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As a kind of tonic Chinese medicine with dual use in medicine and food, there is a large market demanding for Codonopsis pilosula. Taking one-year-old C. pilosula seedlings as materials, we conducted a field experiment to examine the effect of compound fertilizer (750 kg·hm-2), organic fertilizer (15 t·hm-2) and Streptomyces pactum Act12 agent (9 t·hm-2 Act12+10 t·hm-2 organic fertilizer) treatments on root morphology, secondary metabolite content and expression level of lobetyolin metabolic pathway gene of C. pilosula, to clarify the effects of three fertilizers on the root morphology and medicinal quality. Compared to the control (10 t·hm-2 organic fertilizer, conventional fertilization), three fertilization treatments could promote root growth and formation. All fertilization treatments promoted the accumulation of C. pilosula polysaccharides and secondary metabolites. Act12 agent significantly increased the content of lobetyolin, atractylenolideIII, and 5-hydroxymethylfurfural. The qRT-PCR analysis indicated that three fertilization treatments increased the expression level of lobetyolin metabolic pathway genes, with Act12 agent treatment showing the most significant effect. Pearson correlation analysis demonstrated that the expression level of CpHCT and CpFAD genes was significantly positively correlated with atractylenolide III content. In conclusion, three fertilization treatments could effectively improve the yield and quality of C. pilosula. Among the three treatments, Act12 agent performed better than that of compound fertilizer and organic fertilizer, which was an effective measure to increase the yield and quality of C. pilosula.

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Codonopsis , Fertilizantes , Raíces de Plantas , Streptomyces , Codonopsis/crecimiento & desarrollo , Codonopsis/metabolismo , Streptomyces/crecimiento & desarrollo , Streptomyces/metabolismo , Streptomyces/genética , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Plantas Medicinales/crecimiento & desarrollo , Plantas Medicinales/metabolismo , Plantas Medicinales/química

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Emotional disorders inflict an enormous burden on society. Research on brain abnormalities implicated in emotional disorders has witnessed great progress over the past decades. Using cross-sectional and longitudinal designs, resting state functional magnetic resonance imaging (rs-fMRI) and its analytic approaches have been applied to characterize the local properties of patients with emotional disorders. Additionally, brain activity alterations of emotional disorders have shown frequency-specific. Despite the gains in understanding the roles of brain abnormalities in emotional disorders, the limitation of the small sample size needs to be highlighted. Lastly, we proposed that evidence from the positive psychology research stream presents it as a viable discipline, whose suggestions could be developed in future emotional disorders research. Such interdisciplinary research may produce novel treatments and intervention options. This article is categorized under: Psychology > Brain Function and Dysfunction.

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INTRODUCTION: Colorectal cancer (CRC) is experiencing a significant increase in both incidence and mortality rates globally. The expression of Selenium-binding protein 1 (SELENBP1) has been reported to be notably downregulated in various malignancies, yet its biological functions and cellular mechanisms in CRC remain incompletely understood. METHOD: In our investigation, we observed the downregulation of SELENBP1 in CRC tissues through quantitative real-time PCR and western blotting and identified a positive correlation between higher SELENBP1 expression and improved survival prognosis using Kaplan-Meier survival analysis. Through loss-of-function and gain-of-function studies, we demonstrated the tumor-suppressive roles of SELENBP1 in CRC, supported by results from both in vitro and in vivo experiments. Furthermore, we uncovered the pivotal functions of SELENBP1 in suppressing aerobic glycolysis in CRC cells by regulating glucose uptake, lactate generation, and extracellular acidification rate. RESULT: At a mechanistic level, we found that SELENBP1 inhibits the expression of the key glycolytic modulator hypoxia-inducible factor 1 subunit alpha (HIF1α), and the inhibition of glycolysis by SELENBP1 can be reversed by ectopic expression of HIF1α. Therefore, our study highlights the potential of SELENBP1 as a promising target for CRC therapy, given its significant impact on tumor suppression and reprogrammed glucose metabolism. CONCLUSION: These findings contribute to a deeper understanding of the molecular mechanisms underlying CRC progression and may pave the way for the development of targeted therapies for this challenging disease.

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Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.

