Triptonide induces apoptosis and inhibits the proliferation of ovarian cancer cells by activating the p38/p53 pathway and autophagy.

Ovarian cancer is a common malignant tumor in women, and 70 % of ovarian cancer patients are diagnosed at an advanced stage. Drug chemotherapy is an important method for treating ovarian cancer, but recurrence and chemotherapy resistance often lead to treatment failure. In this study, we screened 10 extracts of Tripterygium wilfordii, a traditional Chinese herb, and found that triptonide had potent anti-ovarian cancer activity and an IC50 of only 3.803 nM against A2780 cell lines. In addition, we determined that triptonide had a better antitumor effect on A2780 cell lines than platinum chemotherapeutic agents in vitro and that triptonide had no significant side effects in vivo. We found that triptonide induced apoptosis in ovarian cancer cells through activation of the p38/p53 pathway and it also induced cell cycle arrest at the S phase. In addition, we demonstrated that triptonide could activate lethal autophagy, which led to growth inhibition and cell death in ovarian cancer cells, resulting in an anti-ovarian cancer effect. Triptonide exerts its anti-ovarian cancer effect through activation of the p38/p53 pathway and induction of autophagy to promote apoptosis, which provides a new candidate drug and strategy for the treatment of ovarian cancer.

Novel phenanthrene/bibenzyl trimers from the tubers of Bletilla striata attenuate neuroinflammation via inhibition of NF-κB signaling pathway.

Five novel (9,10-dihydro) phenanthrene and bibenzyl trimers, as well as two previously identified biphenanthrenes and bibenzyls, were isolated from the tubers of Bletilla striata. Their structures were elucidated through comprehensive analyses of NMR and HRESIMS spectroscopic data. The absolute configurations of these compounds were determined by calculating rotational energy barriers and comparison of experimental and calculated ECD curves. Compounds 5b and 6 exhibited inhibitory effects on LPS-induced NO production in BV-2 cells, with IC50 values of 12.59 ± 0.40 and 15.59 ± 0.83 µmol·L-1, respectively. A mechanistic study suggested that these compounds may attenuate neuroinflammation by reducing the activation of the AKT/IκB/NF-κB signaling pathway. Additionally, compounds 3a, 6, and 7 demonstrated significant PTP1B inhibitory activities, with IC50 values of 1.52 ± 0.34, 1.39 ± 0.11, and 1.78 ± 0.01 µmol·L-1, respectively. Further investigation revealed that compound 3a might inhibit LPS-induced PTP1B overexpression and NF-κB activation, thereby mitigating the neuroinflammatory response in BV-2 cells.

The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood-Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms.

BACKGROUND: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. METHODS: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood-brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. RESULTS: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H+/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. CONCLUSIONS: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood-brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood-brain barrier metabolism and transport of active glucuronide conjugates.

Symptom clusters and nutritional status in primary liver cancer patients receiving TACE.

INTRODUCTION: symptom clusters (SCs) are highly prevalent among patients diagnosed with primary liver cancer. Malnutrition poses a heightened risk for a more pronounced total symptom cluster score. OBJECTIVE: this study aimed to identify SCs and assess the nutritional status of patients undergoing transcatheter arterial chemoembolization (TACE). Furthermore, it aimed to investigate the association between nutritional status and symptom clusters. METHODS: primary liver cancer patients who were scheduled to receive TACE were recruited. Symptoms data were collected using the MD Anderson Symptom Inventory (MDASI-C) and the Symptom Module specific to Primary Cancer (TSM-PLC). Nutritional assessment relied on the Nutritional Risk Screening-2002 (NRS-2002) and blood biochemistry. The SCs were extracted using exploratory factor analysis, while the relationship between SCs and nutritional status was evaluated using Spearman correlation analysis. RESULTS: the study included 226 patients, four distinct symptom clusters emerged: emotional-psychological symptom cluster, upper gastrointestinal symptom cluster, post-embolization-related symptom cluster, and liver function impairment symptom cluster. 68.14 % of patients were found to be at high risk of malnutrition. Our study revealed significant differences in Scs scores between patients at risk of malnutrition and those without such risk (p < 0.050). Notably, we observed a positive correlation between NRS-2002 scores and the scores of all symptom clusters (r = 0.205 to 0.419, p < 0.001), while a negative correlation was observed between prealbumin levels and the scores of all symptom clusters (r = -0.183 to -0.454, p < 0.001). CONCLUSION: the study highlights the high risk of malnutrition among liver cancer patients receiving TACE and the positive correlation between high malnutrition risk and Scs scores.

