Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer.

More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.

Elderly patients with advanced HER2-positive breast cancer with liver metastases benefit from low dose disitamab vedotin (RC48): case series and literature review.

Currently, although some antibody-drug conjugates have been shown to be safe and effective in the treatment of drug-resistant relapsed human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+ or IHC 2+/fluorescence in situ hybridization+) breast cancer, they are already approved for clinical use in China. But the clinical needs of advanced HER2-positive patients cannot be met due to adverse reactions, drug resistance, drug accessibility and other problems, thus affecting the prognosis of patients. In particular, the representation of elderly and frail patients in randomized clinical trials is significantly under-represented. We report on two elderly women with breast cancer who developed recurrent metastatic lesions after breast cancer surgery and were again confirmed HER2-positive by histopathology and immunohistochemistry. They all developed multiple metastases in the liver after second- or third-line anti-HER2 therapy. Subsequent treatment with RC48 produced good responses and tolerable adverse reactions. One patient obtained progression-free survival for more than 7 months. Based on preliminary evidence, this study shows that RC48 in HER2-positive breast cancer with liver metastases can achieve rapid remission, thereby reducing tumor load and improving patients' quality of life. In particular, RC48 has low side effects and can be well tolerated by elderly patients after dose adjustment, providing them with treatment opportunities. It needs to be further discussed in the future research.

Network pharmacology analysis of a patented Chinese herbal medicine for alleviating anxiety disorder in in vitro fertilization-embryo transfer.

Objective: Qu's formula 3 (QUF3) is a patented Chinese herbal medicine used to alleviate anxiety disorders during in vitro fertilization-embryo transfer (IVF-ET). This study aimed to identify the potential active constituents and molecular mechanisms of action of QUF3 in alleviating anxiety disorders during IVF-ET. Methods: The active constituents of QUF3 were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and literatures. Potential targets of anxiety disorder and IVF-ET were identified using GeneCards, Online Mendelian Inheritance in Man, and the UniProt Database. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify the potential mechanisms. Molecular docking and molecular dynamics (MD) simulations were performed to visualize and verify the results. Results: Quercetin, sophoranol, luteolin, kaempferol, and neurotoxin inhibitors were identified as the TOP 5 active constituents of QUF3. Forty common targets were shared among QUF3, anxiety disorders, and IVF-ET. Tumour necrosis factor, interleukin-6, vascular endothelial growth factor A, epidermal growth factor, interleukin-1B, cellular tumour antigen p53, matrix metalloproteinase-9, and oestrogen receptor were identified as the TOP 8 potential targets through PPI analysis. A total of 697 biological processes, 20 cellular components, and 54 molecular functions were identified. Further, 91 KEGG pathways were revealed to be enriched. The TOP 5 active constituents were verified to have good binding activity with the TOP 8 potential targets using molecular docking and MD simulations. Conclusions: The mechanism of QUF3 in alleviating anxiety disorders in patients undergoing IVF-ET may be related to the interleukin-17 and tumour necrosis factor signalling pathways, inhibiting inflammatory responses and antioxidants, which may provide a solid foundation for the clinical application and further study of QUF3.

