Enhancing radiosensitivity in triple-negative breast cancer through targeting ELOB.

Enhancing radiotherapy sensitivity is crucial for improving treatment outcomes in triple-negative breast cancer (TNBC) patients. In this study, we investigated the potential of targeting Elongin B (ELOB) to enhance radiotherapy efficacy in TNBC. Analysis of TNBC patient cohorts revealed a significant association between high ELOB expression and poor prognosis in patients who received radiation therapy. Mechanistically, we found that ELOB plays a pivotal role in regulating mitochondrial function via modulating mitochondrial DNA expression and activities of respiratory chain complexes. Targeting ELOB effectively modulated mitochondrial function, leading to enhanced radiosensitivity in TNBC cells. Our findings highlight the importance of ELOB as a potential therapeutic target for improving radiotherapy outcomes in TNBC. Further exploration of ELOB's role in enhancing radiotherapy efficacy may provide valuable insights for developing novel treatment strategies for TNBC patients.

Berberine prevents NAFLD and HCC by modulating metabolic disorders.

Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.

Present situation and prospect of immunotherapy for unresectable locally advanced esophageal cancer during peri-radiotherapy.

Four major studies (Checkmate577, Keynote-590, Checkmate649 and Attraction-4) of locally advanced esophageal cancer published in 2020 have established the importance of immunotherapy, represented by anti-programmed death protein (PD)-1 in postoperative adjuvant treatment and advanced first-line treatment of locally advanced or advanced esophageal cancer and esophagogastric junction cancer, from the aspects of proof of concept, long-term survival, overall survival rate and progression-free survival. For unresectable or inoperable nonmetastatic esophageal cancer, concurrent radiotherapy and chemotherapy is the standard treatment recommended by various guidelines. Because its curative effect is still not ideal, it is necessary to explore radical radiotherapy and chemotherapy in the future, and it is considered to be promising to combine them with immunotherapeutic drugs such as anti-PD-1. This paper mainly discusses how to combine radical concurrent radiotherapy and chemotherapy with immunotherapy for unresectable local advanced esophageal cancer.

Extracellular Vesicles Derived from Human Adipose-Derived Mesenchymal Stem Cells Alleviate Sepsis-Induced Acute Lung Injury through a MicroRNA-150-5p-Dependent Mechanism.

Extracellular vesicles (EVs) derived from human adipose mesenchymal stem cells (hADSCs) may exert a therapeutic benefit in alleviating sepsis-induced organ dysfunction by delivering cargos that include RNAs and proteins to target cells. The current study aims to explore the protective effect of miR-150-5p delivered by hADSC-EVs on sepsis-induced acute lung injury (ALI). We noted low expression of miR-150-5p in plasma and bronchoalveolar lavage fluid samples from patients with sepsis-induced ALI. The hADSC-EVs were isolated and subsequently cocultured with macrophages. It was established that hADSC-EVs transferred miR-150-5p to macrophages, where miR-150-5p targeted HMGA2 to inhibit its expression and, consequently, inactivated the MAPK pathway. This effect contributed to the promotion of M2 polarization of macrophages and the inhibition of proinflammatory cytokines. Further, mice were made septic by cecal ligation and puncture in vivo and treated with hADSC-EVs to elucidate the effect of hADSC-EVs on sepsis-induced ALI. The in vivo experimental results confirmed a suppressive role of hADSC-EVs in sepsis-induced ALI. Our findings suggest that hADSC-EV-mediated transfer of miR-150-5p may be a novel mechanism underlying the paracrine effects of hADSC-EVs on the M2 polarization of macrophages in sepsis-induced ALI.

Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma.

Introduction: Low-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. Methods: We conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis. Results: Our findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3K-Akt signaling pathway and the expression of the transcription factor VDR. Discussion: These findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG.

miR-214 could promote myocardial fibrosis and cardiac mesenchymal transition in VMC mice through regulation of the p53 or PTEN-PI3K-Akt signali pathway, promoting CF proliferation and inhibiting its ng pathway.

