whether postoperative Hb drift in patients undergoing brain tumor craniotomy influences mortality in the immediate perioperative period. METHODS: This retrospective cohort study included patients undergoing craniotomy for brain tumors. We defined no postoperative Hb decrease, mild decrease, moderate decrease, and severe decrease as postoperative Hb drift of ≤25%, 26% to 50%, 51% to 75%, and >75%, respectively. The primary outcome was 30-day mortality after craniotomy. RESULTS: This study included 8159 patients who underwent a craniotomy for brain tumors. Compared with patients with no postoperative Hb drift, the odds of postoperative mortality at 30 days increased in patients with mild postoperative Hb drift (adjusted odds ratio [OR] 2.47, 95% CI 1.72-3.56), moderate drift (adjusted OR 6.56, 95% CI 3.42-12.59), and severe drift (adjusted OR 12.33, 95% CI 3.48-43.62). When postoperative Hb drift was analyzed as a continuous variable, for each 10% increase in Hb drift, the adjusted OR of postoperative mortality at 30 days was 1.46 (95% CI 1.31-1.63). CONCLUSION: In patients undergoing brain tumor craniotomy, a small postoperative Hb drift was associated with increased odds of postoperative mortality at 30 days, even if the nadir Hb level remained greater than the red blood cell transfusion threshold of 7 g/dL. Future randomized clinical trials of perioperative transfusion practices may examine the effect of both nadir Hb and Hb drift.

Association of preoperative glucose concentration with mortality in patients undergoing craniotomy for brain tumor.

OBJECTIVE: Hyperglycemia is associated with worse outcomes in ambulatory settings and specialized hospital settings, but there are sparse data on the importance of preoperative blood glucose measurement before brain tumor craniotomy. The authors sought to investigate the association between preoperative glucose level and 30-day mortality rate in patients undergoing brain tumor resection. METHODS: This retrospective cohort study included patients undergoing craniotomy for brain tumors at West China Hospital, Sichuan University, from January 2011 to March 2021. Surgical mortality rates were evaluated in patients who had normal glycemia (< 5.6 mmol/L) as well as mild (5.6-6.9 mmol/L), moderate (7.0-11.0 mmol/L), and severe hyperglycemia (> 11.0 mmol/L). RESULTS: The study included 12,281 patients who underwent tumor resection via craniotomy. The overall 30-day mortality rate was 2.0% (242/12,281), whereas the rates for normal glycemia and mild, moderate, and severe hyperglycemia were 1.5%, 2.5%, 3.8%, and 6.5%, respectively. Compared with normal glycemia, the odds of mortality at 30 days were higher in patients with mild hyperglycemia (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.05-2.00), moderate hyperglycemia (OR 2.04, 95% CI 1.41-2.96), and severe hyperglycemia (OR 3.76, 95% CI 1.96-7.20; p < 0.001 for trend). When blood glucose was analyzed as a continuous variable, for each 1 mmol/L increase in blood glucose, the adjusted OR of 30-day mortality was 1.13 (95% CI 1.08-1.19). The addition of a preoperative glucose level significantly improved the area under the curve and categorical net reclassification index for prediction of mortality. CONCLUSIONS: In patients undergoing craniotomy for brain tumors, even mild hyperglycemia was associated with an increased mortality rate, at a glucose level that was much lower than the commonly applied level.

Postoperative systemic inflammatory response syndrome predicts increased mortality in patients after elective craniotomy.

