Traditional Medicine Xianglian Pill Suppresses high-fat diet-related colorectal cancer via inactivating TLR4/MyD88 by remodeling gut microbiota composition and bile acid metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Previous studies have revealed that a high-fat diet (HFD) promotes the progression of colorectal cancer (CRC) in close association with disturbances in the intestinal flora and metabolic disorders. Xianglian pill (XLP) is a well-established traditional prescription with unique advantages in controlling intestinal flora imbalance and inflammation. However, its therapeutic effects on HFD-related CRC remain largely unknown. AIM OF THE STUDY: The primary objective of this research was to investigate the anticancer mechanism of XLP in countering HFD-related CRC. MATERIALS AND METHODS: The protective effect of XLP was evaluated using azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC model of mice exposed to a HFD. The degree of colorectal carcinogenesis, including body weight, colon length, and histopathology, was measured in mice treated with XLP and untreated mice. The effect of XLP on gut microbiota and its metabolites was detected using 16s rDNA and liquid chromatography/mass spectrometry analysis. Furthermore, a "pseudo-sterile" mouse model was constructed using antibiotics (Abx) to verify whether the gut microbiota and metabolites play a role in the pathogenesis of CRC. RESULTS: XLP inhibited colorectal tumorigenesis in a dose-dependent fashion. Our findings also highlighted that XLP protected the integrity of the intestinal barrier by reducing the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, as well as the infiltration of pro-inflammatory macrophages. Mechanistically, XLP inhibited the TLR4/MyD88 pathway. Notably, the XLP treatment increased the proportion of probiotics (particularly Akkermansia) and significantly reduced fecal deoxycholic acid (DCA), a microbiota-derived metabolite of bile acids (BA) closely related to Muribaculaceae. Furthermore, after Abx treatment, XLP showed no clear antitumor effects on CRC. Simultaneously, DCA-supplemented feedings promoted colorectal tumorigenesis and provoked obvious colonic inflammation, M1 macrophage infiltration, and colonic injury. In vitro, the results of RAW-264.7 macrophages and normal intestinal epithelial cells treated with DCA corroborated our in vivo findings, demonstrating consistent patterns in inflammatory responses and intestinal barrier protein expression. CONCLUSION: Our findings suggest that XLP inhibits colorectal cancer associated with HFD via inactivating TLR4/MyD88 by remodeling gut microbiota composition and BA metabolism.

Trappc1 intrinsically prevents ferroptosis of naive T cells to avoid spontaneous autoinflammatory disease in mice.

T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T-cell development and homeostasis is unknown. Using CD4cre -Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T-cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1+ CD45.2+ ) and Trappc1 cKO naive T cells (CD45.2+ ) to CD45.1+ syngeneic mice, Trappc1-deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA-seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca2+ , Atf4-CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis-related damage-associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL-6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T-cell homeostasis to avoid proinflammatory naive T-cell death-caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T-cell biology.

Single-cell transcriptomic analysis reveals transcriptional and cell subpopulation differences between human and pig immune cells.

BACKGROUND: The pig is a promising donor candidate for xenotransplantation. Understanding the differences between human and swine immune systems is critical for addressing xenotransplant rejection and hematopoietic reconstitution. The gene transcriptional profile differences between human and pig immune cell subpopulations have not been studied. To assess the similarities and differences between pigs and humans at the levels of gene transcriptional profiles or cell subpopulations are important for better understanding the cross-species similarity of humans and pigs, and it would help establish the fundamental principles necessary to genetically engineer donor pigs and improve xenotransplantation. OBJECTIVE: To assess the gene transcriptional similarities and differences between pigs and humans. METHODS: Two pigs and two healthy humans' PBMCs were sorted for 10 × genomics single-cell sequence. We generated integrated human-pig scRNA-seq data from human and pig PBMCs and defined the overall gene expression landscape of pig peripheral blood immune cell subpopulations by updating the set of human-porcine homologous genes. The subsets of immune cells were detected by flow cytometry. RESULTS: There were significantly less T cells, NK cells and monocytes but more B cells in pig peripheral blood than those in human peripheral blood. High oxidative phosphorylation, HIF-1, glycolysis, and lysosome-related gene expressions in pig CD14+ monocytes were observed, whereas pig CD14+ monocytes exhibited lower levels of cytokine receptors and JAK-STAT-related genes. Pig activated CD4+T cells decreased cell adhesion and inflammation, while enriched for migration and activation processes. Porcine GNLY+CD8+T cells reduced cytotoxicity and increased proliferation compared with human GNLY+CD8+T cells. Pig CD2+CD8+γδT cells were functionally homologous to human CD2+CD4+ γδT cells. Pig CD2-CD8-γδT cells expressed genes with quiescent and precursor characteristics, while CD2-CD8+γδT cells expressed migration and memory-related molecules. Pig CD24+ and CD5+B cells are associated with inflammatory responses. CONCLUSION: Our research with integrated scRNA-seq assays identified the different distribution of pig immune cell subpopulations and the different transcriptional profiles of human and pig immune cells. This study enables a deeper understanding of the development and function of porcine immune cells.