INTRODUCTION: This study aimed to investigate the role of miR-214 in the bidirectional regulation of p53 and PTEN and its influence on myocardial fibrosis and cardiac mesenchymal transformation in mice with viral myocarditis (VMC). METHODS: The study established a VMC model in BALB/c mice by injecting them with the CVB3 virus intraperitoneally. Techniques such as ELISA, H&E staining, Masson staining, immunohistochemical staining, RT-qPCR, western blot, and dual-luciferase reporter gene assay were used to detect the expression levels of relevant factors in tissues and cells. Isolation and culture of cardiac fibroblasts (CFs) were also conducted. RESULTS: The study found that miR-214 bidirectional regulation of p53 and PTEN promotes myocardial fibrosis and cardiac mesenchymal transformation in mice with VMC. The expression levels of collagen-related peptides, inflammatory-related factors, miR-214, mesenchymal transformation-related factors, and fibrosis-related factors were significantly increased, while the expression levels of p53, PTEN, and epithelial/endothelial cell phenotype marker factors were significantly decreased. Downregulation of miR-214 or upregulation of p53 and PTEN expression inhibited inflammatory cell and fibroblast infiltration in VMC mouse myocardial tissue. It reduced the proliferation ability while increasing the apoptosis of cardiac fibroblasts. CONCLUSION: miR-214 plays a significant role in the bidirectional inhibition of p53 and PTEN, which leads to myocardial fibrosis and cardiac mesenchymal transformation in mice with VMC. Downregulation of miR-214 or upregulation of p53 and PTEN expression may provide potential therapeutic targets for treating VMC-induced cardiac fibrosis and mesenchymal transformation.

Utility of CRISPR/Cas mediated electrochemical biosensors.

Electrochemical biosensors represent a class of sensors that employ biological materials as sensitive elements, electrodes as conversion elements, and potential or current as detection signals. The integration of CRISPR/Cas systems into electrochemical biosensors holds immense potential, offering enhanced versatility, heightened sensitivity and specificity, reduced recovery time, and the ability to capture and identify analytes at low concentrations. In this review, we provided a succinct summary of the fundamental principles underlying electrochemical biosensors and CRISPR/Cas systems, and new progress of electrochemical biosensors based on CRISPR/Cas systems in virus, bacteria, and cancer detections. Besides, we discussed its pros and cons, present gaps, potential problem-solvers, and future prospects. To sum up, CRISPR/Cas mediated electrochemical biosensors will surely benefit us a lot in the detection of cells and microorganisms, and of course in other promising fields.

Electroacupuncture-modulated extracellular ATP levels in prefrontal cortex ameliorated depressive-like behavior of maternal separation rats.

Maternal separation (MS) is a type of early-life stress that has been linked to neuropsychiatric disorders, especially depression. Increasing evidence indicates that the adenosine triphosphate (ATP) level in the prefrontal cortex (PFC) is involved in the pathophysiology of depression. To investigate the potential relationship between ATP in PFC and antidepressant effects of electroacupuncture (EA) treatment, we assessed genes involved in ATP biosynthesis as well as the extracellular ATP levels in a rat model exposed to neonatal MS. Our results demonstrated that reduced expression of ABCG2 (an ATP-binding cassette protein) and ATP levels in the PFC of depressive-like rats exposed to MS can be attenuated by EA stimulus at the Baihui (GV20) and Yintang (GV29) acupoints. Moreover, the antidepressant effect of EA treatment was blocked by administration of suramin, a broad purinergic P2 receptor antagonist. Together, these results suggested that electroacupuncture may be able to modulate extracellular ATP levels in the PFC of depressive-like MS rats, potentially contributing to its antidepressant effects.

Disheveled3 enhanced EMT and cancer stem-like cells properties via Wnt/ß-catenin/c-Myc/SOX2 pathway in colorectal cancer.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC). METHODS: UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/ß-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo. RESULTS: DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/ß-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/ß-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice. CONCLUSION: DVL3 promoted EMT and CSLCs properties of CRC via Wnt/ß-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.

Prognostic nutritional index predicts the prognosis of patients with advanced esophageal cancer treated with immune checkpoint inhibitors: a retrospective cohort study.

