Clinical outcomes of radiofrequency ablation using a radiofrequency needle device for varicose ulcer: A non-randomized controlled prospective study.

OBJECTIVE: To evaluate the short-term clinical outcomes of radiofrequency ablation (RFA) using a radiofrequency (RF) needle device for varicose ulcers. METHODS: From September 2020 to September 2021, a total of 80 patients with varicose ulcers were included in this study. Based on the different surgical methods, the patients were divided into RF group and control groups, with 40 cases in each group. In the RF group, RFA was performed using an RF needle device and foam sclerotherapy was used for superficial veins. The control group was treated with conventional high-ligation stripping. The surgical data, hospitalization data, clinical efficacy, and postoperative complications of two groups were compared. Meanwhile, the correlation between RBC, HB, HCT, and ulcer healing time was analyzed. RESULTS: Compared to the control group, RF group had shorter surgery time, duration in the hospital, and less intraoperative bleeding (p < .05). The VCSS and CIVIQ scores in RF group were significantly higher than that in control group (p < .05). The healing time of ulcers was shorter in the RF group (x2 = 19.766, p = .000). The RF group had fewer postoperative complications. There was a positive correlation between RBC, HB, and HCT, and ulcer healing time (p < .05). CONCLUSION: The use of the RF needle device for RFA to treat patients with varicose ulcers showed acceptable short-term clinical outcomes with less incidence of trauma, faster recovery, and fewer complications.

Highly Effective Pyroelectric Catalysis for Simultaneous Tumor-Targeted Dynamic Therapy and Gentle Photothermal Therapy by Oxygen-Vacancy-Rich CeO2-BaTiO3 Nanorods.

Pyroelectric nanostructures could effectively generate temperature-mediated reactive oxygen species (ROS) through the pyroelectric effect, providing promise for treating hypoxic tumors, and therefore, the synergistic application of photothermal therapy (PTT) and pyroelectric dynamic therapy (PEDT) presents an intriguing approach for cancer therapy. However, this method still faces challenges in improving pyroelectric catalysis and achieving precise tumor localization. In this study, a nano-heterojunction based on CeO2-BaTiO3 nanorods (IR1061@PCBNR) is reported, which exhibits highly effective pyroelectric catalysis for simultaneous tumor-targeted dynamic therapy and gentle photothermal therapy through the utilization of the rich oxygen vacancies. The oxygen vacancies create active sites that facilitate the migration of pyroelectrically-induced charge carriers, improving charge separation and ROS generation. IR1061@PCBNR also demonstrates high tumor penetration while minimizing damage to normal cells. This precise nanomedicine strategy holds great potential for advancing dynamic cancer therapies by overcoming the limitations of conventional approaches. This article is protected by copyright. All rights reserved.

Construction of an Escherichia coli cell factory for de novo synthesis of tyrosol through semi-rational design based on phenylpyruvate decarboxylase ARO10 engineering.

Tyrosol (2-(4-hydroxyphenyl) ethanol) is extensively used in the pharmaceutical industry as an important natural product from plants. In previous research, we constructed a recombinant Escherichia coli strain capable of de novo synthesis of tyrosol by integrating the phenylpyruvate decarboxylase ARO10 derived from Saccharomyces cerevisiae. Nevertheless, the insufficient catalytic efficiency of ARO10 required the insertion of multiple gene copies into the genome to attain enhanced tyrosol production. In this study, we constructed a mutation library of ARO10 based on a computer-aided semi-rational design strategy and developed a high-throughput screening method for selecting high-yield tyrosol mutants by introducing the heterologous hydroxylase complex HpaBC. Through multiple rounds of screening and site-saturation mutagenesis, we ultimately identified the two optimal ARO10 mutants, ARO10D331V and ARO10D331C, which respectively achieved a tyrosol titer of 2.02 g/L and 2.04 g/L in shake flasks, both representing more than 50 % improvement compared to the wild-type. Our study demonstrates the great potential of computer-based semi-rational enzyme design strategy in metabolic engineering. The high-throughput screening method for target compound derivative possesses a certain level of generality. Ultimately, we obtained promising mutants capable of achieving industrial-scale production of tyrosol, which also lays a solid foundation for the efficient synthesis of tyrosol derivatives.