Immune dysfunction mediated by the competitive endogenous RNA network in fetal side placental tissue of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder affecting women in their reproductive years. Emerging evidence suggests that the maternal-fetal immune system is crucial for proper pregnancy. However, whether immune function is altered at the end of pregnancy in PCOS women and the underlying molecular mechanisms is currently unexplored. Herein, the basic maternal immune system was investigated (n = 136 in the control group; n = 103 in the PCOS group), and whole-transcriptome sequencing was carried out to quantify the mRNAs, miRNAs, and lncRNAs expression levels in fetal side placental tissue of women with PCOS. GO, KEGG, and GSEA analysis were employed for functional enrichment analysis. The process of identifying hub genes was conducted utilizing the protein-protein interaction network. CIBERSORT and Connectivity Map were deployed to determine immune cell infiltration and predict potential drugs, respectively. A network of mRNA-miRNA-lncRNA was constructed and then validated by qRT-PCR. First, red blood cell count, neutrophil count, lymphocyte count, hypersensitive C-reactive protein, and procalcitonin were significantly elevated, while placental growth factor was hindered in PCOS women. We identified 308 DEmRNAs, 77 DEmiRNAs, and 332 DElncRNAs in PCOS samples. Functional enrichment analysis revealed that there were significant changes observed in terms of the immune system, especially the chemokine pathway. Eight genes, including FOS, JUN, EGR1, CXCL10, CXCR1, CXCR2, CXCL11, and CXCL8, were considered as hub genes. Furthermore, the degree of infiltration of neutrophils was dramatically decreased in PCOS tissues. In total, 57 ceRNA events were finally obtained, and immune-related ceRNA networks were validated. Some potential drug candidates, such as enalapril and RS-100329, could have a function in PCOS therapy. This study represents the inaugural attempt to evaluate the immune system at the end of pregnancy and placental ceRNA networks in PCOS, indicating alterations in the chemokine pathway, which may impact fetal and placental growth, and provides new therapy targets.

Polychlorinated biphenyls exposure and type 2 diabetes: Molecular mechanism that causes insulin resistance and islet damage.

Polychlorinated biphenyls (PCBs) are typical persistent organic pollutants that have been associated with type 2 diabetes (T2DM) in cohort studies. This review aims to comprehensively assess the molecular mechanisms of PCBs-induced T2DM. Recent progress has been made in the research of PCBs in liver tissue, adipose tissue, and other tissues. By influencing the function of nuclear receptors, such as the aryl hydrocarbon receptor (AhR), pregnancy X receptor (PXR), and peroxisome proliferator activated receptor γ (PPARγ), as well as the inflammatory response, PCBs disrupt the balance of hepatic glucose and lipid metabolism. This is associated with insulin resistance (IR) in the target organ of insulin. Through androgen receptor (AR), estrogen receptor α/ß (ERα/ß), and pancreato-duodenal-homeobox gene-1 (PDX-1), PCBs affect the secretion of insulin and increase blood glucose. Thus, this review is a discussion on the relationship between PCBs exposure and the pathogenesis of T2DM. It is hoped to provide basic concepts for diabetes research and disease treatment.

Relationship between phthalates exposure, risk of decreased ovarian reserve, and oxidative stress levels.

Phthalates (PAEs), a group of environmental endocrine disruptors, are associated with oxidative stress and have adverse effects on female ovarian reserves. However, this association has been poorly investigated, particularly with respect to clinical evidence. In this study, we provided clinical evidence of a relationship between exposure levels of PAEs, oxidative stress and decreased ovarian reserve (DOR). Firstly, the urinary concentrations of metabolites of PAEs were measured by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), and the biomarkers of oxidative stress, malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), were determined. Finally, statistical analyses were conducted to describe the relationship between the PAEs exposure, oxidative stress and DOR. We found that the levels of monomethyl phthalate (MMP), monoisobutyl phthalate (MiBP), mono-(2-ethylhexyl) phthalate (MEHP), and mono-(2-ethyl-5-hydroxypentyl) phthalate (MECPP) in the DOR group were significantly higher than those in the control group. There was a significant negative association between AMH and MMP, MiBP levels. and a significant positive association between FSH and MMP levels. PAEs exposure was also associated with a significant increase in MDA levels and decrease in SOD levels. In conclusion, the exposure of PAEs was closely associated with DOR, potentially mediated by oxidative stress pathways; however, small sample size was a limitation in this study.

The effective compounds and mechanisms of Cang-Fu-Dao-Tan Formula in treating polycystic ovary syndrome based on UPLC/Q-TOF-MS/MS, network pharmacology and molecular experiments.