Background: Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, their efficacy is variable, and there are still no effective and convenient biomarkers to identify and assess their efficacy. In recent years, programmed cell death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB) and other commonly used biomarkers still cannot meet clinical needs. PNI is easy to obtain and its predictive value for the prognosis of immunotherapy has been confirmed in many cancer species, but the relationship between PNI and the efficacy of immunotherapy for esophageal cancer is still unclear. Therefore, this study aims to explore the predictive value of PNI in advanced esophageal cancer treated with ICIs. Methods: The clinicopathological features of 78 patients with advanced EC who received immunotherapy in the 900th Hospital of the Joint Logistics Team from September 2018 to May 2022 were retrospectively analyzed. The laboratory test results within 10 days prior to the start of ICI treatment were recorded, including absolute lymphocyte count and albumin (ALB) level. Meanwhile, the effects of pre-treatment prognostic nutritional index (PNI) and body mass index (BMI) on the overall survival (OS) and progression-free survival (PFS) in patients with advanced EC were analyzed. Results: The median age of the enrolled patients was 58 years, and 38 patients (48.7%) received second-or-later-line therapy. The median progression-free survival (mPFS) and median overall survival (mOS) were 7.4 months and 13 months, respectively. The mPFS and mOS were 8.8 months and 15 months, respectively, in the high baseline PNI subgroup, which were significantly higher than those in the low baseline PNI subgroup (4.7 and 8.2 months, respectively; both P<0.05). Multivariate regression analysis showed that low baseline PNI was an independent predictor of poor PFS [hazard studio (HR) =0.35, 95% CI: 0.14-0.85, P=0.020) and poor OS (HR =0.41, 95% CI: 0.17-0.99, P=0.047) and treatment line was an independent predictor of PFS. Baseline BMI was not significantly associated with prognosis. Conclusions: PNI is a simple and effective biomarker for predicting the prognosis of immunotherapy in patients with advanced EC, although further prospective studies are warranted.

Melatonin Alleviates Chromium Toxicity in Maize by Modulation of Cell Wall Polysaccharides Biosynthesis, Glutathione Metabolism, and Antioxidant Capacity.

Melatonin, a pleiotropic regulatory molecule, is involved in the defense against heavy metal stress. Here, we used a combined transcriptomic and physiological approach to investigate the underlying mechanism of melatonin in mitigating chromium (Cr) toxicity in Zea mays L. Maize plants were treated with either melatonin (10, 25, 50 and 100 µM) or water and exposed to 100 µM K2Cr2O7 for seven days. We showed that melatonin treatment significantly decreased the Cr content in leaves. However, the Cr content in the roots was not affected by melatonin. Analyses of RNA sequencing, enzyme activities, and metabolite contents showed that melatonin affected cell wall polysaccharide biosynthesis, glutathione (GSH) metabolism, and redox homeostasis. During Cr stress, melatonin treatment increased cell wall polysaccharide contents, thereby retaining more Cr in the cell wall. Meanwhile, melatonin improved the GSH and phytochelatin contents to chelate Cr, and the chelated complexes were then transported to the vacuoles for sequestration. Furthermore, melatonin mitigated Cr-induced oxidative stress by enhancing the capacity of enzymatic and non-enzymatic antioxidants. Moreover, melatonin biosynthesis-defective mutants exhibited decreased Cr stress resistance, which was related to lower pectin, hemicellulose 1, and hemicellulose 2 than wild-type plants. These results suggest that melatonin alleviates Cr toxicity in maize by promoting Cr sequestration, re-establishing redox homeostasis, and inhibiting Cr transport from the root to the shoot.

Real-world experience with anti-programmed cell death protein 1 immunotherapy in patients with esophageal cancer: A retrospective single-center study.

