The genomes of Dahlia pinnata, Cosmos bipinnatus, and Bidens alba in tribe Coreopsideae provide insights into polyploid evolution and inulin biosynthesis.

BACKGROUND: The Coreopsideae tribe, a subset of the Asteraceae family, encompasses economically vital genera like Dahlia, Cosmos, and Bidens, which are widely employed in medicine, horticulture, ecology, and food applications. Nevertheless, the lack of reference genomes hinders evolutionary and biological investigations in this tribe. RESULTS: Here, we present 3 haplotype-resolved chromosome-level reference genomes of the tribe Coreopsideae, including 2 popular flowering plants (Dahlia pinnata and Cosmos bipinnatus) and 1 invasive weed plant (Bidens alba), with assembled genome sizes 3.93 G, 1.02 G, and 1.87 G, respectively. We found that Gypsy transposable elements contribute mostly to the larger genome size of D. pinnata, and multiple chromosome rearrangements have occurred in tribe Coreopsideae. Besides the shared whole-genome duplication (WGD-2) in the Heliantheae alliance, our analyses showed that D. pinnata and B. alba each underwent an independent recent WGD-3 event: in D. pinnata, it is more likely to be a self-WGD, while in B. alba, it is from the hybridization of 2 ancestor species. Further, we identified key genes in the inulin metabolic pathway and found that the pseudogenization of 1-FEH1 and 1-FEH2 genes in D. pinnata and the deletion of 3 key residues of 1-FFT proteins in C. bipinnatus and B. alba may probably explain why D. pinnata produces much more inulin than the other 2 plants. CONCLUSIONS: Collectively, the genomic resources for the Coreopsideae tribe will promote phylogenomics in Asteraceae plants, facilitate ornamental molecular breeding improvements and inulin production, and help prevent invasive weeds.

Subclone from CT26 resistant to anti-PD-1 therapy associated with increased expression of genes related to glucocorticoids.

BACKGROUND: Although the use of anti-PD-1 antibodies has fundamentally changed traditional cancer treatment, most patients are resistant to anti-PD-1 treatment. Glucocorticoids (GCs) play an important role in tumorigenesis and tumor progression, but the role of endogenous GCs in resistance to anti-PD-1 antibody therapy remains unclear. METHODS: Single cell-derived cell lines (SCDCLs) were generated from a colorectal cancer cell line (CT26) using limiting dilution. We analyzed tumor tissues from anti-PD-1 antibody-treated and untreated mice inoculated with SCDCLs via transcriptome sequencing and flow cytometry to detect pathway activity and immune cell composition changes in the tumor microenvironment. RESULTS: Five SCDCLs were inoculated into wild-type BALB/c mice (all tumorigenic). Single-cell clone (SCC)-2 exhibited the slowest growth rates both in vivo and in vitro compared to other single-cell clones, and better long-term survival than SCC1 and CT26. Flow cytometry showed that SCC2 tumor-bearing mice exhibited significantly higher infiltration of T cells within the tumor tissue, and higher expression of PD-1 on these T cells than the other groups in vivo. However, the SCC2 group showed no response to anti-PD-1 therapy. Transcriptome analysis revealed that the SCC2 group exhibited increased expression of genes related to GC (Hsd11b1, Sgk3, Tgfbr2, and Il7r) compared to SCC2-anti-PD-1 treated tumors. CONCLUSIONS: GC pathway activation is related to resistance to anti-PD-1 therapy.

Causal relationship between anti-inflammatory drugs and cancer: a pan-cancer study with Mendelian randomization.