BACKGROUND: Polycystic ovary syndrome (PCOS), as a common endocrine disease in reproductive-age women, which is characterized by both reproductive and metabolic disorders. Cang-Fu-Dao-Tan Formula (CFDTF) is an effective and relatively safe treatment for PCOS. However, the underlying mechanism is poorly understood. PURPOSE: To explore the effective compounds and mechanisms of CFDTF in treating PCOS based on UPLC/Q-TOF-MS/MS, network pharmacology and molecular experiments. METHODS: The UPLC/Q-TOF-MS/MS and TCMSP, SwissTargetPrediction databases were used to identify the active ingredients of CFDTF. Then GeneCards, Disgenet, Drugbank databases were used to obtain the PCOS related targets. Based above, the Drug-component-target (D-C-T) network and protein-protein-interaction (PPI) network were built to analysis the key targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were performed to find the potential mechanisms. Finally, molecular docking analysis, molecular dynamics (MD) simulations and molecular experiments were used to confirm the interactions among the active compounds, targets and explore the potential mechanisms. RESULTS: A total of 20 compounds were identified by UPLC/Q-TOF-MS/MS, and 136 active compounds by TCMSP from CFDTF. After removing the duplicate results, there were 370 targets related to both CFDTF and PCOS, among which, MAPK3, AKT1, RELA, EGF, TP53 and MYC were proved to have high interactions with the components. The mechanisms of CFDTF against PCOS were related to PI3K-Akt, mTOR, MAPK signaling pathways, and the in vitro experiments proved that the CFDTF positively regulated the cell proliferation and inhibited the apoptosis levels in PCOS cell model. CONCLUSIONS: The combination of UPLC/Q-TOF-MS/MS, systematic network pharmacology and molecular experiments identified that the quercetin, hesperidin, and glycyrrhizin disaccharide are the TOP 3 effective compounds of CFDTF in treating PCOS and the potential mechanisms may involve in regulating proliferation and apoptosis of granulosa cells.

Progress of immune checkpoint inhibitors therapy for non-small cell lung cancer with liver metastases.

Nearly one-fifth of patients with non-small cell Lung Cancer (NSCLC) will develop liver metastases (LMs), and the overall treatment strategy of LMs will directly affect the survival of patients. However, some retrospective studies have found that patients receiving chemotherapy or targeted therapy have a poorer prognosis once LMs develop. In recent years, multiple randomised controlled trials (RCTS) have shown significant improvements in outcomes for patients with advanced lung cancer following the introduction of immune checkpoint inhibitors (ICIs) compared to conventional chemotherapy. ICIs is safe and effective in patients with LMs, although patients with LMs are mostly underrepresented in randomised clinical trials. However, NSCLC patients with LMs have a significantly worse prognosis than those without LMs when treated with ICIs, and the mechanism by which LMs induce systemic anti-tumour immunity reduction is unknown, so the management of LMs in patients with NSCLC is a clinical challenge that requires more optimised therapies to achieve effective disease control. In this review, we summarised the mechanism of ICIs in the treatment of LMs, the clinical research and treatment progress of ICIs and their combination with other therapies in patients with LMs from NSCLC.

Oral Anlotinib Maintenance Therapy for an Advanced Malignant Peritoneal Mesothelioma Diagnosed by Laparoscopy After Initial Misdiagnosis to Obtain Longer Progression-Free Survival: Case Report and Literature Review.

Malignant peritoneal mesothelioma (MPeM) is a rare and highly invasive malignant tumor with a lack of specificity in clinical manifestations, which can easily lead to misdiagnosis and missed diagnosis. Due to the difficulty of early diagnosis, most patients are already in the advanced stage when diagnosed, and the prognosis is poor. At present, there is no standard treatment strategy, and the existing treatment methods are not effective, the duration of remission is short, which cannot meet the clinical needs. Here we describe a patient with advanced MPeM, initially misdiagnosed as ovarian cancer, who responded to treatment with bevacizumab in combination with albumin-bound paclitaxel and cisplatin. In preparation for cytoreductive surgery (CRS), MPeM was confirmed by laparoscopic peritoneal nodule biopsy combined with histological and immunohistochemical results. Subsequently, due to intolerable neurotoxicity after chemotherapy, she received oral anlotinib therapy on April 25, 2022, and remained stable disease (SD) with the medication, having achieved more than 14 months of progression-free survival (PFS) as of the date of our manuscript submission. The patient's total treatment time was over 19 months. These treatments delayed tumor progression, reduced drug side effects, maintained a good quality of life, and further extended overall survival (OS). Our experience is that on the one hand, it is necessary to increase the clinician's understanding of the disease, and make full use of tissue samples and immunohistochemical staining to reduce the occurrence of misdiagnosis. On the other hand, based on preliminary evidence, we found that oral anlotinib offers a viable maintenance treatment strategy for patients with advanced mesothelioma, which needs to be further explored in future studies.