The Genomic and Proteomic Profiles of NTRK Genes and Trk Receptors in Liver Hepatocellular Carcinoma.

Background: The neurotrophic tyrosine kinase (NTRK) gene family includes NTRK1, NTRK2, and NTRK3, which encode tropomyosin receptor kinases TrkA, TrkB, and TrkC, respectively. This study aimed to initially assess the genomic and proteomic profiles of NTRK genes and Trk receptors in liver hepatocellular carcinoma (LIHC). Methods: The ONCOMINE, UALCAN, GEPIA, cBioPortal, FusionGDB, SurvivalMeth, and the Human Protein Atlas databases were searched for NTRK gene expression and protein data in LIHC. Immunohistochemistry was used to detect pan-Trk expression across a commercial microarray containing 96 hepatocellular carcinoma (HCC) and 94 para-cancerous tissue spots. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for pan-Trk. Student's t- and chi-square tests were the main statistical analyses used. Results: The transcriptional levels of NTRK genes in LIHC were not significantly different from healthy controls. Using UALCAN and GEPIA, only high expression of NTRK2 was significantly associated with longer disease-free survival (P = 0.004). The alteration frequencies were low (7% in NTRK1, 1.7% in NTRK2, and 2% in NTRK3). The methylation levels of NTRK genes were all significantly different as analyzed by UALCAN; the high-risk group displayed an unfavorable prognosis compared with the low-risk group for NTRK1 (P = 0.033) and NTRK3 (P = 0.005). The median H-score of pan-Trk in HCC and para-cancerous tissues was not statistically different (186.31 ± 23.86 and 192.38 ± 21.06, P = 0.065). No differences were observed in clinicopathological features of HCC with the median H-score for pan-Trk expression (p > 0.05). The survival rate of patients with pan-Trk expression was also not significantly different. Conclusion: The alteration frequency was low in NTRK genes, including gene fusion and methylation levels. Therefore, pan-Trk expression in HCC tissue has limited value in clinicopathological features and prognosis.

Safety and efficacy of microwave ablation for the treatment of low-risk papillary thyroid microcarcinoma: a prospective multicenter study.

OBJECTIVES: To assess the safety and efficacy of ultrasound-guided thermal ablation for low-risk papillary thyroid microcarcinoma (PTMC) via a prospective multicenter study. METHODS: From January 2017 through June 2021, low-risk PTMC patients were screened. The management details of active surveillance (AS), surgery, and thermal ablation were discussed. Among patients who accepted thermal ablation, microwave ablation (MWA) was performed. The main outcome was disease-free survival (DFS). The secondary outcomes were tumor size and volume changes, local tumor progression (LTP), lymph node metastasis (LNM), and complication rate. RESULTS: A total of 1278 patients were included in the study. The operation time of ablation was 30.21 ± 5.14 min with local anesthesia. The mean follow-up time was 34.57 ± 28.98 months. Six patients exhibited LTP at 36 months, of whom 5 patients underwent a second ablation, and 1 patient received surgery. The central LNM rate was 0.39% at 6 months, 0.63% at 12 months, and 0.78% at 36 months. Of the 10 patients with central LNM at 36 months, 5 patients chose ablation, 3 patients chose surgery and the other 2 patients chose AS. The overall complication rate was 1.41%, and 1.10% of patients developed hoarseness of the voice. All of the patients recovered within 6 months. CONCLUSIONS: Thermal ablation of low-risk PTMC was observed to be safe and efficacious with few minor complications. This technique may help to bridge the gap between surgery and AS as treatment options for patients wishing to have their PTMC managed in a minimally invasive manner. CLINICAL RELEVANCE STATEMENT: This study proved that microwave ablation is a safe and effective treatment method for papillary thyroid microcarcinoma. KEY POINTS: Percutaneous US-guided microwave ablation of papillary thyroid microcarcinoma is a very minimally invasive treatment under local anesthesia during a short time period. The local tumor progression and complication rate of microwave ablation in the treatment of papillary thyroid microcarcinoma are very low.