Background: Numerous epidemiological studies have elucidated the intricate connection between inflammation and cancer, highlighting how sustained inflammatory responses can fuel carcinogenesis by fostering proliferation, angiogenesis, and metastasis, while dampening immune responses and sensitivity to chemotherapy. Previous clinical investigations have underscored the potential of anti-inflammatory medications in either preventing or mitigating tumor formation. Here, the causal relationship between anti-inflammatory drugs and cancer was further explored through Mendelian randomization studies. Methods: Employing Mendelian randomization, we scrutinized the causal links between three anti-inflammatory drugs-NSAIDs, Aspirin, and Anilide-and 37 types of cancer. We primarily utilized inverse variance weighting (IVW) as the primary analytical approach to delineate the causal association between these drugs and cancer types. Concurrently, sensitivity analyses were conducted to ascertain the absence of horizontal pleiotropy and heterogeneity. Results: Our investigation revealed a discernible causal relationship between certain anti-inflammatory drugs and a subset of cancers, albeit without a pervasive impact across all cancer types. Specifically, NSAIDs exhibited a risk-reducing effect on non-small cell lung cancer (OR: 0.76, 95% CI: 0.59-0.97, p-value: 0.03) and gastric cancer (OR: 0.57, 95% CI: 0.34-0.98, p-value: 0.04). Conversely, aspirin was associated with an increased risk of oral malignant tumors (OR: 2.18, 95% CI: 1.13-4.21, p-value: 0.02). Notably, no statistically significant findings were observed for anilide drugs (p < 0.05). Conclusion: We identified several cancers with potential causal links to NSAIDs, including non-small cell lung cancer and gastric cancer. Despite our extensive analysis, we did not identify a substantial causal relationship between the use of anti-inflammatory drugs and the development of various cancers.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Neoadjuvant targeted immunotherapy followed by surgical resection versus upfront surgery for hepatocellular carcinoma with macrovascular invasion: A multicenter study.

Background: This study aimed to investigate the safety and efficacy of preoperative targeted immunotherapy followed by surgical resection for hepatocellular carcinoma (HCC) patients with macrovascular invasion. Method: Clinical information of HCC patients with macrovascular invasion was collected from four medical centers. These patients were divided into two cohorts: the upfront surgery group (n=40) and the neoadjuvant group (n=22). Comparisons between the two groups were made with appropriate statistical methods. Results: HCC Patients with macrovascular invasion in the neoadjuvant group were associated with increased incidence of postoperative ascites (72.73% vs. 37.5%, P=0.008), but shorter postoperative hospital stay (10 days vs. 14 days, P=0.032). Furthermore, targeted immunotherapy followed by surgical resection significantly reduced the postoperative recurrence rate at both 3 months and 1 year (9% versus 28.9%, 32.1% versus 67.9%, respectively; P=0.018), but increased the postoperative nononcologic mortality rate within 1 year (20.1% vs. 2.8%; P= 0.036). Conclusion: For HCC patients with macrovascular invasion, preoperative targeted immunotherapy significantly decreased the postoperative tumor recurrence rate while maintaining relative safety, but such a treatment may also result in chronic liver damage and increased risk of nononcologic mortality.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

Associations of dietary factors with gastric cancer risk: insights from NHANES 2003-2016 and mendelian randomization analyses.

Background: Gastric cancer (GC) continues to be one of the leading causes of cancer-related deaths globally. Diet significantly influences the incidence and progression of GC. However, the relationship between dietary intake and GC is inconsistent. Methods: A study was conducted with adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016 to investigate possible associations between 32 dietary factors and GC. To further detect potential causal relationships between these dietary factors and the risk of GC, a two-sample Mendelian randomization (MR) analysis was conducted. The primary method employed was the inverse variance weighted (IVW) analysis, and its results were further validated by four other methods. Results: Of the 35,098 participants surveyed, 20 had a history of GC. Based on the results of weighted logistic multivariate analysis, it was observed that there was a positive correlation between total fat intake [odds ratio (OR) = 1.09, 95% confidence interval (CI): (1.01-1.17), p = 0.03] and GC as well as negative association of dietary monounsaturated fatty acids (MUFAs) intake [OR = 0.83, 95% CI: (0.76-0.92), p < 0.001]. Further evaluations of the odds of GC across the quartiles of dietary MUFAs showed that the top quartile of total MUFA intake was associated with a lower likelihood of GC in three different models [model1: OR = 0.03, 95% CI: (0.00-0.25), p < 0.01; model2: OR = 0.04, 95% CI: (0.00-0.38), p = 0.01; model3: OR = 0.04, 95% CI: (0.00-0.40), p = 0.01]. For the MR analyses, genetic instruments were selected from the IEU Open GWAS project; IVW analysis showed that GC risk was not associated with MUFAs [OR = 0.82, 95% CI: (0.59-1.14), p = 0.23] or the ratio of MUFAs to total fatty acids [OR = 1.00, 95% CI: (0.75-1.35), p = 0.98]. Similar results were observed when using the other MR methods. Conclusion: The NHANES study revealed that consuming MUFAs was linked to a lower risk of GC, although the results of MR analyses do not provide evidence of a causal relationship. Additional research is therefore necessary to clarify these findings.