The value of indocyanine green-FLOW800 in microvasculature for predicting cerebral hyperperfusion syndrome in moyamoya disease patients.

Among the notable complications of direct hemodynamic reconstruction for moyamoya disease (MMD) is cerebral hyperperfusion syndrome (CHS). In this study, we evaluated hemodynamic changes in small regional microvasculature (SRMV) around the anastomosis site by using indocyanine green (ICG)-FLOW800 video angiography and verified that it better predicted the onset of CHS. Intraoperative ICG-FLOW800 analysis was performed on 31 patients (36 cerebral hemispheres) with MMD who underwent superficial temporal artery-middle cerebral artery (MCA) bypass grafting at our institution. The regions of interest were established in the SRMV and thicker MCA around the anastomosis. Calculations were made for half-peak to time (TTP1/2), cerebral blood volume (CBV), and cerebral blood flow (CBF). According to the presence or absence of CHS after surgery, CHS and non-CHS groups of patients were separated. The results showed that ΔCBV and ΔCBF were substantially greater in SRMV than in MCA (p < 0.001). Compared with the non-CHS group, ΔCBF and ΔCBV of SRMV and MCA were considerably greater in the CHS group (p < 0.001). ΔCBF and ΔCBV on the ROC curve for both SRMV and MCA had high sensitivity and specificity (SRMV: ΔCBF, AUC = 0.8586; ΔCBV, AUC = 0.8158. MCA: ΔCBF, AUC = 0.7993; ΔCBV, AUC = 0.8684). ICG-FLOW800 video angiography verified the differential hemodynamic changes in the peri-anastomotic MCA and SRMV before and after bypass surgery in patients with MMD.

Preeclampsia in pregnant women with polycystic ovary syndrome: risk factor analysis based on a retrospective cohort study.

OBJECTIVES: To compare the clinical characteristics of pregnant women with polycystic ovary syndrome (PCOS) and perinatal outcomes with or without preeclampsia (PE) and to factors that are potentially associated with the onset of PE. MATERIAL AND METHODS: This was a retrospective study of pregnant women diagnosed with PCOS from January 2017 to December 2021. Eligible patients were divided into two groups based on the presence or absence of preeclampsia: a PE group and a non-PE group. Demographics, clinical characteristics, maternal and perinatal outcomes, and potential factors linked to disease recurrence were analyzed. RESULTS: In total, 616 patients were enrolled and respectively classified into the PE group (n = 51) and the non-PE group (n = 565). The incidence of PE in pregnant women with PCOS was 8.28%; this was significantly higher than that in non-PCOS pregnant women (3.22%, p < 0.001). Logistic regression analysis of the predictive factors for PE in women with PCOS revealed that the combination of maternal hyperandrogenism, a pre-pregnancy BMI ≥ 24 kg/m², and a family history of cardiovascular disease (CVD) and assisted reproductive techniques (ART) exhibited the steepest receiver-operating characteristic (ROC) curve value at 0.797 [95% confidence interval (CI): 0.733-0.862]. CONCLUSIONS: Patients with PCOS have a higher incidence of PE. We identified a series of significant and independent factors associated with PE in PCOS: maternal hyperandrogenism, a pre-pregnancy BMI ≥ 24 kg/m², and a family history of CVD and ART.

Bu-Shen-Tian-Jing formulas alleviate the mitochondrial damage induced by oxidative stress in ovarian granulosa cells exposed to DEHP through the HDAC3-HSP90AA pathway.