Therapeutic effects of columbianadin from Angelicae Pubescentis radix on the progression of collagen-induced rheumatoid arthritis by regulating inflammation and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Angelicae pubescentis radix (APR) has a long history in the treatment of rheumatoid arthritis (RA) in China. It has the effects of dispelling wind to eliminate dampness, removing arthralgia and stopping pain in the Chinese Pharmacopeia, but its mechanisms was remained unclear. Columbianadin (CBN), one of the main bioactive compounds of APR, has many pharmacological effects including anti-inflammatory and immunosuppression. However, there are few reports on therapeutic effect of CBN on RA. AIM OF THE STUDY: A comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and multiple molecular biological methods was adopted to evaluate the therapeutic effects of CBN on collagen-induced arthritis (CIA) mice and explore the potential mechanisms. MATERIALS AND METHODS: A variety of pharmacodynamic methods were used to evaluate the therapeutic effect of CBN on CIA mice. The microbial and metabolic characteristics of CBN anti-RA were obtained by metabolomics and 16S rRNA sequencing technology. The potential mechanism of CBN anti-RA was predicted through bioinformatics network analysis, and verified by a variety of molecular biology methods. RESULTS: CBN can effectively improved symptoms of rheumatoid arthritis in CIA mice, including paw swelling and arthritic scores. The inflammatory and oxidative stress were effectively regulated by the treatment of CBN. The fecal microbial communities and serum and urine metabolic compositions were significantly altered in CIA mice, CBN can ameliorate the CIA-associated gut microbiota dysbiosis, and regulate the disturbance of serum and urine metabolome. The acute toxicity test showed that the LD50 of CBN was greater than 2000 mg kg-1. CONCLUSIONS: CBN exert anti-RA effects from four perspectives: inhibiting inflammatory response, regulating oxidative stress, and improving changes in gut microbiota and metabolites. The JAK1/STAT3, NF-κB and Keap1/Nrf2 pathway may be important mechanism for CBN's inflammatory response and oxidative stress activity. CBN could be considered as a potential anti-RA drug for further study.

Expression and prognostic impact of NTF3 and TrkC in hepatocellular carcinoma.

BACKGROUND: Treatment of patients with NTRK fusion-positive cancers using first-generation tropomyosin-related kinase (Trk) inhibitors is associated with high response rates, regardless of tumor histology. However, there have been few studies on neurotrophin-3 (NTF3) and TrkC ligands in hepatocellular carcinoma (HCC). METHODS: We used immunohistochemistry to evaluate NTF3 and TrkC expression levels in tissue samples. Gene expression profiling interactive analysis was used to determine TrkC and NTF3 expression in HCC. Western blotting, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assays were utilized to analyze TrkC and NTF3 levels in HCC cell lines. Proliferation tests and cell migration were also explored. RESULTS: NTF3 and TrkC levels were lower in HCC tissue (median H- scores 149.09 and 54.60, respectively) than those in para-cancerous tissue (192.69 and 71.70, respectively); no statistical difference was found in the survival rate. Positive correlations were observed between NTF3 and TrkC levels in both HCC and para-cancerous tissues. Alpha-fetoprotein was the only clinical characteristic associated with TrkC levels. The transcription of NTF3 was lower in HCC samples compared to normal samples. NTF3 overexpression inhibited the proliferation of MHCC97-L and HepG2 cells but did not significantly affect cell migration. CONCLUSIONS: The transcription of NTF3 was lower in HCC samples compared to normal samples, indicating a potential association with disease-free survival and overall survival in HCC. NTF3 and TrkC expression levels were lower in HCC tissues than those in para-cancerous tissues. Our results indicate that NTF3 may be a prognostic factor for HCC.

Efficient production of hydroxytyrosol by directed evolution of HpaB in Escherichia coli.

Hydroxytyrosol (HT) is an olive-derived phenolic phytochemical that has gained increasing commercial interest due to its natural antioxidant properties. It is widely used in the field of food supplement and medicine. It is reported that 4-hydroxyphenylacetate 3-hydroxylase (EcHpaB) and flavin reductase (EcHpaC) from E. coli BL21(DE3) can successfully express and catalyze the production of HT from tyrosol. In this study, the tyrosol production strain YMG5∗R as chassis cells, and a random mutant library of EcHpaB was established using error-prone PCR to improve the ability of EcHpaB to convert tyrosol to HT. Finally, a highly efficient HT synthetic mutant strainYMG5∗R-HpaBTLEHC with high transformation efficiency was screened by directed evolution. The YMG5∗R-HpaBTLEHC strain efficiently converted 50 mM tyrosol, with a yield of hydroxytyrosol reaching 48.2 mM (7.43 g/L) and a space-time yield reached 0.62 g/L·h. Overall, our study demonstrates the successful development of a highly efficient synthetic enzyme mutant for the production of HT, which has the potential to significantly improve the commercial viability of this natural antioxidant.