CXXC5 drove inflammation and ovarian cancer proliferation via transcriptional activation of ZNF143 and EGR1.

CXXC5, a zinc-finger protein, is known for its role in epigenetic regulation via binding to unmethylated CpG islands in gene promoters. As a transcription factor and epigenetic regulator, CXXC5 modulates various signaling processes and acts as a key coordinator. Altered expression or activity of CXXC5 has been linked to various pathological conditions, including tumorigenesis. Despite its known role in cancer, CXXC5's function and mechanism in ovarian cancer are unclear. We analyzed multiple public databases and found that CXXC5 is highly expressed in ovarian cancer, with high expression correlating with poor patient prognosis. We show that CXXC5 expression is regulated by oxygen concentration and is a direct target of HIF1A. CXXC5 is critical for maintaining the proliferative potential of ovarian cancer cells, with knockdown decreasing and overexpression increasing cell proliferation. Loss of CXXC5 led to inactivation of multiple inflammatory signaling pathways, while overexpression activated these pathways. Through in vitro and in vivo experiments, we confirmed ZNF143 and EGR1 as downstream transcription factors of CXXC5, mediating its proliferative potential in ovarian cancer. Our findings suggest that the CXXC5-ZNF143/EGR1 axis forms a network driving ovarian cell proliferation and tumorigenesis, and highlight CXXC5 as a potential therapeutic target for ovarian cancer treatment.

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling.

Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

Expressions of CXCR3 and PD-1 on T cells and their clinical relevance in colorectal cancer.

PURPOSE: Clinical application of immunotherapy represented by Programmed Death-1 (PD-1) monoclonal antibody has changed the treatment paradigm for colorectal cancer (CRC), and tumor-infiltrating T lymphocytes are critical for anti-PD-1 therapy in CRC. However, there are few studies on the relationship between the expression CXCR3 on T lymphocytes and the clinical aspects of CRC. In this study, we analyzed the expression levels of CXCR3 and PD-1 in CD8+ and CD4+ T lymphocytes in healthy donors (HDs) and patients with CRC. METHODS: We detected the expressions of CXCR3 and PD-1 on T lymphocytes in peripheral blood of healthy donors as well as peripheral blood, tumor tissue and para-cancerous tissues of patients with CRC using flow cytometry. We also analyzed the relationship between the expressions of CXCR3 and PD-1 on T lymphocytes and the pathological characteristics of CRC using t test. RESULTS: Expression of CXCR3 on tumor-infiltrating T lymphocytes was lower, whereas the expression of PD-1 was higher than that on para-cancerous tissues and PB in patients with CRC. In patients with lymph node metastasis of CRC, the expressions levels of CXCR3+ PD-1+ on tumor-infiltrating CD8+ and CD4+ T lymphocytes were higher than those in patients without lymph node metastasis. The levels of CXCR3+ PD-1+ expressions differed depending on the primary tumor site. CONCLUSION: Expressions of CXCR3 and PD-1 on tumor-infiltrating T lymphocytes are related to the development of CRC and metastasis, providing clues for exploring the pathogenesis of CRC and developing new strategies for tumor immunotherapy.

Precisely modulating the chromatin tracker via substituent engineering: reporting pathological oxidative stress during mitosis.

