Thyroid hormone enhances efficacy of cisplatin in lung cancer patients via down-regulating GLUT1 expression and reversing the Warburg effect.

Cisplatin (CDDP) is a standard non-small cell lung cancer (NSCLC) chemotherapy, but its efficacy is hampered by resistance, partly due to the Warburg effect. This study investigates how thyroid hormones enhance the Warburg effect, increasing sensitivity to cisplatin in lung cancer. Clinical data from advanced NSCLC patients were analyzed based on thyroid hormone levels, categorizing patients into high and low groups. Cellular experiments involved Control, 10uM CDDP, 10uM CDDP + 0.1uM T3, and 10uM CDDP + 0.1uM T4 categories. Parameters were measured in A549 and PC9 lung cancer cells, including proliferation, apoptosis, mitochondrial membrane potential, ROS production, glycolysis enzyme activity, lactic acid level, and ATP content. Gene and protein expressions were assessed using qPCR and Western Blot. Analysis revealed higher FT3 levels correlated with prolonged progression-free survival before chemotherapy (median PFS: high FT3 group = 12.67 months, low FT3 group = 7.03 months, p = 0.01). Cellular experiments demonstrated that thyroid hormones increase lung cancer cell sensitivity to cisplatin, inhibiting proliferation and enhancing efficacy. The mechanism involves thyroid hormones and cisplatin jointly down-regulating MSI1/AKT/GLUT1 expression, reducing lactic acid and glycolysis. This Warburg effect reversal boosts ATP levels, elevates ROS, and decreases MMP, enhancing cisplatin effectiveness in A549 and PC9 cells. In conclusion, elevated free T3 levels in advanced NSCLC patients correlate with prolonged progression-free survival under cisplatin chemotherapy. Cellular experiments reveal that thyroid hormones enhance lung cancer cell sensitivity to cisplatin by reversing the Warburg effect, providing a mechanistic basis for improved therapeutic outcomes.

Sodium selenite inhibits proliferation of lung cancer cells by inhibiting NF-κB nuclear translocation and down-regulating PDK1 expression which is a key enzyme in energy metabolism expression.

As a trace element that maintains homeostasis in human body, selenium has significant anti-tumor activity. However, its exact molecular mechanism remains to be elucidated. Sodium selenite (SSe) is the most widely-distributed inorganic selenium in nature. In this study, we selected SSe as the research object to explore its anti-tumor mechanism in lung cancer. In vitro experiment showed that SSe could inhibit the activation of NF-κB signaling pathway, knowing that NF-κB is an important intracellular nuclear transcription factor that regulates the expression of pyruvate dehydrogenase kinase 1 (PDK1), a key energy metabolism switch affecting the survival status of the whole cell.At the same time, Bay11-7082(NF-κB signaling pathway inhibitors) and SSe resulted in phosphorylation of p65 and IκBα, decreased expression of PDK1 and Bcl-2,and increased expression of Bax in lung cancer cells. Our further study demonstrated that the reduction of PDK1 activity inhibited lactate secretion, reduced mitochondrial membrane potential, caused the release of Cytochrome C (Cyto C), activated mitochondrial respiration, and promoted the apoptosis of lung cancer cells. The in vivo experiment revealed that SSe inhibited the activation of NF-κB signaling pathway, decreased the expression of PDK1, and induced lung cancer cell proliferation and apoptosis. All these findings indicated that SSe promoted lung cancer cell apoptosis by inhibiting the activation of NF-κB signaling pathway, down-regulating PDK1 and activating mitochondrial apoptosis pathway.

Association between self-reported sedentary behavior and health-related quality of life among infertile women with polycystic ovary syndrome.