An efficient method for qualitation and quantitation of multi-components of the herbal medicine Qingjin Yiqi Granules.

Qingjin Yiqi Granules (QJYQ) is a Traditional Chinese Medicines (TCMs) prescription for the patients with post-COVID-19 condition. It is essential to carry out the quality evaluation of QJYQ. A comprehensive investigation was conducted by establishing deep-learning assisted mass defect filter (deep-learning MDF) mode for qualitative analysis, ultra-high performance liquid chromatography and scheduled multiple reaction monitoring method (UHPLC-sMRM) for precise quantitation to evaluate the quality of QJYQ. Firstly, a deep-learning MDF was used to classify and characterize the whole phytochemical components of QJYQ based on the mass spectrum (MS) data of ultra-high performance liquid chromatography quadrupole time of flight tandem mass spectrometry (UHPLC-Q-TOF/MS). Secondly, the highly sensitive UHPLC-sMRM data-acquisition method was established to quantify the multi-ingredients of QJYQ. Totally, nine major types of phytochemical compounds in QJYQ were intelligently classified and 163 phytochemicals were initially identified. Furthermore, fifty components were rapidly quantified. The comprehensive evaluation strategy established in this study would provide an effective tool for accurately evaluating the quality of QJYQ as a whole.

Using infodemiology metrics to assess patient demand for oculoplastic surgeons in the United States: insights from Google Search Trends.

PURPOSE: The aim of this study was to compare state-by-state concentrations of oculoplastic surgeons against patient demand using Google Search Trends data, in order to identify potential areas of unmet need. METHODS: Google Trends data from 2004 to 2019 was collected to determine relative search volumes for the keyword "blepharoplasty" in each US state and the District of Columbia. Oculoplastic surgeon density was calculated by dividing the number of active American Society of Plastic and Reconstructive Surgeons members in 2019 by the State Census Bureau population estimates. Relative search volume values were divided by the local concentration of surgeons, and results were normalized between 0 and 100 to obtain a relative demand index for each state. RESULTS: Oculoplastic surgeon density varied widely across the country. The greatest concentrations of surgeons per 100,000 people were in D.C. (0.708) and Rhode Island (0.378), while the lowest were in Montana, New Mexico, North Dakota, South Dakota, and Wyoming (all 0). Relative search volumes were tightly distributed, ranging between 100 (Hawaii) and 45 (Vermont). The highest relative demand was found in low surgeon density states, such as Hawaii, Montana, New Mexico, North Dakota, South Dakota, and Wyoming. The lowest relative demand was found in DC (5), Rhode Island (12), and Utah (12). CONCLUSIONS: Our results revealed vast disparities in surgical concentrations across the US and highlighted a number of areas with a relative undersupply of oculoplastic surgeons. Further investigation is necessary to examine the underlying factors impacting the supply and distribution of oculoplastic surgeons.

Ferroptosis regulator FANCD2 is associated with immune infiltration and predicts worse prognosis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related death. Although immunotherapy has been shown to improve survival in LUAD patients, only a select group of LUAD patients could benefit from it. The correlation between ferroptosis and the tumor immune environment requires further investigation in the setting of LUAD. An analysis using The Cancer Genome Atlas (TCGA)-LUAD cohort systematically evaluated the expression levels of ferroptosis regulators between LUAD and normal tissues and demonstrated the correlation of ferroptosis regulators with the immune checkpoint B7-H3 expression. Based on consensus clustering analysis, we divided LUAD patients into two subtypes according to the expression pattern of ferroptosis regulators. Cluster 2 patients showed more favorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001) than Cluster 1 patients. CIBERSORT analysis indicated that Cluster 1 patients harbored higher infiltrated levels of uncharacterized cells, CD4+ T cells (nonregulatory), and myeloid dendritic cells, while Cluster 2 patients were more correlated with B cells, M1 macrophages, natural killer cells (NK cells) and regulatory T cells (Tregs). More importantly, we identified FANCD2 as a potentially unfavorable prognostic factor that was overexpressed in LUAD and positively associated with the checkpoint molecule B7-H3 expression. In addition, higher FANCD2 expression was related to a higher tumor immune dysfunction and exclusion (TIDE) score, indicating lower responder rates to cancer immunotherapeutics. In summary, our study suggested a relationship between immune infiltration and ferroptosis and that FANCD2 is a potential biomarker for clinical outcomes and a therapeutic target for LUAD therapy concerning ferroptotic regulation. Our findings may help to advance personalized treatment and improve the prognosis of LUAD.