An in-depth understanding of cancer-cell mitosis presents unprecedented advantages for solving metastasis and proliferation of tumors, which has aroused great interest in visualizing the behavior via a luminescence tool. We developed a fluorescent molecule CBTZ-yne based on substituent engineering to acquire befitting lipophilicity and electrophilicity for anchoring lipid droplets and the nucleus, in which the low polarity environment and nucleic acids triggered a "weak-strong" fluorescence and "short-long" fluorescence-lifetime response. Meaningfully, CBTZ-yne visualized chromatin condensation, alignment, pull-push, and separation as well as lipid droplet dynamics, for the first time, precisely unveiling the asynchronous cellular mitosis processes affected by photo-generation reactive oxygen species according to the subtle change of fluorescence-lifetime. Our work suggested a new guideline for tracking the issue of the proliferation of malignant tumors in photodynamic therapy.

Adenosine Deaminase as a Potential Diagnostic and Prognostic Biomarker for Severe Fever with Thrombocytopenia Syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a serious infectious disease caused by the Dabie bandavirus, with a high mortality rate. Currently, there are no effective vaccines or specific treatments for SFTS. Early diagnosis and accurate severity assessment are crucial. METHODS: This study included 171 cases of SFTS, COVID-19, and hepatitis B virus (HBV) patients and healthy controls. We compared the serum adenosine deaminase (ADA) activity across these groups. The diagnostic and prognostic efficiency of serum ADA for SFTS was evaluated by using receiver operating characteristic (ROC) curve analysis. We also examined the correlation between serum ADA in SFTS patients and clinical lab parameters as well as serum cytokines. RESULTS: SFTS patients had significantly higher serum ADA activity than those of COVID-19, HBV patients, and healthy controls. Nonsurvivor SFTS patients had notably higher ADA than survivors. ROC analysis indicated ADA as an effective SFTS diagnostic and prognostic biomarker. ADA correlated with prognosis, viral load, APTT, PT, AST, ferritin, negatively with HDL-c and LDL-c, and positively with cytokines like IL-6, TNF-α, and IL-1ß. Multiorgan failure patients showed significant ADA increase. CONCLUSION: Elevated serum ADA activity in SFTS patients is linked with disease severity and prognosis, showing potential as a diagnostic and prognostic biomarker for SFTS.

Cucurbitacin IIa promotes the immunogenic cell death­inducing effect of doxorubicin and modulates immune microenvironment in liver cancer.

The immunogenic cell death (ICD) has aroused great interest in cancer immunotherapy. Doxorubicin (DOX), which can induce ICD, is a widely used chemotherapeutic drug in liver cancer. However, DOX­induced ICD is not potent enough to initiate a satisfactory immune response. Cucurbitacin IIa (CUIIa), a tetracyclic triterpene, is a biologically active compound present in the Cucurbitaceae family. The present study assessed the effects of the combination of DOX and CUIIa on the viability, colony formation, apoptosis and cell cycle of HepG2 cells. In vivo anticancer effect was performed in mice bearing H22 tumor xenografts. The hallmark expression of ICD was tested using immunofluorescence and an ATP assay kit. The immune microenvironment was analyzed using flow cytometry. The combination of CUIIa and DOX displayed potent apoptosis inducing, cell cycle arresting and in vivo anticancer effects, along with attenuated cardiotoxicity in H22 mice. The combination of DOX and CUIIa also facilitated ICD as manifested by elevated high­mobility group box 1, calreticulin and ATP secretion. This combination provoked a stronger immune response in H22 mice, including dendritic cell activation, increment of cytotoxic T cells and T helper 1 cells. Moreover, the proportion of immunosuppressive cells including myeloid­derived suppressor cells, T regulatory cells and M2­polarized macrophages, decreased. These data suggested that CUIIa is a promising combination partner with DOX for liver cancer treatment, probably via triggering ICD and remolding the immune microenvironment.

Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy.

Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-XL, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

An immune-related gene prognostic prediction risk model for neoadjuvant chemoradiotherapy in rectal cancer using artificial intelligence.