A systematic two-sample and bidirectional MR process highlights a unidirectional genetic causal effect of allergic diseases on COVID-19 infection/severity.

BACKGROUND: Allergic diseases (ADs) such as asthma are presumed risk factors for COVID-19 infection. However, recent observational studies suggest that the assumed correlation contradicts each other. We therefore systematically investigated the genetic causal correlations between various ADs and COVID-19 infection/severity. METHODS: We performed a two-sample, bidirectional Mendelian randomization (MR) study for five types of ADs and the latest round of COVID-19 GWAS meta-analysis datasets (critically ill, hospitalized, and infection cases). We also further validated the significant causal correlations and elucidated the potential underlying molecular mechanisms. RESULTS: With the most suitable MR method, asthma consistently demonstrated causal protective effects on critically ill and hospitalized COVID-19 cases (OR < 0.93, p < 2.01 × 10-2), which were further confirmed by another validated GWAS dataset (OR < 0.92, p < 4.22 × 10-3). In addition, our MR analyses also observed significant causal correlations of food allergies such as shrimp allergy with the risk of COVID-19 infection/severity. However, we did not find any significant causal effect of COVID-19 phenotypes on the risk of ADs. Regarding the underlying molecular mechanisms, not only multiple immune-related cells such as CD4+ T, CD8+ T and the ratio of CD4+/CD8+ T cells showed significant causal effects on COVID-19 phenotypes and various ADs, the hematology traits including monocytes were also significantly correlated with them. Conversely, various ADs such as asthma and shrimp allergy may be causally correlated with COVID-19 infection/severity by affecting multiple hematological traits and immune-related cells. CONCLUSIONS: Our systematic and bidirectional MR analyses suggest a unidirectional causal effect of various ADs, particularly of asthma on COVID-19 infection/severity, but the reverse is not true. The potential underlying molecular mechanisms of the causal effects call for more attention to clinical monitoring of hematological cells/traits and may be beneficial in developing effective therapeutic strategies for allergic patients following infection with COVID-19.

Dihydrophenanthro[b]furan derivatives from the tubers of Bletilla striata.

Two pairs of new dihydrophenanthro[b]furan enantiomers blephebibnols G-H (1-2), one new dihydrophenanthro[b]furan derivative blephebibnol I (3), along with four known analogues (4-7), were isolated from the tubers of Bletilla striata. Their structures including the absolute configurations were determined by the combination of spectroscopic data analysis, ECD and NMR calculations. Compounds 1a, 1b, and 2b showed inhibition of NO production in LPS-stimulated BV-2 cells, with IC50 values ranging from 4.11 to 14.65 µM. Further mechanistic study revealed that 1a suppressed the phosphorylation of p65 subunit to regulate the NF-κB signaling pathway. In addition, some compounds displayed selective cytotoxic activities against HCT-116, HepG2, A549, or HGC27 cancer cell lines with IC50 values ranging from 0.1 to 8.23 µM.

Lactobacillus paracasei R3 Alleviates Tumor Progression in Mice with Colorectal Cancer.

Lactobacillus paracasei (L. paracasei), a common probiotic lactobacillus, has important functions in the food industry and human health. However, different strains of L. paracasei inevitably show differences in activity and colonization resistance, leading to differentiation in their functions, as well as their physical or chemical properties. The purpose of this study was to evaluate the characteristics of L. paracasei R3 (L.p R3) isolated from healthy human feces and determine whether the criteria for edible probiotics is met. The hemolysis type, biofilm-forming ability, antibiotic susceptibility, toxicity, and effective activity of L.p R3 were determined by establishing its probiotic activity traits in vitro and in vivo. The results showed that L.p R3 had a moderate biofilm formation ability, was sensitive to 11 antibiotics, was resistant to eight antibiotics, and was not hemolytic. The culture characteristics, morphology, and biochemical responses of the strain were consistent with the seed batch characteristics. In toxicity assays, L.p R3-fed mice showed no abnormalities in body weight, growth, or various organs. Additionally, L.p R3 was found to be effective in the prevention and treatment of colorectal cancer. In conclusion, our results revealed that L.p R3 has potential value as an edible probiotic without toxic side effects and alleviated the tumor progression of colorectal cancer in mice.