The "real-world" data of programmed cell death protein 1 (PD-1) inhibitors in esophageal cancer (EPC) are still an unmet medical need, including the clinical efficacy and safety. Seventy-seven EPC data were studied retrospectively; the progression-free survival (PFS), risk factors (clinical stages larger than stage II, metastatic sites larger than 2, treatment lines larger than the first line, previous surgical treatment, combined positive score [CPS] expression, etc.), and the safety were analyzed. The median PFS for all patients was 7.2 months, clinical stage > stage II; the number of treatment lines > first line was significantly correlated with prognosis (all P < 0.05). Subgroup analysis showed that the median PFS of patients with clinical stage ≤ II was better; the results were the same for the patients with ≤2 metastatic sites, first-line PD-1 inhibitors, and not previously received radical surgery (all P < 0.05). Meanwhile, the incidence of adverse events (AEs) of varying degrees was 25.97% (20/77) in 20 patients and 6.49% (5/77) of grade 3/4 AEs. The highest AE was myelosuppression (15.58%), followed by liver function injury (7.79%). In addition, ≥2 lines of treatment and >2 metastatic sites predicted poor outcomes for patients with EPC who had failed first-line therapy or progressed with the combined immunotherapy and chemotherapy treatment strategy (all P < 0.05).

Effects of Compound Elicitors on the Biosynthesis of Triterpenoids and Activity of Defense Enzymes from Inonotus hispidus (Basidiomycetes).

Inonotus hispidus has various health-promoting activities, such as anticancer effects and immune-stimulating activity. The commercialization of valuable plant triterpenoids faces major challenges, including low abundance in natural hosts and costly downstream purification procedures. In this work, orthogonal design was used to compound methyl jasmonate (MeJA), salicylic acid (SA), oleic acid, and Cu2+, and the effects of combinations on the total triterpenes biosynthesized were studied. The optimal combination was screened out and its effect on the activity of PAL, CAT, and SOD was studied. The optimal concentration of oleic acid was 2% when MeJA was 100 mol/L, and the total triterpenoid content and mycelia production were 3.918 g and 85.17 mg/g, respectively. MeJA treatment induced oxidative stress, and at the same time increased the activity of related defense enzymes. Oleic acid is thought to regulate cell permeability by recombining cell membranes. It promotes the material exchange process between cells and the environment without affecting cell growth. When oleic acid was used in combination with MeJA, a synergistic effect on triterpene production was observed. In conclusion, our findings provide a strategy for triterpenoid enrichment of I. hispidus.

PKG II secreted via the classical endoplasmic reticulum-Golgi apparatus secretory pathway blocks the activation of EGFR through phosporalting its threonine 406 and has an anti-tumor effect.

BACKGROUND: Protein kinase G type II (PKG II) is a serine/threonine-protein kinase that was originally isolated from the small intestinal mucosa with primary functions in the secretion of small intestinal mucosal cells, secretion of renin and aldosterone, and chondrocyte activities. Recent studies have shown that PKG II exerts anti-tumor effects, while a previous study by our group confirmed that PKG II inhibited the proliferation and migration of cancer cells. Interestingly, PKG II, which was typically bound to the intracellular side of the membrane, was detected in the serum and cell culture medium as a diagnostic biomarker of tumor growth. Thus, the aim of the present study was to elucidate the function and the targets of PKG II, and the mechanism underlying the secretion of this kinase. METHODS: Construction of peptides and plasmids, RNA interference, Immunoelectron microscopy, Co-immunoprecipitation, N-glycosylation assay and Isolation of the Golgi apparatus were applied to investigate the secretory mechanism, and the targets and function of PKG II. RESULTS: PKG II was secreted by enterochromaffin (EC) cells, which were components of the endocrine system in the gastrointestinal tract. Myristoylation of glycine 2 and the N-terminal sequence, especially the amino acids 3-30, acted as a signal peptide to induce the secretion of PKG II via the conventional protein secretory pathway. Moreover, recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells. CONCLUSIONS: These results revealed a correlation between the endocrine system and the secretion of protein kinase, suggesting a novel protein secretory pathway. The resuls also indicated that secreted PKG II was a potential diagnostic biomarker and an inhibitor of tumor.

Maternal Subclinical Hypothyroidism in Rats Impairs Spatial Learning and Memory in Offspring by Disrupting Balance of the TrkA/p75NTR Signal Pathway.