The Effects of IL-23/IL-18-Polarized Neutrophils on Renal Ischemia-Reperfusion Injury and Allogeneic-Skin-Graft Rejection in Mice.

Neutrophils display heterogeneity and plasticity with different subgroups and immune-regulatory functions under various surrounding conditions. Neutrophils induced by IL-23/IL-18 (referred to N(IL-23+IL-18) neutrophils) have a unique gene-expression profile, with highly expressing IL-17, MHC-II, and costimulatory molecules. The adoptive transfer of N(IL-23+IL-18) neutrophils significantly increased the pathogenesis in a renal ischemia-reperfusion injury mouse model. N(IL-23+IL-18) neutrophils directly and efficiently induced allogeneic T cell proliferation in vitro. N(IL-23+IL-18) neutrophils enhanced the syngeneic T cell response to allogeneic antigens in mixed-lymphocyte reaction assays. The adoptive transfer of the donor or host N(IL-23+IL-18) neutrophils significantly enhanced the antidonor antibody production in an allogeneic-skin-transplanted mouse model, accompanied by increased Tfh cells in the spleens. Therefore, the neutrophil subset induced by IL-23/IL-18 promotes tissue injury and antidonor humoral response in the allogeneic transplantation mouse model.

Soil acidification and salinity: the importance of biochar application to agricultural soils.

Soil acidity is a serious problem in agricultural lands as it directly affects the soil, crop production, and human health. Soil acidification in agricultural lands occurs due to the release of protons (H+) from the transforming reactions of various carbon, nitrogen, and sulfur-containing compounds. The use of biochar (BC) has emerged as an excellent tool to manage soil acidity owing to its alkaline nature and its appreciable ability to improve the soil's physical, chemical, and biological properties. The application of BC to acidic soils improves soil pH, soil organic matter (SOM), cation exchange capacity (CEC), nutrient uptake, microbial activity and diversity, and enzyme activities which mitigate the adverse impacts of acidity on plants. Further, BC application also reduce the concentration of H+ and Al3+ ions and other toxic metals which mitigate the soil acidity and supports plant growth. Similarly, soil salinity (SS) is also a serious concern across the globe and it has a direct impact on global production and food security. Due to its appreciable liming potential BC is also an important amendment to mitigate the adverse impacts of SS. The addition of BC to saline soils improves nutrient homeostasis, nutrient uptake, SOM, CEC, soil microbial activity, enzymatic activity, and water uptake and reduces the accumulation of toxic ions sodium (Na+ and chloride (Cl-). All these BC-mediated changes support plant growth by improving antioxidant activity, photosynthesis efficiency, stomata working, and decrease oxidative damage in plants. Thus, in the present review, we discussed the various mechanisms through which BC improves the soil properties and microbial and enzymatic activities to counter acidity and salinity problems. The present review will increase the existing knowledge about the role of BC to mitigate soil acidity and salinity problems. This will also provide new suggestions to readers on how this knowledge can be used to ameliorate acidic and saline soils.

Berberine inhibits high fat diet-associated colorectal cancer through modulation of the gut microbiota-mediated lysophosphatidylcholine.

Dietary fat intake is positively associated with elevated risk of colorectal cancer (CRC). Currently, clinical treatments remian inadequate bacause of the complex pathogenesis of CRC induced by a high-fat diet (HFD). Mechanistically, imbalances in gut microbiota are associated with HFD-associated colorectal tumourigenesis. Therefore, we investigated the anti-tumor activity of berberine (BBR) in modulating the dysregulated gut microbiota and related metabolites by preforming 16S rDNA sequencing and liquid chromatography/mass spectrometry. As expected, BBR treatment significantly decreased the number of colonic polyps, ameliorated gut barrier disruption, and inhibited colon inflammation and related oncogenic pathways in AOM/DSS-induced CRC model mice fed with an HFD. Furthermore, BBR alleviated gut microbiota dysbiosis and increased the abundance of beneficial gut microorganisms, including Akkermansia and Parabacteroides, in HFD-fed CRC mice. In addition, metabolomics analysis demonstrated significantly altered the glycerophospholipid metabolism during the progression of HFD-associated CRC in mice, whereas BBR treatment reverted these changes in glycerophospholipid metabolites, particularly lysophosphatidylcholine (LPC), which was confirmed to promote CRC cell proliferation and ameliorate cell junction impairment. Notably, BBR had no clear anti-tumor effects on HFD-fed CRC model mice with gut microbiota depletion, whereas transplantation of BBR-treated gut microbiota to gut microbiota-depleted CRC mice recapitulated the inhibitory effects of BBR on colorectal tumourigenesis and LPC levels. This study demonstrated that BBR inhibited HFD-associated CRC directly through modulating gut microbiota-regulated LPC levels, thereby providing a promising microbiota-modulating therapeutic strategy for the clinical prevention and treatment of Western diet-associated CRC.