BACKGROUND: High sedentary behavior and poor health-related quality of life (HRQoL) were common among women with polycystic ovary syndrome (PCOS). However, the association of sedentary behavior with HRQoL among infertile women with PCOS is still unknown. This study aimed to investigate the association of sedentary behavior with HRQoL among them. METHODS: A cross-sectional study was conducted with 283 participants recruited from infertility outpatient clinic. A self-administered, structured questionnaire including the modified PCOS health-related QoL questionnaire (MPCOSQ), the International Physical Activity Questionnaire short form (IPAQ-SF), the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7) was used. Anthropometric and laboratory indictors related to PCOS were also collected. Multivariable linear regression analyses were performed to identify the associations. Bonferroni correction was utilized for multiple testing correction. RESULTS: Sedentary behavior was associated with reduced HRQoL among this group. Specifically, over seven hours per day of sedentary behavior was strongly associated with total and several aspects of HRQoL (ß ranged from - 0.378 to - 0.141, all P < 0.0063) after adjusting for physical activity, anxiety and depression. In addition, elevated BMI (ß = - 0.407, P < 0.001) and anxiety (ß ranged from - 0.410 to - 0.245, all P < 0.0063) were associated with poor HRQoL, while physical activity and depression were not. CONCLUSION: Sedentary behavior is an important behavior among infertile women with PCOS as it was associated with poorer HRQoL. Future interventions seeking to improve HRQoL should be considered to reduce sedentary behavior and psychological burden as primary intervention targets.

The role of hypoxia-inducible factor 1-alpha in inflammatory bowel disease.

Inflammatory bowel disease (IBD) develops as a result of a combination of genetic predisposition, dysbiosis of the gut microbiota, and environmental influences, which is mainly represented by ulcerative colitis (UC) and Crohn's disease (CD). IBDs can result in inflammatory hypoxia by causing intestinal inflammation and vascular damage. The hypoxia-inducible factor 1-alpha (HIF-1α), as a transcription factor, can regulate the cellular adaptation to low oxygen levels and support the development and function of the gut barrier. HIF-αplays its functions through translocating into the nucleus, dimerizing with HIF-1ß, and binding to hypoxia-responsive elements of HIF-1 target genes. So far, most studies have addressed the function of HIF-1α in murine models of IBD. In this review, we aim to outline the major roles of HIF-1α in the IBD.

Feasibility and preliminary experience of single-incision plus one-port laparoscopic total gastrectomy with Overlap esophagojejunostomy for gastric cancer: A study of 10 cases.

Background: This study aimed to explore the feasibility and safety of single-incision plus one-port laparoscopic total gastrectomy (SITG + 1) with Overlap esophagojejunostomy (SITG + 1-Overlap) and to share preliminary experiences. Methods: This retrospective study included 10 patients with gastric cancer located in the cardia or body who underwent SITG + 1-Overlap between August 2020 and October 2021.The demographics, tumor characteristics, postoperative outcomes, and short-term complications of all the enrolled patients were summarized and statistically analyzed. Data were expressed as mean ± standard deviation (SD) if they were normally distributed. Otherwise, Median (Quartile1, Quartile3) was used. Results: In the collective perioperative data of these 10 patients who underwent radical gastrectomy, the median of the length of transumbilical incision and blood loss were 3.0 cm and 100.0 ml respectively, and the mean operation time and 385.5 ± 51.6 min. Postoperative data indicated that the gastric tube was removed on 2.0 (2.0, 3.0) days, and the timing of first feeding, activity, flatus, and defecation was 1.5 (1.0, 2.0) days, 2.0 (2.0, 2.0) days, 3.0 (2.0, 3.0) days, and 3.8 ± 0.6 days, respectively. The timing of drainage tube removal was 4.6 ± 1.0 days after operation. The duration of hospital stay was 7.5 ± 1.2 days and the VAS pain scores for the 3 days following surgery were 3.0 (2.0, 3.3), 2.0 (2.0, 3.0), and 1.5 (1.0, 2.0) respectively. The mean number of retrieved lymph nodes was 30.7 ± 13.2. Most biochemical indicators gradually normalized with the recovery of the patients after surgery. No 30-day postoperative complications were noted. Conclusions: For the first time, our preliminary data indicate the feasibility and safety of Overlap esophagojejunostomy in SITG + 1 surgery. This modified Overlap procedure has the potential to simplify the reconstruction procedure and lower the technical challenge of SITG + 1 radical gastrectomy for cardia or upper gastric cancer in the early and advanced stages.