Klebsiella michiganensis: a nitrogen-fixing endohyphal bacterium from Ustilago maydis.

Ustilago maydis is a pathogenic fungus in Basidiomycota causing corn smut disease. A strain of U. maydis YZZF202006 was isolated from the tumor of corn smut collected from Jingzhou city in China. The intracellular bacteria were confirmed inner hyphal of the strain YZZF202006 by PCR amplification and fluorescence in situ hybridization (FISH) and SYTO-9. An endohyphal bacterium YZUMF202001 was isolated from the protoplasts of the strain YZZF202006. It was gram-negative, short rod-shaped with smooth light yellow colony. The endohyphal bacterium was genomic evidenced as Klebsiella michiganensis on the basis of average nucleotide identity (ANI) analysis and the phylogram. Then K. michiganensis was GFP-Labeled and reintroduced into U. maydis, which confirmed the bacterium can live in hyphae of U.maydis. The bacterium can grow on N-free culture media. Its nitrogenase activity was reached av. 646.25 ± 38.61 nmol·mL- 1·h- 1 C2H4 by acetylene reduction assay. A cluster of nitrogen fixation genes (nifJHDKTXENXUSVWZMFLABQ) was found from its genome. The endohyphal K. michiganensis may play an important role to help nitrogen fixation for fungi in the future.

Association between nutritional status and platelet-to-lymphocyte ratio in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization / Asociación entre el estado nutricional y el índice plaquetas-linfocitos en pacientes con carcinoma hepatocelular sometidos a quimioembolización transarterial

Introduction: nutritional status and platelet-to-lymphocyte ratio (PLR) have been found to be associated with prognosis in patients with hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE).Objectives: to evaluate the association between nutritional status and PLR in patients with HCC undergoing TACE. Methods: a total of 152 HCC patients received TACE were enrolled. The nutritional status was evaluated by Patient-Generated Subjective Global Assessment (PG-SGA). Patients with PG-SGA A and PG-SGA (B or C) were classified as the well-nourished and malnourished groups. Results: according to the PG-SGA, 130 (85.5 %) patients were malnourished. The median PLR was significantly different between well-nourishedand malnourished groups (p = 0.008). A positive correlation was found between PLR and PG-SGA score (r = -0.265, p = 0.001). The optimalPLR cutoff value was 102.165 to predict malnutrition, with a sensitivity of 65.4 %, specificity of 72.7 %, and an area under the curve (AUC) of0.677 (95 % confidence interval (CI): 0.550-0.804; p = 0.008). A logistic stepwise regression model showed that the PLR was associated withnutritional status in Model 1 without adjustment, as well as if adjusted by age, sex, type of TACE (c-TACE/DEB-TACE) and Child–Pugh stage (oddsratio, 0.190; 95 % CI: 0.062-0.582; p=0.004). Conclusions: nutritional status measured by PG-SGA was significantly associated with PLR in patients with HCC undergoing TACE. (AU)

Introducción: se ha encontrado que el estado nutricional y el índice plaquetas-linfocitos (PLR) se asocian con el pronóstico en pacientes con carcinoma hepatocelular (CHC) sometidos a quimioembolización transarterial (TACE).Objetivos: evaluar la asociación entre el estado nutricional y la PLR en pacientes con CHC sometidos a TACE. Métodos: se evaluaron 152 pacientes con CHC que recibieron TACE. El estado nutricional fue evaluado por Evaluación Global Subjetiva Generada por el Paciente (PG-SGA). Los pacientes con PG-SGA A y PG-SGA (B o C) se clasificaron como los grupos bien nutridos y desnutridos. Resultados: según la PG-SGA, 130 (85,5 %) pacientes estaban desnutridos. La mediana de PLR fue significativamente diferente entre los grupos bien nutridos y desnutridos (p = 0,008). Se encontró una correlación positiva entre PLR y la puntuación PG-SGA (r = -0,265, p = 0,001). El valor de corte óptimo de PLR fue de 102,165 para predecir la malnutrición, con una sensibilidad del 65,4 %, una especificidad del 72,7 % y un área bajo la curva (AUC) de 0,677 (intervalo de confianza [IC] del 95 %: 0,550-0,804; p = 0,008). Un modelo de regresión logística escalonada mostró que el PLR se asoció con el estado nutricional en el Modelo 1 sin ajuste, así como cuando se ajustó por edad, sexo, tipo de TACE (c-TACE/DEB-TACE) y etapa Child-Pugh (odds ratio, 0,190; IC 95 %: 0,062-0,582; p = 0,004).Conclusiones: el estado nutricional medido por PG-SGA se asoció significativamente con PLR en pacientes con CHC sometidos a TACE. (AU)