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PURPOSE: In clinical practice, the success of preimplantation genetic testing for monogenic diseases (PGT-M) for thalassemia was hindered by the absence of probands, incomplete family members, or failure in detecting embryonic gene mutation sites. This study aimed to address these issues. METHODS: This retrospective study included 342 couples undergoing PGT-M for α- or ß-thalassemia at three reproductive medicine centers from 2019 to 2022. Various methods were used to construct parental haplotypes. A total of 1778 embryos were analyzed and selected for transfer based on chromosomal ploidy and PGT-M results. Follow-up involved amniocentesis results and clinical outcomes. RESULTS: Haplotypes were established using DNA samples from probands or parents, as well as sibling blood samples, single sperm, and affected embryos, achieving an overall success rate was 99.4% (340/342). For α-thalassemia and ß-thalassemia, the concordance between embryo single nucleotide polymorphism (SNP) haplotype analysis results and mutation loci detection results was 93.8% (1011/1078) and 98.2% (538/548), respectively. Multiple annealing and looping-based amplification cycles (MALBAC) showed a higher whole genome amplification success rate than multiple displacement amplification (MDA) (98.8% (1031/1044) vs. 96.2% (703/731), p < 0.001). Amniocentesis confirmed PGT-M outcomes in 100% of cases followed up (99/99). CONCLUSION: This study summarizes feasible solutions to various challenging scenarios encountered in PGT-M for thalassemia, providing valuable insights to enhance success rate of PGT-M in clinical practice.

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OBJECTIVE: This study aimed to establish a uniform standard for the interpretation of HER2 gene and protein statuses in intrahepatic cholangiocarcinoma (ICC). We also intended to explore the clinical pathological characteristics, molecular features, RNA expression and immune microenvironment of HER2-positive ICC. METHODS: We analyzed a cohort of 304 ICCs using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to identify HER2 status. Comprehensive analyses of the clinicopathological, molecular genetic, and RNA expression characterizations of ICCs with varying HER2 statuses were performed using next-generation sequencing. We further investigated the tumor microenvironment of ICCs with different HER2 statuses using IHC and multiplex immunofluorescence staining. RESULTS: HER2/CEP17 ratio of ≥ 2.0 and HER2 copy number ≥ 4.0; or HER2 copy number ≥ 6.0 were setup as FISH positive criteria. Based on this criterion, 13 (4.27%, 13/304) samples were classified as having HER2 amplification. The agreement between FISH and IHC results in ICC was poor. HER2-amplified cases demonstrated a higher tumor mutational burden compared to non-amplified cases. No significant differences were observed in immune markers between the two groups. However, an increased density of CD8 + CTLA4 + and CD8 + FOXP3 + cells was identified in HER2 gene-amplified cases. CONCLUSION: FISH proves to be more appropriate as the gold standard for HER2 evaluation in ICC. HER2 gene-amplified ICCs exhibit poorer prognosis, higher mutational burden, and T cell exhaustion and immune suppressed microenvironment.

Asunto(s)

Neoplasias de los Conductos Biliares , Colangiocarcinoma , Amplificación de Genes , Mutación , Receptor ErbB-2 , Microambiente Tumoral , Humanos , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Colangiocarcinoma/inmunología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/inmunología , Femenino , Receptor ErbB-2/genética , Persona de Mediana Edad , Masculino , Anciano , Hibridación Fluorescente in Situ , Adulto , Biomarcadores de Tumor/genética , Linfocitos T/inmunología , Linfocitos T/patología , Pronóstico , Agotamiento de Células T

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Concise and scalable formal syntheses of (-)-quinocarcinamide and (-)-quinocarcin have been achieved in 9 steps with 9% overall yield from simple commercially available chemicals. The synthetic strategy features an ortho-regioselective Pictet-Spengler cyclization for the construction of the tetrahydroisoquinoline skeleton, a stereoselective formal intramolecular [3 + 2] cross cycloaddition of cyclopropane 1,1-diester with an imine for the construction of the 3,8-diazabicyclo[3.2.1]octane skeleton.