CONTEXT: di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However, BSTJF2 has much lower cytotoxicity than BSTJF1. OBJECTIVE: To investigate the effects of BSTJFs on ovarian granulosa cells exposed to DEHP and determine the potential molecular mechanisms. METHODS AND MATERIALS: Human granulosa-like tumor cell line (KGN) cells were divided into control, DEHP, BSTJF1 and BSTJF2 groups. The DEHP group were given 1 µM DEHP for 24 h. They were then given BSTJF1 at 200 µg/mL or BSTJF2 at 100 µg/mL for 24 h. The control group was treated with the same concentration of DMSO (0.1%). Oxidative stress and mitochondrial function were measured. The mRNA and protein expression levels of HDAC3 and HSP90AA were determined. Integrative network pharmacology analysis of BSTJF2 was also performed. RESULTS: DEHP (1 µM) significantly suppressed the proliferation of KGN cells by 17%, significantly increased ROS levels by 28% and MDA levels by 47%, significantly decreased MMP levels by 22% and mtDNA copy by 30%. DEHP significantly increased protein expression of HDAC3 by 21%and HSP90AA by 64%. All these changes were significantly reversed by BSTJFs. Integrative network pharmacology analysis revealed HSP90AA was a key target (degree = 8). Both RGFP966 and BSTJF2 significantly reversed the increased expression of HDAC3 and HSP90AA, attenuated oxidative stress, and mitochondrial damage which were induced by DEHP. CONCLUSION: BSTJFs might have therapeutic potential on oxidative stress and mitochondrial damage through the HDAC3/HSP90AA pathway which encourages further clinical trials.

Osteopontin promotes gastric cancer progression via phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.

BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors. Osteopontin (OPN) is thought to be closely related to the occurrence, metastasis and prognosis of many types of tumors. AIM: To investigate the effects of OPN on the proliferation, invasion and migration of GC cells and its possible mechanism. METHODS: The mRNA and protein expression of OPN in the GC cells were analyzed by real-time quantitative-reverse transcription polymerase chain reaction and western blotting, and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC. Next, the effects of OPN knockdown on GC cells migration and invasion were examined. The short hairpin RNA (shRNA) and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer's instructions. Non transfected cells were classified as control in the identical transfecting process. 24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay, and cell invasiveness and migration were detected by Trans well assay. Meanwhile, the expression of protein kinase B (AKT), matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF) in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting. RESULTS: The results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells. OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation, invasion and migration of SGC-7901 cells. Moreover, in the experiments of investigating the underlying mechanism, results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF, it also decreased the phosphorylation of AKT. Meanwhile, the protein expression levels of MMP-2, VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002). CONCLUSION: These results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to up-regulate MMP-2 and VEGF expression, which contribute SGC-7901 cells to proliferation, invasion and migration. Thus, our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.

Quasi-dendritic sulfonate-based organic small molecule for high-quality NIR-II bone-targeted imaging.

The visualization of bone imaging in vivo is of great significance for the understanding of some bone-related diseases or physiological processes. Herein, a bone-targeted NIR-II small molecule (TTQF-SO3), which was modified with multiple sulfonate groups, was successfully fabricated for the second near-infrared (NIR-II) bone imaging. In vitro studies revealed that TTQF-SO3 showed high affinity for hydroxyapatite and excellent macrophage accumulation ability. In in vivo assays, TTQF-SO3 displayed high bone uptake ability and high NIR-II bone imaging quality, demonstrating the specific bone-targeting ability of the sulfonate-containing probe. In addition, the noninvasive NIR-II imaging detection in bone calcium loss was successfully verified in osteoporosis mice models. Moreover, the negative charge characteristic of TTQF-SO3 showed efficient lymphoid enrichment in living mice by intravenous injection. Overall, these warrant that our TTQF-SO3 is an optimal bone-targeted diagnostic agent for high-quality NIR-II imaging, highlighting its potential promise for clinical translation.

Oral fruquintinib combined with tegafur-gimeracil-oteracil potassium for advanced colorectal cancer to obtain longer progression-free survival: A case report.