Targeting ferroptosis opens new avenues for the development of novel therapeutics.

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies. Over the past decade, considerable progress has been made in developing pharmacological agonists and antagonists for the treatment of these ferroptosis-related conditions. Here, we provide a detailed overview of our current knowledge regarding ferroptosis, its pathological roles, and its regulation during disease progression. Focusing on the use of chemical tools that target ferroptosis in preclinical studies, we also summarize recent advances in targeting ferroptosis across the growing spectrum of ferroptosis-associated pathogenic conditions. Finally, we discuss new challenges and opportunities for targeting ferroptosis as a potential strategy for treating ferroptosis-related diseases.

Evaluating the potential of Bacillus licheniformis YZCUO202005 isolated from lichens in maize growth promotion and biocontrol.

Lichens exist in an organismal organization of mycobiont, photobiont, and non-photoautotrophic bacteria. These organisms contribute to the growth of lichens even in poor nutrition substrates. However, studies on the isolation and application of non-photoautotrophic bacteria in plant growth and biocontrol are scanty. Therefore, a study was conducted to isolate and evaluate the potential of non-photoautotrophic bacteria from lichen tissues in maize plant growth promotion and biocontrol of plant pathogens (fungi and bacteria). Five bacterial strains were isolated and tested for their ability to produce indole-3-Acetic Acid (IAA). One bacterium named YZCUO202005 produced IAA, siderophores and biofilms, solubilized phosphate and potassium and exhibited extracellular enzymes (cellulases, proteases, amylase, and ß -1,3-Glucanase). Based on the 16S rRNA sequence analysis results, YZCUO202005 was identified as Bacillus licheniformis. The strain inhibited the growth of five pathogenic fungi with an inhibition percent of between 58.7% and 71.7% and two pathogenic bacteria. Under greenhouse conditions, YZCUO202005 was tested for its abilities to enhance maize seed germination, and vegetative growth. Compared with the control treatment, the strain significantly enhanced the growth of stem length (i.e. 18 ± 0.64 cm, 78 ± 0.92 cm), leaf length (i.e. 10 ± 0.36 cm, 57 ± 1.42 cm), leaf chlorophyll levels (i.e., 13 ± 0.40, 40 ± 0.43 SPAD), and root length (i.e, 9.8 ± 2.25 cm, 22.5 ± 6.59 cm). Our results demonstrated that B. licheniformis YZCUO202005 from lichens has the potential to promote plant growth and reduce fungal and bacterial pathogens' growth. Furthermore, the results suggest that lichens are naturally rich sources of plant growth promotion and biocontrol agents that would be used in agriculture.

T1 relaxation time analysis in predicting hepatic dysfunction and prognosis in patients with HCC undergoing transarterial chemoembolization.