Background: This study aimed to establish and validate a prognostic model based on immune-related genes (IRGPM) for predicting disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy, and to elucidate the immune profiles associated with different prognostic outcomes. Methods: Transcriptomic and clinical data were sourced from the Gene Expression Omnibus (GEO) database and the West China Hospital database. We focused on genes from the RNA immune-oncology panel. The elastic net approach was employed to pinpoint immune-related genes significantly impacting DFS. We developed the IRGPM for rectal cancer using the random forest technique. Based on the IRGPM, we calculated prognostic risk scores to categorize patients into high-risk and low-risk groups. Comparative analysis of immune characteristics between these groups was conducted. Results: In this study, 407 LARC samples were analyzed. The elastic net identified a signature of 20 immune-related genes, forming the basis of the IRGPM. Kaplan-Meier survival analysis revealed a lower 5-year DFS in the high-risk group compared to the low-risk group. The receiver operating characteristic (ROC) curve affirmed the model's robust predictive capability. Validation of the model was performed in the GSE190826 cohort and our institution's cohort. Gene expression differences between high-risk and low-risk groups predominantly related to cytokine-cytokine receptor interactions. Notably, the low-risk group exhibited higher immune scores. Further analysis indicated a greater presence of activated B cells, activated CD8 T cells, central memory CD8 T cells, macrophages, T follicular helper cells, and type 2 helper cells in the low-risk group. Additionally, immune checkpoint analysis revealed elevated PDCD1 expression in the low-risk group. Conclusions: The IRGPM, developed through random forest and elastic net methodologies, demonstrates potential in distinguishing DFS among LARC patients receiving standard treatment. Notably, the low-risk group, as defined by the IRGPM, showed enhanced activation of adaptive immune responses within the tumor microenvironment.

Three-Four Photon Transition Mn(II) Complex Monitoring Lysosome-Related ATP in Real Time via Fluorescence Lifetime Imaging.

Currently, in situ monitoring of the adenosine triphosphate (ATP) level in lysosomes is critical to understand their involvement in various biological processes, but it remains difficult due to the interferences of limited targeting and low resolution of fluorescent probes. Herein, we report a classic Mn(II) probe (FX2-MnCl2) with near-infrared (NIR) nonlinear (NLO) properties, accompanied by three-four photon transition and fivefold fluorescence enhancement in the presence of ATP. FX2-MnCl2 combines with ATP through dual recognition sites of diethoxy and manganese ions to reflect slightly fluorescence lifetime change. Through the synergy of multiphoton fluorescence imaging (MP-FI) and multiphoton fluorescence lifetime imaging microscopy (MP-FLIM), it is further demonstrated that FX2-MnCl2 displays lysosome-specific targeting behavior, which can monitor lysosome-related ATP migration under NIR laser light. This work provides a novel multiphoton transformation fluorescence complex, which might be a potential candidate as a simple and straightforward biomarker of lysosome ATP in vitro for clinical diagnosis.

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between cardiovascular diseases and frozen shoulder.

BACKGROUND: Although prior observational studies indicate an association between cardiovascular diseases (CVDs) and frozen shoulder (FS), the potential causal relationship between them remains uncertain. This study aims to explore the genetic causal relationship between CVDs and FS using Mendelian randomization (MR). METHODS: Genetic variations closely associated with FS were obtained from the FinnGen Consortium. Summary data for CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), stroke, and ischemic stroke (IS), were sourced from several large-scale genome-wide association studies (GWAS). MR analysis was performed using inverse variance weighting (IVW), MR Egger, and weighted median methods. IVW, as the primary MR analysis method, complemented by other sensitivity analyses, was utilized to validate the robustness of the results. Further reverse MR analysis was conducted to explore the presence of reverse causal relationships. RESULTS: In the forward MR analysis, genetically determined risk of stroke and IS was positively associated with FS (OR [95% CI] = 1.58 (1.23-2.03), P < 0.01; OR [95% CI] = 1.46 (1.16-1.85), P < 0.01, respectively). There was no strong evidence of an effect of genetically predicted other CVDs on FS risk. Sensitivity analyses confirmed the robustness of the results. In the reverse MR analysis, no causal relationships were observed between FS and various CVDs. CONCLUSION: The study suggests that stroke increases the risk of developing FS. However, further basic and clinical research is needed to substantiate our findings.

Ghrelin in Focus: Dissecting Its Critical Roles in Gastrointestinal Pathologies and Therapies.