Maternal stevioside supplementation improves intestinal immune function of chicken offspring potentially via modulating gut microbiota and down-regulating the promoter methylation level of suppressor of cytokine signaling 1 (SOCS1).

The intestinal immune function of chickens is limited during the early growing stage. Maternal nutritional intervention has been suggested to affect the innate immunity of offspring. The present study aimed to investigate the effects of maternal stevioside supplementation on the intestinal immune function of chicken offspring. A total of 120 Jinmao yellow-feathered breeder hens were fed a basal diet or a diet supplemented with 250 mg/kg stevioside for 5 weeks. During the last week, 200 breeding eggs from each group were collected for incubation. After hatching, 80 male offspring (40 chickens from each group) were randomly selected and fed the same basal diet for 28 d. In addition, 90 well-shaped fertile eggs of non-treated breeder hens were incubated for the in ovo injection experiment. Steviol dissolved in 20% glycerol was injected at 7 d of incubation. The results showed that maternal stevioside supplementation could improve embryonic development, jejunal integrity and proliferation in the jejunal crypt (P < 0.05). Maternal stevioside supplementation could also increase the innate transcription levels of cytokines and endotoxin tolerance-related factors in the jejunum of chicken offspring (P < 0.05). At 28 d of age, the offspring following maternal stevioside supplementation exhibited higher jejunal secretory immunoglobulin A and serum interferons levels (P < 0.05). A higher abundance of Lactobacillales induced by maternal stevioside supplementation was positively correlated with intestinal immune-related factors (P < 0.05). The in ovo injection with steviol did not alter either embryonic development or intestinal immune function of hatching chickens (P > 0.05). Furthermore, maternal stevioside supplementation could induce hypo-methylation on the promoter region of suppressor of cytokine signaling 1 (SOCS1). In conclusion, maternal stevioside supplementation could improve the intestinal immune function of chicken offspring potentially via modulating the gut microbiota and down-regulating the promoter methylation level of SOCS1.

Functional assessment of missense variants of uncertain significance in the cancer susceptibility gene PALB2.

Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.

Integrative Analysis Identifies a TNFα-Derived Gene Signature for Predicting Prognosis, Tumor Immunity, and Treatment Sensitivity in Gastric Cancer.

Objective: TNF-α is an essential pro-inflammatory cytokine in the tumor microenvironment of gastric cancer (GC), possessing a key biological and clinical impact. Here, we conducted an integrative analysis of the role of TNFα-derived genes in GC prognosis and precision medicine. Methods: We pooled transcriptome and clinical features of GC patients from TCGA and GSE15459 projects. TNFα signaling was quantified through the ssGSEA algorithm, and TNFα-derived genes were screened with WGCNA. Thereafter, a LASSO model was established. The somatic mutation was analyzed across GC specimens. Immune cell infiltrations were inferred through ESTIMATE and ssGSEA algorithms, followed by measuring the immune checkpoint expression. AKR1B1, CPVL, and CTSL expressions were measured in gastric mucosal cells GES-1 and GC cells (HGC-27, MKN-28, and AGS) through RT-qPCR and Western blotting. Results: A TNFα-derived gene signature (containing AKR1B1, CPVL, and CTSL) was developed for GC. A high-risk score indicated more undesirable OS, DFS, DSS, and PFS outcomes. Time-independent ROC curves and multivariate cox regression models confirmed that the signature reliably and independently predicted GC prognosis. Additionally, risk scores displayed significant correlations to more severe histological grades and pathological stages. A low-risk score was characterized by increased somatic mutation, while a high-risk score was characterized by immune and stromal activation, enhanced immune cell infiltrations, and increased expression of immune checkpoint molecules. Experimental results confirmed the significant upregulation of AKR1B1, CPVL, and CTSL in GC cells. Conclusion: Collectively, stratification based on the TNFα-derived gene signature might enable GC patients to predict prognosis, benefit from immunotherapy, and assist in formulating novel therapeutic regimens.