A Novel Bunyavirus Discovered in Oriental Shrimp (Penaeus chinensis).

Herein, we describe a novel bunyavirus, oriental wenrivirus 1 (OWV1), discovered in moribund oriental shrimp (Penaeus chinensis) collected from a farm in China in 2016. Like most bunyaviruses, OWV1 particles were enveloped, spherical- to ovoid-shaped, and 80-115 nm in diameter. However, its genome was found to comprise four segments of (-)ssRNA. These included an L RNA segment (6,317 nt) encoding an RNA-directed RNA polymerase (RdRp) of 2,052 aa, an M RNA segment (2,978 nt) encoding a glycoprotein precursor (GPC) of 922 aa, an S1 RNA segment (1,164 nt) encoding a nucleocapsid (N) protein of 243 aa, and an S2 RNA segment (1,382 nt) encoding a putative non-structural (NSs2) protein of 401 aa. All the four OWV1 RNA segments have complementary terminal decanucleotides (5'-ACACAAAGAC and 3'-UGUGUUUCUG) identical to the genomic RNA segments of uukuviruses and similar to those of phleboviruses and tenuiviruses in the Phenuiviridae. Phylogenetic analyses revealed that the RdRp, GPC, and N proteins of OWV1 were closely related to Wenzhou shrimp virus 1 (WzSV-1) and Mourilyan virus (MoV) that infect black tiger shrimp (P. monodon). Phylogenetic analyses also suggested that OWV1 could be classified into a second, yet to be established, species of the Wenrivirus genus in the Phenuiviridae. These wenriviruses also clustered with Wenling crustacean virus 7 from shrimps and bunya-like brown spot virus from white-clawed crayfish. Of note there were no homologs of the NSs2 of OWV1 and MoV/WzSV-1 in GenBank, and whether other crustacean phenuiviruses also possess a similar S2 RNA segment warrants further investigation. In addition, we established a TaqMan probe-based reverse-transcription quantitative PCR method for detection of OWV1, and it was detected as 1.17 × 102-1.90 × 107 copies/ng-RNA in gills of 23 out of 32 P. chinensis samples without an obvious gross sign. However, the discovery of OWV1 highlights the expanding genomic diversity of bunyaviruses.

Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development.

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .

α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells.

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.

Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

Investigating efficacy of "microbiota modulation of the gut-lung Axis" combined with chemotherapy in patients with advanced NSCLC: study protocol for a multicenter, prospective, double blind, placebo controlled, randomized trial.

BACKGROUND: Most NSCLCs metastasised out of the lungs at the time of diagnosis and cannot be surgically removed . Cytotoxic chemotherapy drugs have become the main treatment in recent decades, especially in patients with NSCLC without EGFR, ALK, and ROS gene mutations. The prognosis of lung cancer is poor, and the overall 5-year survival rate is only 9-13%. Therefore the treatment of advanced NSCLC remains a significant medical need. Recent studies have shown a significant relationship between the gut-lung axis microecology and malignant tumors. Intestinal probiotics are likely to play a role in inhibiting tumorigenesis through "intestinal-pulmonary axis microecological regulation". This study will seek to investigate the efficacy of "Microbiota modulation of the Gut-Lung Axis" combined with chemotherapy in patients with advanced NSCLC. METHODS: The research is a multicenter, prospective, double blind, placebo controlled, randomized trial. Based on the theoretical basis of "intestinal and lung axis microecological adjustment", combined with traditional platinum-containing two-drug chemotherapy, the efficacy of the new therapy on patients with advanced NSCLC was observed. Collect the basic information of the patient, and study the effect of platinum-based combined chemotherapy on the diversity of intestinal flora in patients with lung cancer after receiving chemotherapy treatment, feces before and after chemotherapy, and the status and extent of adverse reactions during chemotherapy . A total of 180 subjects were included, divided into a control group (platinum-containing dual-drug chemotherapy) and an intervention group (platinum-containing dual-drug chemotherapy combined with Bifico), and were randomly assigned to the group 1:1. DISCUSSION: As a result, intestinal-pulmonary microecological balance could become a new target for the treatment of lung cancer. This study explores the combination of intestinal microecological regulation and chemotherapy to provide new treatment strategies and basis for lung cancer patients. It can help prolong the survival time of lung cancer patients and improve the quality of life, thereby generating huge economic and social benefits. The results can be promoted and applied to units engaged in the treatment of lung cancer. TRIAL REGISTRATION NUMBER: NCT03642548, date: August 22, 2018, the first version protocol. The URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03642548?term=NCT03642548&draw=2&rank=1 .