OBJECTIVE: To evaluate the value of T1 mapping in predicting hepatic dysfunction and prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). MATERIAL AND METHODS: 100 consecutive patients with treatment-naive HCC treated with TACE were prospectively analyzed. Clinical, laboratory, and MRI parameters (liver and tumor T1 relaxation times (T1L, T1T)) before and/or following TACE were measured and calculated. Clinical parameters included the Child-Turcotte-Pugh (CTP) classification, Barcelona Clinic Liver Cancer Classification (BCLC) criteria, and albumin-bilirubin (ALBI) score. Laboratory parameters were the gold standard for hepatic dysfunction. T1L and T1T were combined by stepwise multivariate logistic regression to yield a T1-related probability index (T1com) for further analysis. Study endpoints included hepatic dysfunction and progression-free survival (PFS) rate. RESULTS: 38 patients (38%) were diagnosed with hepatic dysfunction following TACE. There was no significant difference in clinical parameters between the groups with and without hepatic dysfunction. Logistic regression analysis showed that T1L and T1T were independent risk factors for assessing hepatic dysfunction. T1com showed a better AUC than T1L and T1T (0.81 vs. 0.76 and 0.69, P = 0.007 and 0.006). Patients with low T1com (≤0.42) showed a better median PFS than patients with high T1com (>0.42) (167.0 vs. 215.9 days, P = 0.010). In comparison, CTP, BCLC, and ALBI scores were not statistically significant in predicting PFS in HCC patients treated with TACE (P > 0.05). CONCLUSION: Compared with widely used clinical parameters, T1 was more capable of predicting hepatic dysfunction after TACE. Stratification of patients with HCC undergoing TACE according to T1 may help clinicians to develop treatment strategies in preventing the occurrence of hepatic dysfunction and improving individual prognoses.

Knockdown of UBQLN1 Functions as a Strategy to Inhibit CRC Progression through the ERK-c-Myc Pathway.

PURPOSE: Colorectal cancer (CRC) is characterized by the absence of obvious symptoms in the early stage. Due to the high rate of late diagnosis of CRC patients, the mortality rate of CRC is higher than that of other malignant tumors. Accumulating evidence has demonstrated that UBQLN1 plays an important role in many biological processes. However, the role of UBQLN1 in CRC progression is still elusive. METHODS AND RESULTS: we found that UBQLN1 was significantly highly expressed in CRC tissues compared with normal tissues. Enhanced/reduced UBQLN1 promoted/inhibited CRC cell proliferation, colony formation, epithelial-mesenchymal transition (EMT) in vitro, and knockdown of UBQLN1 inhibited CRC cells' tumorigenesis and metastasis in nude mice in vivo. Moreover, the knockdown of UBQLN1 reduced the expression of c-Myc by downregulating the ERK-MAPK pathway. Furthermore, the elevation of c-Myc in UBQLN1-deficient cells rescued proliferation caused by UBQLN1 silencing. CONCLUSIONS: Knockdown of UBQLN1 inhibits the progression of CRC through the ERK-c-Myc pathway, which provides new insights into the mechanism of CRC progression. UBQLN1 may be a potential prognostic biomarker and therapeutic target of CRC.

Association between nutritional status and platelet-to-lymphocyte ratio in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization.

Introduction: Introduction: nutritional status and platelet-to-lymphocyte ratio (PLR) have been found to be associated with prognosis in patients with hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE). Objectives: to evaluate the association between nutritional status and PLR in patients with HCC undergoing TACE. Methods: a total of 152 HCC patients received TACE were enrolled. The nutritional status was evaluated by Patient-Generated Subjective Global Assessment (PG-SGA). Patients with PG-SGA A and PG-SGA (B or C) were classified as the well-nourished and malnourished groups. Results: according to the PG-SGA, 130 (85.5 %) patients were malnourished. The median PLR was significantly different between well-nourished and malnourished groups (p = 0.008). A positive correlation was found between PLR and PG-SGA score (r = -0.265, p = 0.001). The optimal PLR cutoff value was 102.165 to predict malnutrition, with a sensitivity of 65.4 %, specificity of 72.7 %, and an area under the curve (AUC) of 0.677 (95 % confidence interval (CI): 0.550-0.804; p = 0.008). A logistic stepwise regression model showed that the PLR was associated with nutritional status in Model 1 without adjustment, as well as if adjusted by age, sex, type of TACE (c-TACE/DEB-TACE) and Child-Pugh stage (odds ratio, 0.190; 95 % CI: 0.062-0.582; p = 0.004). Conclusions: nutritional status measured by PG-SGA was significantly associated with PLR in patients with HCC undergoing TACE.