A comprehensive strategy integrating metabolomics with multiple chemometric for discovery of function related active markers for assessment of foodstuffs: A case of hawthorn (Crataegus cuneata) fruits.

There is a growing demand for functional foodstuffs naturally rich in nutrients and bioactive compounds associated with putative health benefits. This study followed a strategy integrating metabolomic with chemometric to identify quality markers that can be used to distinguish function related bioactivity of fruits, using hawthorn (Crataegus cuneata) fruit as an example. The integrated strategy was reduced to characterization of metabolic processes and discovered potential bioactive ingredients that were further investigated for functionalities. This comprehensive process provided guidance for discovery of function-related active markers for assessment of foodstuffs.

Dietary curcumin supplementation ameliorates placental inflammation in rats with intra-uterine growth retardation by inhibiting the NF-κB signaling pathway.

Intra-uterine growth restriction (IUGR) is a serious, commonly occurring reproductive problem in humans. This study aimed to investigate the effects of daily curcumin supplementation during pregnancy on placental inflammation, in a rat model of IUGR. Pregnant rats were divided into three groups based on diet: (1) normal protein (19%) (NP), (2) low protein (8%) (LP), and (3) low protein + 100 mg curcumin/kg bw per day (LPC). The results showed that curcumin accumulation in the serum, placenta and liver. Fetal weight and placental total protein levels were increased in the LPC group compared with those in the LP group. Dietary curcumin supplementation normalized the low protein diet-induced decrease of placental weight, blood sinusoid area, and proliferating cell nuclear antigen (PCNA) protein expression levels. It also reversed the low protein diet-induced increase of serum triglyceride levels and tumor necrosis factor alpha-like (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) concentrations in both the placenta and serum. Additionally, it normalized the enhanced gene expression levels of the pro-inflammatory cytokines in the LP group to that in the NP group. Furthermore, it downregulated the inhibitor of kappa Balpha (IκBα) and nuclear factor kappa Balpha (NF-κB) phosphorylation. In conclusion, daily curcumin supplementation ameliorates placental inflammation in rats with IUGR by inhibiting the NF-κB signaling pathway.

Effect of maternal curcumin supplementation on intestinal damage and the gut microbiota in male mice offspring with intra-uterine growth retardation.