Mutual regulation between butyrate and hypoxia-inducible factor-1α in epithelial cell promotes expression of tight junction proteins.

Inflammatory bowel disease is a kind of multi-aetiological chronic disease that is driven by multidimensional factors. Hypoxia-inducible factor-1α (HIF-1α) plays an important role in anti-inflammatory and cellular responses to hypoxia. Previous studies have found that B or T-cell-specific HIF-1α knock out mice exhibit severe colonic inflammation. However, we know very little about other functions of HIF-1α in intestinal epithelial cells (IECs). In our study, HIF-1αΔIEC mice were used to study the function of HIF-1α in IECs. HIF-1α was knocked down in Caco-2 cells by transfection with a small interfering (si) RNA. Immunohistochemical staining and western blotting were used to detect the expression of zonula occluden-1 (ZO-1) and Occludin. The content of colon was harvested for high-performance liquid chromatography analysis to examine the levels of butyrate in the gut. Our research found that HIF-1α played a protective role in dextran sulphate sodium-induced colitis, which was partly due to its regulation of tight junction (TJ) protein expression. Further study revealed that HIF-1α mediated TJ proteins levels by moderating the content of butyrate. Moreover, we found that butyrate regulated TJ protein expression, which is dependent on HIF-1α. These results indicated that there is a mutual regulatory mechanism between butyrate and HIF-1α, which has an important role in the maintenance of barrier function of the gastrointestinal tract.

Poor sleep quality of third trimester exacerbates the risk of experiencing postnatal depression.

This study sought to investigate the effects of subjectively-determined poor prenatal sleep quality on postnatal depression (PND), after adjusting for prenatal psychological distress and perceived stress. From March 2016 to December 2017, we conducted a prospective longitudinal study using a convenience sample of 228 perinatal women. The participants completed the Pittsburgh Sleep Quality Index (PSQI), the 10-item Kessler Psychological Distress Scale (K10) and the Perceived Stress Scale (PSS) during the third trimester (Time 1 or T1), and completed the Edinburgh Postnatal Depression Scale (EPDS) at 1 months postpartum (Time 2 or T2). Logistic regression analyses were used to analyze the associations between subjective prenatal sleep quality and postnatal depression. The results showed that prenatal psychological distress (OR = 2.551, 95% CI = 1.221 ~ 5.329, P = 0.013) and perceived stress (OR = 2.881, 95% CI = 1.398 ~ 5.938, P= 0.007) were the strongest predictors of PND. Independent of this, poor subjective sleep quality (OR = 2.391, 95% CI = 1.072 ~ 5.556, P = 0.044) during pregnancy also predicted postnatal depressive symptoms. Treatment of psychological distress and perceived stress appears important for reducing the incidence of PND. Nonetheless, future studies might explore treatments to improve prenatal sleep quality.