BACKGROUND: After the failure of second-line standard therapy, effective treatment options for metastatic colorectal cancer are limited, and the duration of remission cannot meet clinical needs. In addition, associated drug toxicity may lead to treatment interruption that may affect patient outcomes. Therefore, more safe, effective and convenient treatments are urgently needed. CASE SUMMARY: Here, we describe a patient with advanced colorectal cancer with multiple metastases in both lungs. Oxaliplatin combined with 5-fluorouracil or capecitabine was given as the first-line treatment, and bevacizumab combined with irinotecan was given as the second-line treatment after disease progression. However, treatment was interrupted due to recurrent grade 2 nausea and grade 1 diarrhea. He received targeted therapy with fruquintinib starting on August 26, 2020 and responded well for 12 mo. After slow progression of the lung metastases, progression-free survival was again achieved over 13.5 mo by continued treatment of fruquintinib in combination with tegafur-gimeracil-oteracil potassium chemotherapy. Overall treatment duration was more than 25.5 mo. The treatments delayed tumor progression, reduced drug side effects, maintained a good quality of life, and further extended overall survival. CONCLUSION: This case report detailed preliminary evidence showing that the combination of fruquintinib with tegafur-gimeracil-oteracil potassium chemotherapy double oral therapy may result in longer progression-free survival in patients with advanced colorectal cancer.

Application of WeChat Public Account for Lifestyle Management of Polycystic Ovary Syndrome.

Null.

Novel insights into chloroplast genome evolution in the green macroalgal genus Ulva (Ulvophyceae, Chlorophyta).

To understand the evolutionary driving forces of chloroplast (or plastid) genomes (plastomes) in the green macroalgal genus Ulva (Ulvophyceae, Chlorophyta), in this study, we sequenced and constructed seven complete chloroplast genomes from five Ulva species, and conducted comparative genomic analysis of Ulva plastomes in Ulvophyceae. Ulva plastome evolution reflects the strong selection pressure driving the compactness of genome organization and the decrease of overall GC composition. The overall plastome sequences including canonical genes, introns, derived foreign sequences and non-coding regions show a synergetic decrease in GC content at varying degrees. Fast degeneration of plastome sequences including non-core genes (minD and trnR3), derived foreign sequences, and noncoding spacer regions was accompanied by the marked decrease of their GC composition. Plastome introns preferentially resided in conserved housekeeping genes with high GC content and long length, as might be related to high GC content of target site sequences recognized by intron-encoded proteins (IEPs), and to more target sites contained by long GC-rich genes. Many foreign DNA sequences integrated into different intergenic regions contain some homologous specific orfs with high similarity, indicating that they could have been derived from the same origin. The invasion of foreign sequences seems to be an important driving force for plastome rearrangement in these IR-lacking Ulva cpDNAs. Gene partitioning pattern has changed and distribution range of gene clusters has expanded after the loss of IR, indicating that genome rearrangement was more extensive and more frequent in Ulva plastomes, which was markedly different from that in IR-containing ulvophycean plastomes. These new insights greatly enhance our understanding of plastome evolution in ecologically important Ulva seaweeds.

Contribution of labor related gene subtype classification on heterogeneity of polycystic ovary syndrome.

OBJECTIVE: As one of the most common endocrine disorders in women of reproductive age, polycystic ovary syndrome (PCOS) is highly heterogeneous with varied clinical features and diverse gestational complications among individuals. The patients with PCOS have 2-fold higher risk of preterm labor which is associated with substantial infant morbidity and mortality and great socioeconomic cost. The study was designated to identify molecular subtypes and the related hub genes to facilitate the susceptibility assessment of preterm labor in women with PCOS. METHODS: Four mRNA datasets (GSE84958, GSE5090, GSE43264 and GSE98421) were obtained from Gene Expression Omnibus database. Twenty-eight candidate genes related to preterm labor or labor were yielded from the researches and our unpublished data. Then, we utilized unsupervised clustering to identify molecular subtypes in PCOS based on the expression of above candidate genes. Key modules were generated with weighted gene co-expression network analysis R package, and their hub genes were generated with CytoHubba. The probable biological function and mechanism were explored through Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, STRING and Cytoscape software were used to identify the protein-protein interaction (PPI) network, and the molecular complex detection (MCODE) was used to identify the hub genes. Then the overlapping hub genes were predicted. RESULTS: Two molecular subtypes were found in women with PCOS based on the expression similarity of preterm labor or labor-related genes, in which two modules were highlighted. The key modules and PPI network have five overlapping five hub genes, two of which, GTF2F2 and MYO6 gene, were further confirmed by the comparison between clustering subgroups according to the expression of hub genes. CONCLUSIONS: Distinct PCOS molecular subtypes were identified with preterm labor or labor-related genes, which might uncover the potential mechanism underlying heterogeneity of clinical pregnancy complications in women with PCOS.