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Sugar is vital for plant growth and determines fruit quality via its content and composition. This study explores the differential sugar accumulation in two plum varieties, 'Fengtangli (FTL)' and 'Siyueli (SYL)'. The result showed that 'FTL' fruit displayed higher soluble solids and sugar content at various development stages. Metabolomic analysis indicated increased sorbitol in 'FTL', linked to elevated sorbitol-6-phosphate-dehydrogenase (S6PDH) activity. Transcriptome analysis identified a key gene for sorbitol synthesis, PsS6PDH4, which was significantly higher expressed in 'FTL' than in 'SYL'. The function of the PsS6PDH4 gene was verified in strawberry, apple, and plum fruits using transient overexpression and virus-induced gene silencing techniques. The results showed that overexpression of the PsS6PDH4 gene in strawberry, apple, and plum fruits promoted the accumulation of soluble solids content and sorbitol, while inhibition of the gene reduced soluble solids content and sorbitol content. Meanwhile, analysis of the relationship between PsS6PDH4 gene expression, sorbitol, and soluble solids content in four different plum varieties revealed a significant correlation between PsS6PDH4 gene expression and soluble solids content as well as sorbitol content. This research discovered PsS6PDH4 as a crucial regulator of sugar metabolism in plum, with potential applications in improving fruit sweetness and nutritional value in various fruit species. Understanding these molecular pathways can lead to innovative approaches for enhancing fruit quality, benefiting sustainable agriculture and consumer preferences in the global fruit industry.

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Frutas , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas , Prunus domestica , Sorbitol , Sorbitol/metabolismo , Prunus domestica/genética , Prunus domestica/metabolismo , Frutas/genética , Frutas/metabolismo , Frutas/crecimiento & desarrollo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Fragaria/genética , Fragaria/metabolismo , Azúcares/metabolismo , Malus/genética , Malus/metabolismo

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The optimization of hydrogel structure is crucial for adsorption capacity, mechanical stability, and reusability. Herein, a chitosan and laponite-XLS co-doped poly(acrylic acid-co-acrylamide) hydrogel (CXAA) with honeycomb-like porous structures is synthesized by cooperative cross-linking of 2-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) and laponite-XLS in reticular frameworks of acrylic acid (AAc) and acrylamide (AM). The CXAA exhibits extraordinary mechanical performances including tough tensile strength (3.36 MPa) and elasticity (2756 %), which facilitates recycling in practical adsorption treatment and broadens potential applications. Since the regular porous structures can fully expose numerous adsorption sites and electronegative natures within polymer materials, CXAA displays efficient and selective adsorption properties for cationic dyes like methylene blue (MB) and malachite green (MG) from mixed pollutants and can reach record-high values (MB = 6886 mg g-1, MG = 11,381 mg g-1) compared with previously reported adsorbents. Therefore, CXAA exhibits promising potential for separating cationic and anionic dyes by their charge disparities. Mechanism studies show that the synergistic effects of HACC, laponite-XLS, and functional groups in monomers promote highly efficient adsorption. Besides, the adsorption capacity of CXAA remains stable even after undergoing five cycles of regeneration. The results confirm that CXAA is a promising adsorbent for effectively removing organic dyes in wastewater.

Asunto(s)

Cationes , Colorantes , Hidrogeles , Hidrogeles/química , Adsorción , Colorantes/química , Colorantes/aislamiento & purificación , Porosidad , Cationes/química , Quitosano/química , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/aislamiento & purificación , Azul de Metileno/química , Silicatos/química , Fenómenos Mecánicos , Purificación del Agua/métodos , Acrilamida/química , Colorantes de Rosanilina

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Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca2+ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca2+ governing components Na+-Ca2+ exchanger, phosphorylation of SERCA2a, mTOR (Ser2481) and ULK1 (Ser757), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser555), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.

Asunto(s)

Proteína Quinasa CDC2 , Restricción Calórica , Mitofagia , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-akt , Animales , Masculino , Ratones , Autofagia/fisiología , Proteína Quinasa CDC2/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Remodelación Ventricular/fisiología

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Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Proteínas de la Membrana , Miocarditis , Nucleotidiltransferasas , Piroptosis , Animales , Miocarditis/inmunología , Miocarditis/patología , Miocarditis/inducido químicamente , Miocarditis/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Ratones , Masculino , Humanos , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Transducción de Señal , Ratones Endogámicos C57BL , Ratones Noqueados , ADN Mitocondrial/metabolismo , ADN Mitocondrial/genética , Femenino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Gasderminas