Berberine induces apoptosis in non-small-cell lung cancer cells by upregulating miR-19a targeting tissue factor.

BACKGROUND: Berberine (BBR) from the widely used Chinese herbal medicine Huanglian has an array of pharmacological and biochemical properties, including anti-neoplastic activity. However, the specific mechanisms underlying these properties are unknown. The aim of this study was to explore the anti-tumor mechanisms of BBR in non-small cell lung cancer (NSCLC). METHODS: The effects of BBR on NSCLC tumor development and programmed cell death were investigated both in vivo and in vitro. Luciferase reporter assays were used to determine whether tissue factor (TF) was a target of miR-19a. RESULTS: BBR suppressed NSCLC growth and promoted apoptosis in NSCLC cells by modulating miR-19a and TF expression. Luciferase assays showed that TF was a direct inhibitory target of miR-19a in NSCLC cells. BBR induced apoptosis through the miR-19a/TF/MAPK axis. CONCLUSION: The results suggest that BBR induces apoptosis of NSCLC cells via the miR-19a/TF/MAPK signaling pathway.

Conjugative Transfer of the pVA1-Type Plasmid Carrying the pirABvp Genes Results in the Formation of New AHPND-Causing Vibrio.

Acute hepatopancreatic necrosis disease (AHPND) has caused sharp declines in aquaculture industries of whiteleg shrimp Penaeus vannamei in Asia and the Americas since 2010. Vibrio parahaemolyticus, V. campbellii, V. owensii, and V. punensis have been proved to cause AHPND. However, the mechanisms underlying the burgeoning number of Vibrio species that cause AHPND is not known. All of AHPND-causing Vibrio bacteria (VAHPND) harbor a highly homologous plasmid (designated as pVA1-type) carrying pirABvp toxin genes. In this study, we demonstrate conclusively that the pVA1-type plasmid can be transferred from VAHPND to non-pathogenic bacteria. We constructed a pVPGX1-Cmr plasmid (a pVA1-type plasmid) by adding a chloramphenicol resistance gene as a marker in a donor AHPND-causing V. parahaemolyticus 20130629002S01 (Vp2S01). Horizontal transfer of this plasmid was successfully performed from the AHPND-Vp2S01 to a non-pathogenic strain of V. campbellii at the transfer efficiency of 2.6×10-8 transconjugant/recipient, and DNase I treatment did not eliminate the transfer. The recipient V. campbellii acquired the pVA1-type plasmid and was shown to produce pirABvp RNA and proteins. Challenge studies using the transconjugant caused 100% mortality in exposed groups of P. vannamei. The challenged shrimp, infected with the transconjugant bacteria, showed typical gross signs and histological lesions of AHPND. These results demonstrated the conjugative transfer of an AHPND pVA1-type plasmid. It provides timely information for explaining the increased species of AHPND-causing Vibrio bacteria and will be useful in the development of management strategies leading to the prevention and control of AHPND.

Immunomodulatory effects of intestinal lung axis microecology and other factors on the prognosis of advanced non-small cell lung cancer.

Overall survival (OS) of lung cancer varies greatly with individual patients in the global setting. Multiple factors may affect the prognosis. Different antibiotics have significant effects on the prognosis of lung cancer patients. The intestinal microbiome, nutritional status and inflammatory factors all have significant impact on OS of lung cancer patients.

Safety Strategies of Genetically Engineered T Cells in Cancer Immunotherapy.

T-cell therapy using genetically engineered T cells modified with either T cell receptor or chimeric antigen receptor holds great promise for cancer immunotherapy. The concerns about its toxicities still remain despite recent successes in clinical trials. Temporal and spatial control of the engineered therapeutic T cells may improve the safety profile of these treatment regimens. To achieve these goals, numerous approaches have been tested and utilized including the incorporation of a suicide gene, the switch-mediated activation, the combinatorial antigen recognition, etc. This review will summarize the toxicities caused by engineered T cells and novel strategies to overcome them.