Global research trends between gut microbiota and lung cancer from 2011 to 2022: A bibliometric and visualization analysis.

Background: An increasing number of studies have found that the gut microbiota was related to the occurrence and development of lung cancer. Nonetheless, publication trends and research hotspots in this field remain unknown. The study aimed to perform a bibliometric analysis to systematically identify publication trends and research hotspots in the field of gut microbiota and lung cancer research within a 12-year panorama. Methods: Publications related to the gut microbiota and lung cancer between 1 January 2011 and 25 October 2022 were retrieved from the Web of Science Core Collection (WoSCC) database. The online analytic tool of the WoSCC was used to analyze various bibliometric parameters. The bibliometrics website, CiteSpace, and VOSviewer were used to identify research trends and hotspots. Results: A total of 375 publications related to the gut microbiota and lung cancer were extracted from WoSCC and identified for analysis. The number of annual publications has grown rapidly since 2018 and reached a peak in 2022. China was the most prolific country in this field, with 120 publications, followed by the United States (114), with the highest H-index of 31. Additionally, France ranked the highest with an average of 133 citations, while the leading institution and journal were the Unicancer and the International Journal of Molecular Sciences, respectively. Interestingly, Routy Bertrand was the most prolific author and also the most cited author in terms of H-index and citations. Reference and keyword burst detection indicated that the research hotspots mainly included 1) the gut microbiota directly affects the efficacy of immunotherapy for lung cancer, 2) the application of different gut bacteria on lung cancer, and 3) the mechanism of the gut microbiota on lung cancer. Conclusion: The findings of this study revealed the general publication trends and evolving research hotspots in the field of gut microbiota and lung cancer at a global level. The research hotspots focused on the clinical application of the gut microbiota combined with immunotherapy in lung cancer and its mechanism. The findings of this study provide new perspectives on the field, which may shed light on a beneficial impact on further etiological studies, diagnosis, and treatment for lung cancer.

Bibliometric and visual analysis in the field of ketogenic diet on cancer from 2012 to 2021.

Increasing evidence demonstrated that the ketogenic diet (KD) played a positive effect on cancer treatment. However, no systematic review and bibliometric analysis were conducted in this field. This study aimed to explore the current status, and reveal the potential trends and hotspots to provide a reference for future research. Publications were extracted from the Web of Science Core Collection. CiteSpace (5.6.R3) software and the website of bibliometrics were used for visual analysis. A total of 500 publications with 334 articles and 166 reviews were included, with the timespan of 2012 to 2021. The United States was the most productive country. Majority of the top 10 institutions were from the United States, and Harvard University was the top-contributing institution. The most prolific author and the co-cited author was Thomas N Seyfried from Boston College. The highest cited reference was published in PLoS ONE, authored by Abdelwahab Mohammed G, with 161 citations. Glioma and breast cancer were the most common types of cancer in this field, while hepatocellular carcinoma and pancreatic cancer were the new hotspots. The anti-tumor mechanism of KD mainly focused on regulating metabolism, decanoic acid, oxidative stress, fatty acid oxidation, and cell apoptosis. Additionally, the presence of "chemotherapy" and "radiotherapy" in the keywords indicated that KD combined with anti-tumor research was a topic, while "immunotherapy" has became a recent frontiers. Notably, as a metabolic therapy, KD was deserved more attention in the treatment of hepatocellular carcinoma and pancreatic cancer, and KD combined with immunotherapy was the new hotspot and frontier. Additionally, more molecular studies and high-quality uniformly, randomized, controlled clinical trials are urgently warranted to evaluate the effect of KD in multiple cancers.

Traditional Chinese Medicines as Effective Reversals of Epithelial-Mesenchymal Transition Induced-Metastasis of Colorectal Cancer: Molecular Targets and Mechanisms.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Distant metastasis is the major cause of cancer-related mortality in patients with CRC. Epithelial-mesenchymal transition (EMT) is a critical process triggered during tumor metastasis, which is also the main impetus and the essential access within this duration. Therefore, targeting EMT-related molecular pathways has been considered a novel strategy to explore effective therapeutic agents against metastatic CRC. Traditional Chinese medicines (TCMs) with unique properties multi-target and multi-link that exert their therapeutic efficacies holistically, which could inhibit the invasion and metastasis ability of CRC cells via inhibiting the EMT process by down-regulating transforming growth factor-ß (TGF-ß)/Smads, PI3K/Akt, NF-κB, Wnt/ß-catenin, and Notch signaling pathways. The objective of this review is to summarize and assess the anti-metastatic effect of TCM-originated bioactive compounds and Chinese medicine formulas by mediating EMT-associated signaling pathways in CRC therapy, providing a foundation for further research on the exact mechanisms of action through which TCMs affect EMT transform in CRC.