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Laparoscopic total mesorectal excision is the main surgical approach for treating rectal cancer, but there is still no clear consensus on the issue of low ligation of the inferior mesenteric artery during the procedure. Robotic surgery has been shown to have certain advantages over laparoscopic surgery in multiple studies, but further research is needed to better understand the outcomes of robotic surgery in the context of low ligation procedures. In this study, we included 1590 patients with mid-low rectal cancer. Among them, 942 patients underwent low ligation surgery (LL), divided into 138 in the robotic group and 804 in the laparoscopic group. The high ligation surgery (HL) group consisted of 648 patients. The results of LL vs HL showed that the LL group had faster bowel movement recovery (P = 0.003), lower anastomotic leak rate (P = 0.032), and lower International Prostate Symptom Score (IPSS) at 6 months postoperatively (P < 0.001). The results of Rob-LL vs Lap-LL showed that the Rob-LL group had longer operative time (P < 0.001), less blood loss (P = 0.001), more lymph nodes retrieved (P = 0.045), and lower Wexner score at 2 weeks postoperatively (P = 0.029). The concept of low ligation of the inferior mesenteric artery is a promising surgical approach that can accelerate the patient's functional recovery. When combined with robotic technology, it may offer more benefits than laparoscopic techniques.

Asunto(s)

Laparoscopía , Arteria Mesentérica Inferior , Neoplasias del Recto , Procedimientos Quirúrgicos Robotizados , Humanos , Arteria Mesentérica Inferior/cirugía , Neoplasias del Recto/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Ligadura/métodos , Masculino , Femenino , Laparoscopía/métodos , Persona de Mediana Edad , Tempo Operativo , Anciano , Resultado del Tratamiento , Fuga Anastomótica/prevención & control , Fuga Anastomótica/etiología , Pérdida de Sangre Quirúrgica/estadística & datos numéricos

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Aberrant DNA methylation patterns in the promoter region of PLCG2 are associated with dysregulated signaling pathways and cellular functions. Its role in colorectal cancer cells is still unknown. In this study, qRT-PCR is used to measure DNMT3B expression in colorectal cancer. Western blot analysis and immunohistochemistry are used to analyze DNMT3B and PLCG2 protein levels in colorectal tissues and cell lines. Cell Counting Kit-8 (CCK-8) and colony formation assays are used to assess the proliferation of colorectal cancer cells. Methylation-specific PCR (MSP) and bisulfite-sequencing PCR (BSP) are used to measure DNA methylation level. Our results show that DNMT3B is overexpressed in colorectal cells in the TCGA datasets according to Kaplan-Meier plots. DNMT3B is significantly overexpressed in tumor tissues compared to that in adjacent nontumor tissues. Western blot analysis results demonstrate high expression of DNMT3B in tumor tissues. Compared to normal colonic epithelial cells, colorectal cancer cell lines exhibit elevated level of PLCG2 methylation. Overexpression of PLCG2 effectively prevents the growth of colorectal cancer xenograft tumors in vivo. PLCG2 is identified as a key downstream regulatory protein of DNMT3B in colorectal cancer. DNMT3B inhibits PLCG2 transcription through methylation of the PLCG2 promoter region. DNMT3B controls colorectal cancer cell proliferation through PLCG2, which is useful for developing therapeutic approaches that target PLCG2 expression for the treatment of colorectal cancer.

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Doxorubicin (DOX), a common chemotherapeutic agent in cancer therapy, is accompanied by pronounced cardiotoxicity. Ferroptosis has been implicated in the pathogenesis and therapeutics of DOX-induced cardiotoxicity (DIC). Asiatic acid (AA), a pentacyclic triterpene from the Chinese medicinal herb Centella asiatica, displays antioxidant, anti-inflammatory, and antiapoptotic activities. In this study, we investigated the beneficial effects of AA against DOX-induced ferroptosis and cardiotoxicity and the underlying mechanisms. A chronic DIC model was established by challenging mice with DOX (5 mg/kg, i.p.) once per week for 4 weeks. Concurrent with DOX insult, the mice were administered AA (25 mg·kg-1·d-1, i.g.). Cardiac function and mechanical properties of isolated cardiomyocytes were evaluated at the end of treatment. We showed that AA administration preserved cardiac function, significantly reduced cardiac injury, and improved cardiomyocyte contractile function in DIC mice. The beneficial effects of AA were causally linked to the inhibition of DOX-induced ferroptosis both in vivo and in vitro. We revealed that AA attenuated DOX-induced iron accumulation in HL-1 cells by increasing FPN-mediated iron export, in a Nrf2-dependent manner. AA upregulated Nrf2 expression and promoted Nrf2 nuclear translocation in DOX-treated HL-1 cells. Moreover, AA-offered benefits against DOX-induced cardiac dysfunction and ferroptosis were abolished by Nrf2 inhibitor ML385 (30 mg·kg-1·d-1, i.p.) administrated 30 min before AA in DIC mice. Our data favor that AA promotes FPN-mediated iron export to inhibit iron overload and ferroptosis in DIC, suggesting its therapeutic potential in the treatment of DIC.