Maternal subclinical hypothyroidism (SCH) during pregnancy can adversely affect the neurodevelopment of the offspring. The balance of nerve growth factor (NGF)-related tropomyosin receptor kinase A/p75 neurotrophin receptor (TrkA/p75NTR) signaling in the hippocampus is important in brain development, and whether it affects cognitive function in maternal SCH's offspring is not clear. In this study, we found that compared with the control (CON) group, expression of proliferation-related proteins [NGF, p-TrkA, phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phospho-cAMP response element-binding protein (p-CREB)] decreased in the hippocampus of the offspring in the SCH group, overt hypothyroidism (OHT) group, and the group with levothyroxine (L-T4) treatment for SCH from gestational day 17 (E17). In contrast, expression of apoptosis-related proteins [pro-NGF, p75NTR, phospho-C-Jun N-terminal kinase (p-JNK), p53, Bax and cleaved caspase-3] was increased. The two groups with treatment with L-T4 for SCH from E10 and E13, respectively, showed no significant difference compared with the CON group. L-T4 treatment enhanced relative expression of NGF by increasing NGF/proNGF ratio in offspring from maternal SCH rats. In conclusion, L-T4 treatment for SCH from early pregnancy dramatically ameliorated cognitive impairment via TrkA/p75NTR signaling, which involved activation of the neuronal proliferation and inhibition of neuronal apoptosis in SCH rats' offspring.

The Mechanism of Ferroptosis and Applications in Tumor Treatment.

Iron-dependent ferroptosis is a new form of cell death in recent years, which is driven by lipid peroxidation. The lethal lipid accumulation caused by glutathione depletion or inactivation of glutathione peroxidase 4 (GPX4) is characteristic of the ferroptosis process. In recent years, with the in-depth study of ferroptosis, various types of diseases have been reported to be related to ferroptosis. In other words, ferroptosis, which has attracted widespread attention in the fields of biochemistry, oncology, and especially materials science, can undoubtedly provide a new way for patients. This review introduces the relevant mechanisms of ferroptosis, the relationship between ferroptosis and various cancers, as well as the application of ferroptosis in tumor treatment. We also sorted out the genes and drugs that regulate ferroptosis. Moreover, small molecule compound-induced ferroptosis has a strong inhibitory effect on tumor growth in a drug-resistant environment, which can enhance the sensitivity of chemotherapeutic drugs, suggesting that ferroptosis is very important in the treatment of tumor drug resistance, but the details are still unclear. How to use ferroptosis to fight cancer, and how to prevent drug-resistant tumor cells have become the focus and direction of research. At the end of the article, some existing problems related to ferroptosis are summarized for future research.

Primary macronodular adrenal hyperplasia (PMAH) can be generated by a new ARMC5 germline variant (c.52C>T (p.Gln18X)).

Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing syndrome (CS). In many cases of the PMAH family, variant in ARMC5, a putative tumor suppressor gene, are thought to induce the disease. The purpose of this study was to report a large Chinese family, in which a new germline heterozygous variant of ARMC5 (c.52C>T (p.Gln18X)) was found. A 64-year-old female patient (proband) was admitted to the hospital due to bilateral adrenal masses. In order to clarify the nature and function of adrenal masses, the proband completed several relevant screening tests of the adrenal function. After an ectopic receptor screening test and genetic testing, a new ARMC5 gene variant was found that might had led to the occurrence of PMAH. Because of its characteristic of autosomal dominant inheritance, the proband's relatives were recommended to conduct the genetic test. We collected the family members' genetic information, in which have 27 individuals, the proband tested the whole exon sequence, and 12 participants tested the Sanger sequence. Finally, 7 individuals were found have the same germline variant of ARMC5 as the proband. Subsequent computer analysis predicted that the variant significantly impaired protein function and resulted in inactivation of ARMC5. We found a new germline ARMC5 variant (c.52C>T (p.Gln18X)), which may induced PMAH. ARMC5 sequencing can improve the identification of clinical forms of PMAH and allow early diagnosis of the disease.