Melatonin mediates elevated carbon dioxide-induced photosynthesis and thermotolerance in tomato.

Increasing carbon dioxide (CO2 ) promotes photosynthesis and mitigates heat stress-induced deleterious effects on plants, but the regulatory mechanisms remain largely unknown. Here, we found that tomato (Solanum lycopersicum L.) plants treated with high atmospheric CO2 concentrations (600, 800, and 1000 µmol mol-1 ) accumulated increased levels of melatonin (N-acetyl-5-methoxy tryptamine) in their leaves and this response is conserved across many plant species, including Arabidopsis, rice, wheat, mustard, cucumber, watermelon, melon, and hot pepper. Elevated CO2 (eCO2 ; 800 µmol mol-1 ) caused a 6.8-fold increase in leaf melatonin content, and eCO2 -induced melatonin biosynthesis preferentially occurred through chloroplast biosynthetic pathways in tomato plants. Crucially, manipulation of endogenous melatonin levels by genetic means affected the eCO2 -induced accumulation of sugar and starch in tomato leaves. Furthermore, net photosynthetic rate, maximum photochemical efficiency of photosystem II, and transcript levels of chloroplast- and nuclear-encoded photosynthetic genes, such as rbcL, rbcS, rbcA, psaD, petB, and atpA, significantly increased in COMT1 overexpressing (COMT1-OE) tomato plants, but not in melatonin-deficient comt1 mutants at eCO2 conditions. While eCO2 enhanced plant tolerance to heat stress (42°C) in wild-type and COMT1-OE, melatonin deficiency compromised eCO2 -induced thermotolerance in comt1 plants. The expression of heat shock proteins genes increased in COMT1-OE but not in comt1 plants in response to eCO2 under heat stress. Further analysis revealed that eCO2 -induced thermotolerance was closely linked to the melatonin-dependent regulation of reactive oxygen species, redox homeostasis, cellular protein protection, and phytohormone metabolism. This study unveiled a crucial mechanism of elevated CO2 -induced thermotolerance in which melatonin acts as an essential endogenous signaling molecule in tomato plants.

Paeonol ameliorates endometrial hyperplasia in mice via inhibiting PI3K/AKT pathway-related ferroptosis.

BACKGROUND: Paeonol (Pae) is one of the active ingredients from components of Guizhi Fuling Capsule, a traditional Chinese medicine widely used for the treatment of women's diseases, which exhibits various biological and pharmacological activities. PURPOSE: The objective of this study was to investigate the molecular mechanism underlying the role of Pae in protecting against endometrial hyperplasia (EH). METHODS: CCK-8 assay was performed to detect the effect of Pae on cell proliferation. Hematoxylin and eosin (H&E) staining was performed to evaluate uterine tissue structure. A network pharmacology study was performed to search the disease targets. Single-cell transcriptome analysis was performed with uterine tissues from 3 healthy donors and 3 EH patients on 10X Genomics platform. Changes in lipid peroxidation were detected by the MDA reaction. IHC assay, Western blot, immunofluorescence and RT-qPCR were used to study the effects of estradiol and Pae on the expression levels of GPX4, PI3K, AKT, p-PI3K, p-AKT in mice. RESULTS: Pae treatment resulted in a decrease in cell viability of endometrial epithelial cells. Loss of uterus weight and morphology changes were observed in mice. In addition, Fe iron concentration and MDA levels increased, while the expression of GPX4, p-PI3K and p-AKT diminished. CONCLUSIONS: Pae exhibited obvious alleviative activity in estradiol-induced mice via PI3K/AKT signaling pathway-regulated ferroptosis.