This review elucidates the critical role of ghrelin, a peptide hormone mainly synthesized in the stomach in various gastrointestinal (GI) diseases. Ghrelin participates in diverse biological functions ranging from appetite regulation to impacting autophagy and apoptosis. In sepsis, it reduces intestinal barrier damage by inhibiting inflammatory responses, enhancing GI blood flow, and modulating cellular processes like autophagy and apoptosis. Notably, in inflammatory bowel disease (IBD), serum ghrelin levels serve as markers for distinguishing between active and remission phases, underscoring its potential in IBD treatment. In gastric cancer, ghrelin acts as an early risk marker, and due to its significant role in increasing the proliferation and migration of gastric cancer cells, the ghrelin-GHS-R axis is poised to become a target for gastric cancer treatment. The role of ghrelin in colorectal cancer (CRC) remains controversial; however, ghrelin analogs have demonstrated substantial benefits in treating cachexia associated with CRC, highlighting the therapeutic potential of ghrelin. Nonetheless, the complex interplay between ghrelin's protective and potential tumorigenic effects necessitates a cautious approach to its therapeutic application. In post-GI surgery scenarios, ghrelin and its analogs could be instrumental in enhancing recovery and reducing complications. This article accentuates ghrelin's multifunctionality, shedding light on its influence on disease mechanisms, including inflammatory responses and cancer progression, and examines its therapeutic potential in GI surgeries and disorders, advocating for continued research in this evolving field.

Betulinic acid arrests cell cycle at G2/M phase by up-regulating metallothionein 1G inhibiting proliferation of colon cancer cells.

Betulinic acid (BA) is a pentacyclic triterpene found in many plant species and has a broad-spectrum anti-tumor effect in various cancers, including colon cancer (CRC). However, its anticancer mechanism in CRC is no clear. RNA sequencing and bioinformatics analysis showed BA up-regulated 378 genes and down-regulated 137 genes in HT29 cells, while 2303 up-regulated and 1041 down-regulated genes were found in SW480 cells. KEGG enrichment analysis showed BA significantly stimulated the expression of metallothionein 1 (MT1) family genes in both HT29 and SW480 cells. Metallothionein 1G (MT1G) was the gene with the highest upregulation of MT1 family genes induced by BA dose-dependently. High MT1G expression enhanced the sensitivity of CRC cells to BA, whereas, MT1G knockdown had the opposite effect in vitro and in vivo. GSEA and GSCA showed genes affected by BA treatment were involved in cell cycle and G2/M checkpoint in CRC. Flow cytometry further exhibited BA reduced the percentage of G0/G1 cells and increased the percentage of G2/M cells in a dose-dependent manner, which could be rescued by MT1G knockdown. Moreover, MT1G also counteracted the BA-induced changes in cell cycle-related proteins (CDK2 and CDK4) and p-Rb. In summary, we have revealed a new anti-tumor mechanism that BA altered the cell cycle progression of CRC cells by upregulating MT1G gene, thereby inhibiting the proliferation of CRC cells.

Haplotype-resolved chromosome-level genome of hexaploid Jerusalem artichoke provides insights into its origin, evolution, and inulin metabolism.

Jerusalem artichoke (Helianthus tuberosus) is a global multifunctional crop. It has wide applications in the food, health, feed, and biofuel industries and in ecological protection; it also serves as a germplasm pool for breeding of the global oil crop common sunflower (Helianthus annuus). However, biological studies of Jerusalem artichoke have been hindered by a lack of genome sequences, and its high polyploidy and large genome size have posed challenges to genome assembly. Here, we report a 21-Gb chromosome-level assembly of the hexaploid Jerusalem artichoke genome, which comprises 17 homologous groups, each with 6 pseudochromosomes. We found multiple large-scale chromosome rearrangements between Jerusalem artichoke and common sunflower, and our results show that the hexaploid genome of Jerusalem artichoke was formed by a hybridization event between a tetraploid and a diploid Helianthus species, followed by chromosome doubling of the hybrid, which occurred approximately 2 million years ago. Moreover, we identified more copies of actively expressed genes involved in inulin metabolism and showed that these genes may still be undergoing loss of function or sub- or neofunctionalization. These genomic resources will promote further biological studies, breeding improvement, and industrial utilization of Helianthus crops.