Introduction: Patients undergoing craniotomy are at high risk of perioperative morbidity and mortality due to excessive inflammatory responses. The purpose of the present study is to evaluate the prognostic utility of postoperative systemic inflammatory response syndrome (SIRS) in patients undergoing craniotomy. Methods: We performed a retrospective cohort study of patients who underwent craniotomy between January 2011 and March 2021. SIRS was diagnosed based on two or more criteria (hypo-/hyperthermia, tachypnea, leukopenia/leukocytosis, tachycardia). We used univariate and multivariate analysis for the development of SIRS with postoperative 30-day mortality. Results: Of 12,887 patients who underwent craniotomy, more than half of the patients (n = 6,725; 52.2%) developed SIRS within the first 7 days after surgery, and 157 (1.22%) patients died within 30 days after surgery. In multivariable analyses, SIRS (OR, 1.57; 95% CI, 1.12-2.21) was associated with 30-day mortality. Early SIRS was not predictive of 30-day mortality, whereas delayed SIRS was predictive of 30-day mortality. Abnormal white blood cell (WBC) counts contributed the most to the SIRS score, followed by abnormal body temperature, respiratory rate, and heart rate. Conclusion: Postoperative SIRS commonly occurs after craniotomy and is an independent predictor of postoperative 30-day mortality. This association was seen only in delayed SIRS but not early SIRS. Moreover, increased WBC counts contributed the most to the SIRS score.

A nanoplatform reshaping intracellular osmolarity and redox homeostasis against colorectal cancer.

Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemoresistance remaining a major obstacle in CRC treatment. Sodium persulfate (Na2S2O8) is a novel agent capable of producing •SO4- and Na+ for chemodynamic therapy (CDT). This can induce pyroptosis and ferroptosis instead of conventional apoptosis in tumor cells. Meanwhile, IR780-iodide (IR780), as an excellent phototherapy agent, can generate hyperthermia and generate a large amount of reactive oxygen species (ROS) to synergize with the CDT of Na2S2O8, with potential to overcome chemoresistance in CRC. However, the low stability of Na2S2O8 and the poor solubility of IR780 limit their applications in the medical field. Accordingly, for the first time, D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), Na2S2O8 and IR780 were rationally designed in a cascade-amplifying nanoplatform (Na2S2O8-IR780 NPs) via a co-assembly strategy. Combining Na2S2O8 and IR780 in a nanoplatform improves the stability of Na2S2O8 and the solubility of IR780. As a result, the Na2S2O8-IR780 NPs exhibited excellent antitumor efficacy in CRC cell lines and five chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. This photo-chemodynamic nanoplatform provides a brand-new paradigm by manipulating osmolarity and redox homeostasis to overcome chemo-resistance and holds great potential for the treatment of CRC.

Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis.

Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F1 FO -ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B-ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment.

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/ß-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA.

BACKGROUND: Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined. METHODS: The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/ß-catenin axis in CRC proliferation and metastasis. RESULTS: Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m6A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) and inhibited its kinase activity, thus releasing ß-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression. CONCLUSIONS: Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/ß-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3ß, releasing ß-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression.

Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, yet successful treatment still remains a challenge. In this study, we found that oxiconazole (OXI), a broad-spectrum antifungal agent, exhibits certain anti-tumor effect against CRC. Autophagy arrest and subsequent apoptosis are characterized as pivotal events involving OXI-induced growth suppression of CRC cells. Mechanistically, OXI downregulates the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme, for reactive oxygen species (ROS) detoxication, to initiate autophagy by inactivating the Akt/mTOR pathway and inhibiting RAB7A-mediated fusion of autophagosome and lysosome, which lead to extreme accumulation of autophagosomes and subsequent growth suppression of CRC cells. Consistently, interfering with autophagy or overexpressing PRDX2 significantly impedes OXI-induced growth suppression of CRC cells. Moreover, OXI plus oxaliplatin, a mainstay drug for CRC treatment, achieves an improved anti-tumor effect. Taken together, our findings bring novel mechanistic insights into OXI-induced autophagy arrest and the growth inhibitory effect on CRC cells, and suggest a promisingly therapeutic role of OXI for CRC treatment.

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Oxidative Stress in Cancer Immunotherapy: Molecular Mechanisms and Potential Applications.