Introducción: Introducción: se ha encontrado que el estado nutricional y el índice plaquetas-linfocitos (PLR) se asocian con el pronóstico en pacientes con carcinoma hepatocelular (CHC) sometidos a quimioembolización transarterial (TACE). Objetivos: evaluar la asociación entre el estado nutricional y la PLR en pacientes con CHC sometidos a TACE. Métodos: se evaluaron 152 pacientes con CHC que recibieron TACE. El estado nutricional fue evaluado por Evaluación Global Subjetiva Generada por el Paciente (PG-SGA). Los pacientes con PG-SGA A y PG-SGA (B o C) se clasificaron como los grupos bien nutridos y desnutridos. Resultados: según la PG-SGA, 130 (85,5 %) pacientes estaban desnutridos. La mediana de PLR fue significativamente diferente entre los grupos bien nutridos y desnutridos (p = 0,008). Se encontró una correlación positiva entre PLR y la puntuación PG-SGA (r = -0,265, p = 0,001). El valor de corte óptimo de PLR fue de 102,165 para predecir la malnutrición, con una sensibilidad del 65,4 %, una especificidad del 72,7 % y un área bajo la curva (AUC) de 0,677 (intervalo de confianza [IC] del 95 %: 0,550-0,804; p = 0,008). Un modelo de regresión logística escalonada mostró que el PLR se asoció con el estado nutricional en el Modelo 1 sin ajuste, así como cuando se ajustó por edad, sexo, tipo de TACE (c-TACE/DEB-TACE) y etapa Child-Pugh (odds ratio, 0,190; IC 95 %: 0,062-0,582; p = 0,004). Conclusiones: el estado nutricional medido por PG-SGA se asoció significativamente con PLR en pacientes con CHC sometidos a TACE.

EM-2, a natural sesquiterpene lactone from Elephantopus mollis H.B.K., enhanced the sensitivity of breast cancer cells to epirubicin by blocking protective autophagy.

BACKGROUND: EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., showed a good anti-breast cancer effect when combined with epirubicin (EPI). However, its synergistic sensitization mechanism remains unclear. PURPOSE: This study aimed to determine the therapeutic effect and possible synergistic mechanism of EM-2 with EPI in vivo and in vitro and to provide an experimental basis for the treatment of human breast cancer. METHODS: Cell proliferation was measured with MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) levels were examined through flow cytometry, and the expression levels of proteins related to apoptosis, autophagy, endoplasmic reticulum stress, and DNA damage were detected through Western blot analysis. Moreover, the caspase inhibitor Z-VAD-FMK, autophagy inhibitors bafilomycin A1 and chloroquine, ER stress inhibitor 4-phenylbutyric acid, and ROS scavenger N-acetyl cysteine were applied to verify signaling pathways. Breast cancer cell lines were used to evaluate the antitumor functions of EM-2 and EPI in vitro and in vivo. RESULTS: We demonstrated that in MDA-MB-231 and SKBR3 cells, the IC50 of EPI combined with EM-2 (IC20) was 37.909 and 33.889 times lower than that of EPI alone, respectively. Further study verified that in EPI-resistant lines (MDA-MB-231/EPI), the IC50 of EPI combined with EM-2 (IC20) was 26.305 times lower than that of EPI alone. Mechanistically, EM-2 could reverse the protective effect of EPI against autophagy in SKBR3 and MDA-MB-231 cells. EM-2 and EPI could trigger ER stress. When EM-2 and EPI were used in combination, ER stress was continuously activated, and ER stress-mediated apoptosis was induced. Meanwhile, EM-2 combined with EPI promoted DNA damage then induced apoptosis. In vivo, the volume of breast cancer xenografts in the combination group was smaller than that in the control, EM-2, and EPI groups. Immunohistochemical experiments demonstrated that the combination of EM-2 and EPI could block autophagy and promote ER stress in vivo. CONCLUSION: EM-2 enhances the sensitivity of MDA-MB-231, SKBR3, and EPI-resistant cells to EPI.

Living ring-opening polymerization of ß-butyrolactone initiated by mononuclear zirconium compounds containing sterically hindered N,O-chelate and anionic dimethylamide ligands.