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Biothiols, including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play distinct yet crucial roles in various mitochondrial physiological activities. However, due to their similar chemical structures, distinguishing and detecting Cys/Hcy/GSH poses a considerable challenge. In this study, we developed a dual-channel, mitochondrial-targeted fluorescent probe termed QX-NBD, designed specifically for discriminating Cys/Hcy from GSH. The incorporation of a quinolinium group endowed the probe with excellent mitochondrial targeting capabilities. This functionality arose from the positively charged group's ability to selectively bind to negatively charged mitochondrial membranes through electrostatic interactions. Additionally, the ether bond between 4-chloro-7-nitro-1,2,3-benzoxadiazole and the near-infrared fluorophore QX-OH rendered the probe susceptible to nucleophilic attack by biothiols. Upon the introduction of Cys/Hcy, the probe exhibited dual fluorescence emissions in red and green. Conversely, the presence of GSH resulted in only red fluorescence emission. The detection limits of the probe for Cys and Hcy at 542 nm in buffer solution were determined to be 0.044 µM and 0.042 µM, respectively. Similarly, the detection limit for all these biothiols was 0.028 µM at 678 nm. Furthermore, the response times for Cys/Hcy/GSH were recorded as 4.0 min, 5.5 min, and 9.5 min, respectively. Moreover, the probe was employed to monitor fluctuations in biothiol levels during oxidative stress in both HeLa cells and zebrafish, demonstrating its applicability and utility in biological contexts.

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Colorantes Fluorescentes , Homocisteína , Mitocondrias , Pez Cebra , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Animales , Humanos , Mitocondrias/metabolismo , Mitocondrias/química , Células HeLa , Homocisteína/análisis , Homocisteína/metabolismo , Homocisteína/análogos & derivados , Compuestos de Sulfhidrilo/análisis , Compuestos de Sulfhidrilo/química , Glutatión/análisis , Glutatión/metabolismo , Cisteína/análisis , Espectrometría de Fluorescencia/métodos , Límite de Detección , Imagen Óptica/métodos

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BACKGROUND: Although chemotherapy is effective for treating advanced gastric carcinoma (aGC), it may lead to an adverse prognosis. Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for improving efficacy and outcomes in aGC patients. AIM: To determine the efficacy and safety of cetuximab (CET) combined with the FOLFOX4 regimen (infusional fluorouracil, folinic acid, and oxaliplatin) as first-line therapy for patients with aGC, who received evidence-based care (EBC). METHODS: A total of 117 aGC patients who received EBC from March 2019 to March 2022 were enrolled. Of these, 60 in the research group (RG) received CET + FOLFOX4 as first-line therapy, whereas 57 in the control group (CG) received FOLFOX4. The efficacy [clinical response rate (RR) and disease control rate (DCR)], safety (liver and kidney dysfunction, leukopenia, thrombocytopenia, rash, and diarrhea), serum tumor marker expression [STMs; carbohydrate antigen (CA) 19-9, CA72-4, and carcinoembryonic antigen (CEA)], inflammatory indicators [interleukin (IL)-2 and IL-10], and quality of life (QOL) of the two groups were compared. RESULTS: A markedly higher RR and DCR were observed in the RG compared with the CG, with an equivalent safety profile between the two groups. RG exhibited notably reduced CA19-9, CA72-4, CEA, and IL-2 levels following treatment, which were lower than the pre-treatment levels and those in the CG. Post-treatment IL-10 was statistically increased in RG, higher than the pre-treatment level and the CG. Moreover, a significantly improved QOL was evident in the RG. CONCLUSION: The CET + FOLFOX4 regimen is highly effective as first-line treatment for aGC patients receiving EBC. It facilitates the suppression of STMs, ameliorates the serum inflammatory microenvironment, and enhances QOL, without increased adverse drug effects.