PURPOSE: The present study investigated whether maternal curcumin supplementation might protect against intra-uterine growth retardation (IUGR) induced intestinal damage and modulate gut microbiota in male mice offspring. METHODS: In total, 36 C57BL/6 mice (24 females and 12 males, 6-8 weeks old) were randomly divided into three groups based on the diet before and throughout pregnancy and lactation: (1) normal protein (19%), (2) low protein (8%), and (3) low protein (8%) + 600 mg kg-1 curcumin. Offspring were administered a control diet until postnatal day 35. RESULTS: Maternal curcumin supplementation could normalize the maternal protein deficiency-induced decrease in jejunal SOD activity (NP = 200.40 ± 10.58 U/mg protein; LP = 153.30 ± 5.51 U/mg protein; LPC = 185.40 ± 9.52 U/mg protein; P < 0.05) and T-AOC content (NP = 138.90 ± 17.51 U/mg protein; LP = 84.53 ± 5.42 U/mg protein; LPC = 99.73 ± 12.88 U/mg protein; P < 0.05) in the mice offspring. Maternal curcumin supplementation increased the maternal low protein diet-induced decline in the ratio of villus height-to-crypt depth (NP = 2.23 ± 0.19; LP = 1.90 ± 0.06; LPC = 2.56 ± 0.20; P < 0.05), the number of goblet cells (NP = 12.72 ± 1.16; LP = 7.04 ± 0.53; LPC = 13.10 ± 1.17; P < 0.05), and the ratio of PCNA-positive cells (NP = 13.59 ± 1.13%; LP = 2.42 ± 0.74%; LPC = 6.90 ± 0.96%; P < 0.05). It also reversed the maternal protein deficiency-induced increase of the body weight (NP = 13.00 ± 0.48 g; LP = 16.49 ± 0.75 g; LPC = 10.65 ± 1.12 g; P < 0.05), the serum glucose levels (NP = 5.32 ± 0.28 mmol/L; LP = 6.82 ± 0.33 mmol/L; LPC = 4.69 ± 0.35 mmol/L; P < 0.05), and the jejunal apoptotic index (NP = 6.50 ± 1.58%; LP = 10.65 ± 0.75%; LPC = 5.24 ± 0.71%; P < 0.05). Additionally, maternal curcumin supplementation enhanced the gene expression level of Nrf2 (NP = 1.00 ± 0.12; LP = 0.73 ± 0.10; LPC = 1.34 ± 0.12; P < 0.05), Sod2 (NP = 1.00 ± 0.04; LP = 0.85 ± 0.04; LPC = 1.04 ± 0.04; P < 0.05) and Ocln (NP = 1.00 ± 0.09; LP = 0.94 ± 0.10; LPC = 1.47 ± 0.09; P < 0.05) in the jejunum. Furthermore, maternal curcumin supplementation normalized the relative abundance of Lactobacillus (NP = 31.56 ± 6.19%; LP = 7.60 ± 2.33%; LPC = 17.79 ± 2.41%; P < 0.05) and Desulfovibrio (NP = 3.63 ± 0.93%; LP = 20.73 ± 3.96%; LPC = 13.96 ± 4.23%; P < 0.05), and the ratio of Firmicutes/Bacteroidota (NP = 2.84 ± 0.64; LP = 1.21 ± 0.30; LPC = 1.79 ± 0.15; P < 0.05). Moreover, Lactobacillus was positively correlated with the SOD activity, and it was negatively correlated with Il - 1ß expression (P < 0.05). Desulfovibrio was negatively correlated with the SOD activity and the jejunal expression of Sod1, Bcl - 2, Card11, and Zo - 1 (P < 0.05). CONCLUSIONS: Maternal curcumin supplementation could improve intestinal integrity, oxidative status, and gut microbiota in male mice offspring with IUGR.

The Effects of Differentially-Expressed Homeobox Family Genes on the Prognosis and HOXC6 on Immune Microenvironment Orchestration in Colorectal Cancer.

Background: The homeobox (HOX) gene family encodes highly conserved transcription factors, that play important roles in the morphogenesis and embryonic development of vertebrates. Mammals have four similar HOX gene clusters, HOXA, HOXB, HOXC, and HOXD, which are located on chromosomes 7, 17,12 and 2 and consist of 38 genes. Some of these genes were found to be significantly related to a variety of tumors; however, it remains unknown whether abnormal expression of the HOX gene family affects prognosis and the tumor microenvironment (TME) reshaping in colorectal cancer (CRC). Therefore, we conducted this systematic exploration to provide additional information for the above questions. Methods: RNA sequencing data from The Cancer Genome Atlas (TCGA) and mRNA expression data from Gene Expression Omnibus (GEO) combined with online tumor analysis databases (UALCAN, TIMER, PrognoScan) were utilized to explore the relationship among abnormal expression of HOX family genes, prognosis and the tumor immune microenvironment in CRC. Results: 1. Differential expression and prognosis analysis: 24 genes were significantly differentially expressed in CRC compared to adjacent normal tissues, and seven upregulated genes were significantly associated with poor survival. Among these seven genes, univariate and multivariate Cox regression analysis revealed that only high expression of HOXC6 significantly contributed to poor prognosis; 2. The influence of overexpressed HOXC6 on the pathway and TME: High HOXC6 expression was significantly related to the cytokine pathway and expression of T cell attraction chemokines, the infiltration ratio of immune cells, expression of immune checkpoint markers, tumor mutation burden (TMB) scores and microsatellite instability-high (MSI-H) scores; 3. Stratified analysis based on stages: In stage IV, HOXC6 overexpression had no significant impact on TMB, MSI-H, infiltration ratio of immune cells and response prediction of immune checkpoint blockers (ICBs), which contributed to significantly poor overall survival (OS). Conclusion: Seven differentially expressed HOX family genes had significantly worse prognoses. Among them, overexpressed HOXC6 contributed the most to poor OS. High expression of HOXC6 was significantly associated with high immunogenicity in nonmetastatic CRC. Further research on HOXC6 is therefore worthwhile to provide potential alternatives in CRC immunotherapy.