Immunotherapy is an effective treatment option that revolutionizes the management of various cancers. Nevertheless, only a subset of patients receiving immunotherapy exhibit durable responses. Recently, numerous studies have shown that oxidative stress induced by reactive oxygen species (ROS) plays essential regulatory roles in the tumor immune response, thus regulating immunotherapeutic effects. Specifically, studies have revealed key roles of ROS in promoting the release of tumor-associated antigens, manipulating antigen presentation and recognition, regulating immune cell phenotypic differentiation, increasing immune cell tumor infiltration, preventing immune escape and diminishing immune suppression. In the present study, we briefly summarize the main classes of cancer immunotherapeutic strategies and discuss the interplay between oxidative stress and anticancer immunity, with an emphasis on the molecular mechanisms underlying the oxidative stress-regulated treatment response to cancer immunotherapy. Moreover, we highlight the therapeutic opportunities of manipulating oxidative stress to improve the antitumor immune response, which may improve the clinical outcome.

Target identification of anti-diabetic and anti-obesity flavonoid derivative (Fla-CN).

Fla-CN is a flavonoid derivative with anti-diabetic and anti-obesity effects; however, its biological targets are still unknown. In this study, we developed bifunctional affinity-based probes to identify the direct targets of Fla-CN. When using probe 3, we observed the co-location of probe 3 and mitochondria in both HepG2 and 3T3-L1 cells. The putative target proteomes were obtained using activity-based protein profiling (ABPP) and photo-affinity labelling. Pyruvate carboxylase, mitochondrial malate dehydrogenase, mitochondrial complex I, and F1FO-ATPase were validated as the direct targets of Fla-CN by surface plasmon resonance (SPR) and biochemical assays. It was elucidated that the Tyr651, Gln870 and Lys912 were the key amino acid residues near the binding site of pyruvate carboxylase with Fla-CN. The direct interaction of Fla-CN and the above four targets allowed elucidation of its complicated molecular mechanism, including the activation of adenosine 5-monophosphate (AMP)-activated protein kinase (AMPK), and the inhibition of gluconeogenesis. Further investigation for activation of AMPK in normal and insulin resistance (IR) HepG2 cells, indicated that Fla-CN could target insulin resistance tissues.

PHLDB2 Mediates Cetuximab Resistance via Interacting With EGFR in Latent Metastasis of Colorectal Cancer.

BACKGROUND & AIMS: Latent metastasis of colorectal cancer (CRC) frequently develops months or years after primary surgery, followed by adjuvant therapies, and may progress rapidly even with targeted therapy administered, but the underlying mechanism remains unclear. Here, we aim to explore the molecular basis for the aggressive behavior of latent metastasis in CRC. METHODS: Transcriptional profiling and pathway enrichment analysis of paired primary and metastatic tumor samples were performed. The underlying mechanisms of pleckstrin homology-like domain, family B, member 2 (PHLDB2) in CRC were investigated by RNA immunoprecipitation assay, immunohistochemistry, mass spectrometry analysis, and Duolink in situ proximity ligation assay (Sigma-Aldrich, Shanghai, China). The efficacy of targeting PHLDB2 in cetuximab treatment was elucidated in CRC cell lines and mouse models. RESULTS: Based on the transcriptional profile of paired primary and metastatic tumor samples, we identified PHLDB2 as a potential regulator in latent liver metastasis. A detailed mechanistic study showed that chemotherapeutic agent-induced oxidative stress promotes methyltransferase-like 14 (METTL14)-mediated N6-methyladenosine modification of PHLDB2 messenger RNA, facilitating its protein expression. Up-regulated PHLDB2 stabilizes epidermal growth factor receptor (EGFR) and promotes its nuclear translocation, which in turn results in EGFR signaling activation and consequent cetuximab resistance. Moreover, Arg1163 (R1163) of PHLDB2 is crucial for interaction with EGFR, and the R1163A mutation abrogates its regulatory function in EGFR signaling. CONCLUSIONS: PHLDB2 plays a crucial role in cetuximab resistance and is proposed to be a potential target for the treatment of CRC.