Skin and heart allograft rejection solely by long-lived alloreactive TRM cells in skin of severe combined immunodeficient mice.

Whether induced tissue-resident memory T (TRM) cells in nonlymphoid organs alone can mediate allograft rejection is unknown. By grafting alloskin or heart into severe combined immunodeficient or Rag2KO mice in which a piece of induced CD4+ and/or CD8+ TRM cell-containing MHC-matched or syngeneic skin was transplanted in advance, we addressed this issue. The induced CD4+ TRM cells in the skin alone acutely rejected alloskin or heart grafts. RNA-seq analysis showed that induced CD4+ TRM cells in skin favorably differentiated into TH17-like polarization during the secondary immune response. Inhibition of the key TH17 signaling molecule RORγt attenuated TRM cell-mediated graft rejection. Thus, we offer a unique mouse model to specifically study TRM cell-mediated allograft rejection without the involvement of lymphocytes in lymphoid organs and tissues. Our study provides strong evidence supporting the hypothesis that long-lived alloreactive TRM cells resident in other organs/tissues substantially contribute to organ allograft rejection.

The formation of spreading front: the singular limit of three-component reaction-diffusion models.

Understanding the invasion processes of biological species is a fundamental issue in ecology. Several mathematical models have been proposed to estimate the spreading speed of species. In recent decades, it was reported that some mathematical models of population dynamics have an explicit form of the evolution equations for the spreading front, which are represented by free boundary problems such as the Stefan-like problem (e.g., Mimura et al., Jpn J Appl Math 2:151-186, 1985; Du and Lin, SIAM J Math Anal 42:377-405, 2010). To understand the formation of the spreading front, in this paper, we will consider the singular limit of three-component reaction-diffusion models and give some interpretations for spreading front from the viewpoint of modeling. As an application, we revisit the issue of the spread of the grey squirrel in the UK and estimate the spreading speed of the grey squirrel based on our result. Also, we discuss the relation between some free boundary problems related to population dynamics and mathematical models describing Controlling Invasive Alien Species. Lastly, we numerically consider the traveling wave solutions, which give information on the spreading behavior of invasive species.

Upper Limb Proprioceptive Acuity Assessment Based on Three-Dimensional Position Measurement Systems.

The aim of the current work was to verify three-dimensional directional effects on the reproduction error precision of the human upper limb position. Thirty male subjects without history of upper limb pathology were recruited from Renmin University of China. A three-dimensional position reproduction task in six directions (up, down, left, right, far, and near) was performed by each subject. The results suggested that the proprioceptive sense of upper limb position depends on the direction, with smaller absolute errors in Directions 4 (right) and 5 (far) than in Directions 1 (up), 2 (down), 3 (left), and 6 (near). Proprioception near the end of the elbow joint range of motion may be more reliable and sensitive. Subjects reproduced fewer ranges in the horizontal plane (Directions 3, 5, and 6) and they overshot the target position along the z-axis (vertical direction) except for Direction 6. Overestimations of position in the z-axis may be caused by overestimations of force.

Test-retest reliability of tip, key, and palmar pinch force sense in healthy adults.

BACKGROUND: No previous studies have investigated the test-retest reliability of tip, key, and palmar pinch force sense in healthy adults. The present study explores the test-retest reliability of tip, key, and palmar pinch force sense for different force levels in healthy adults during an ipsilateral force reproduction task. METHODS: Fifty-six healthy subjects were instructed to produce varying levels of reference forces (10, 30, and 50% maximal voluntary isometric contraction (MVIC)) using three types of pinches (tip pinch, palmar pinch, and key pinch) and to reproduce these forces using the same hand. The subjects were tested twice by the same experienced testers, 1 week apart. RESULTS: Based on the high values of the intraclass correlation coefficient (ICC), the tip pinch (0.783-0.895) and palmar pinch (0.752-0.903) force sense tests demonstrated good reliability for all the variables. The ICCs for the key pinch (0.712-0.881) indicated fair to good relative test-retest reliability. CONCLUSION: 1) This study demonstrates that high test-retest reliability of tip, key, and palmar pinch force sense in healthy adults can be achieved using standardized positioning and the proposed approach. 2) According to the reliability measurements, 30 and 50% maximal voluntary isometric contraction (MVIC) are the most reliable pinch force sense levels.