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This study was designed to explore the role of RIP3 in DOX-induced cardiotoxicity and its underlying molecular mechanisms. Our results demonstrate that RIP3 exacerbates DOX-induced cardiotoxicity through promoting oxidative stress and pyroptosis by regulating the AKT/Nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway. Inhibition of RIP3 using GSK-872 attenuated DOX-induced cardiac remodeling and contractile dysfunction. Moreover, using GSK-872 in vivo, the results revealed that inhibition of RIP3 alleviated DOX-induced cardiotoxicity by the resulting inhibition of oxidative stress and pyroptosis. In addition, inhibition of RIP3 increased the protein levels of AKT and Nrf2 in DOX-treated mouse hearts. Furthermore, the AKT inhibitor LY294002 lessened RIP3 reduction-offered protection against DOX-induced H9c2 cell injury by moderating oxidative stress and pyroptosis. Taken together, these data demonstrate that RIP3 activation orchestrates DOX-induced cardiotoxicity through elevated oxidative stress and pyroptosis in an AKT/Nrf2-dependent manner. Those findings highlight the clinical relevance and therapeutic potential of targeting RIP3 for the treatment of DOX-induced cardiotoxicity.

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BACKGROUND: The cranial-caudal-medial approach (CCMA) has been proposed for laparoscopic right hemicolectomy nowadays. This study aimed to investigate the safety and oncological efficacy of CCMA in the treatment of right-sided colon cancer compared to the medial-lateral approach (MLA). METHODS: Patients diagnosed with right-sided colon cancer were included from February 2015 to June 2018, retrospectively, dividing into the CCMA group and the MLA group. We compared the basic characteristics and the short-term and long-term outcomes in two groups. RESULTS: Two hundred and ninety-six patients were included in this study. The baseline characteristics were similar in two groups. Compared with MLA group, CCMA group exhibited shorter operation time (136.3 ± 25.3 min vs. 151.6 ± 21.5 min, P < 0.001), lower estimated blood loss (44.1 ± 15.2 ml vs. 51.4 ± 26.9 min, P = 0.010), and more harvested lymph nodes (18.5 ± 7.1 vs. 16.5 ± 5.7, P = 0.021). The 5-year overall survival (OS) rate for the CCMA group was 76.5%, and the 5-year disease-free survival (DFS) rate was 72.3%, both of which were not inferior to the MLA group. No significant difference was found between two groups in terms of other clinical parameters. CONCLUSION: The CCMA in laparoscopic right hemicolectomy is safe and feasible, making the anatomical plane clearer. This approach can shorten the operation time, reduce intraoperative blood loss, harvest more lymph nodes, and yield satisfactory oncological outcomes.

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Colectomía , Neoplasias del Colon , Laparoscopía , Puntaje de Propensión , Humanos , Colectomía/métodos , Femenino , Masculino , Laparoscopía/métodos , Estudios Retrospectivos , Neoplasias del Colon/cirugía , Neoplasias del Colon/patología , Persona de Mediana Edad , Tasa de Supervivencia , Estudios de Seguimiento , Anciano , Tempo Operativo , Pronóstico

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OBJECTIVE: Currently, the most commonly used methods for linkage analysis of pre-implantation genetic testing for monogenic disorders (PGT-M) are next generation sequencing (NGS) and SNP array. We aim to investigate whether the application efficacy of Asian screening array (ASA) in PGT-M preclinical workup for the Chinese population is superior to NGS based single nucleotide polymorphism (SNP) panels. METHODS: We conducted a retrospective analysis by reviewing 294 couples from a single center over the past 4 years and compared the detection results between NGS-based SNP panels and ASA. Using the numbers of informative SNPs upstream and downstream flanking of variants, we assessed the detection efficiency of both methods in monogenic diseases, chromosomal microdeletion syndrome and males with de novo variants, among other scenarios. RESULTS: Results indicate that ASA offers a greater number of informative SNPs compared with NGS-based SNP panels. Additionally, data analysis for ASA is generally more straightforward and may require less computational resources. While ASA can address most PGT-M challenges, we have also identified certain genes in previous tests that are not suitable for PGT-M using ASA. CONCLUSION: The application of ASA in PGT-M preclinical workup for Chinese populations has good practical value as it can perform linkage analysis for most genetic variants. However, for certain variants, NGS or other testing methods, such as mutated allele revealed by sequencing with aneuploidy and linkage analysis (MARSALA), may still be necessary for completion.

RESUMEN

Ferroptosis, an iron-dependent form of regulated cell death, has received increasing attention for its pathophysiologic contribution to the onset and development of doxorubicin-induced cardiotoxicity. Moreover, modulation of ferroptosis with specific inhibitors may provide new therapeutic opportunities for doxorubicin-induced cardiotoxicity. Here, we will review the molecular mechanisms and therapeutic promise of targeting ferroptosis in doxorubicin-induced cardiotoxicity.