The ring-opening polymerization of ß-lactones into polyhydroxyalkanoates (PHA), biodegradable polymers with high molecular weight and narrow polydispersity, is of significant interest. The mononuclear zirconium compound containing sterically hindered N,O-chelate and anionic dimethylamide ligands was used as an initiator for the polymerization of ß-butyrolactone (BBL), resulting in polyhydroxylbutyrate (PHB) with a number-average molecular weight of 12 000 g mol-1. Kinetic studies demonstrate a first-order dependence on ß-butyrolactone (BBL) concentration at room temperature, accompanied by narrow molecular weight distributions (ca. 1.03-1.07), indicating a well-controlled living polymerization.

Sq-2, a biotinylated annonaceous acetogenin, induces apoptosis, autophagy and S-phase arrest by activating the MAPK pathway in breast cancer cells.

Squamocin, an annonaceous acetogenin isolated from plants in the Annonaceae family, has antitumour activity. In this study, we report that Sq-2, a biotinylated squamocin monomer, has a favorable antitumour effect on MDA-MB-231 and SKBR3 breast cancer cells in vitro. MTT assays show that Sq-2 has a better antitumour effect on MDA-MB-231 cells than Sq-5 and Sq-6. Furthermore, RNA-Seq and KEGG enrichment analyses reveal that Sq-2 activates the MAPK signaling pathway, and results of western blot analysis demonstrate that Sq-2 activates the JNK and p38 pathways in MDA-MB-231 and SKBR3 cells. Flow cytometry and western blot analysis reveal that Sq-2 induces cell apoptosis by increasing the expressions of cleaved Caspase-3 and cleaved PARP as well as the ratio of Bax/Bcl-2. Inhibition of the Caspase family by Z-VAD-FMK attenuates the viability of MDA-MB-231 cells, indicating that Sq-2 induces apoptosis in a Caspase-dependent manner. Additionally, pretreatment with the p38 inhibitor SB203580 or JNK inhibitor SP600125 partially reverses the increase in the apoptosis rate and decrease in cell viability prompted by Sq-2. Furthermore, Sq-2 treatment decreases the expression level of CyclinD1 and increases the expression levels of p21, p27, CyclinA1, and CDK2, causing S-phase arrest in MDA-MB-231 and SKBR3 cells. Further study indicates that Sq-2 stimulates autophagy in MDA-MB-231 and SKBR3 cells, and inhibition of autophagy by bafilomycin A1 increases cell viability and promotes cell survival. Sq-2, a novel biotin-squamocin compound, shows a significant inhibitory effect on the propagation of SKBR3 and MDA-MB-231 breast cancer cells. Furthermore, Sq-2 treatment not only induces S-phase arrest and activates the JNK and p38 pathways to trigger apoptosis but also causes autophagy to promote apoptosis in MDA-MB-231 and SKBR3 cells.

Do chromosomal inversion carriers really need preimplantation genetic testing?

PURPOSE: This study aimed to evaluate the rates of euploidy, aneuploidy, and mosaicism in preimplantation genetic testing for structural rearrangements (PGT-SR) cycles from chromosomal inversion carriers. In addition, this work also focused on assessing the impact of some contributors on the incidence of parental originating aneuploidy and mosaicism. METHODS: This retrospective review enrolled chromosomal inversion carrier couples of whom the females were under 38 years old undergoing PGT-SR at a single academic reproductive center. Subgroups were divided according to the gender of carriers, the inversion type, and the semen parameters of male carriers (male factor infertility (MF) or non-MF). Patient demographics, cycle characteristics, and PGT-SR outcomes were compared among subgroups. RESULTS: A total of 71 PGT-SR cycles from 57 inversion carrier couples were included for analysis. Among the 283 blastocysts, 48.4% were identified as euploidy, 27.9% as aneuploidy, and the remaining 23.7% as mosaicism. Only 32.9% of aneuploid embryos and 1.5% of mosaic embryos involved the parental inversion chromosomes. Notably, the female inversion carriers seemed to produce more parental originating aneuploid embryos than male inversion carriers (45.5% vs 23.9%, p = 0.044). CONCLUSIONS: The type of inversion and sperm parameters of male chromosomal inversion carriers did not affect the ploidy status of embryos. The incidence of parental originating aneuploidy in inversion carrier couples is lower than expected. For male chromosomal inversion carriers with normal sperm condition whose female partners are under 38 years old, natural conception combined with prenatal diagnosis could be provided as an option during fertility counseling.