Jianming Yang, Geng Pei, Xuan Sun, Yawen Xiao, Chunhui Miao, Lu Zhou, Bangmao Wang, Liu Yang, Mingyu Yu, Zhi-Song Zhang, Evan T Keller, Zhi Yao, Quan Wang <<<

BACKGROUND: The pathogenesis of inflammatory bowel diseases (IBD) is multifactorial, and diagnostic and treatment strategies for IBD remain to be developed. RhoB regulates multiple cell functions; however, its role in colitis is unexplored.RESULTS: Here, we found RhoB was dramatically increased in colon tissues of ulcerative colitis (UC) patients and mice with DSS-induced colitis. Compared with wild type mice, RhoB+/- and RhoB-/- mice developed milder DSS-induced colitis and increased goblet cell numbers and IEC proliferation. Decreased RhoB promoted goblet cell differentiation and epithelial regeneration through inhibiting Wnt signaling pathway and activating p38 MAPK signaling pathway. Moreover, increased SCFA-producing bacteria and SCFA concentrations were detected in intestinal microbiome of both RhoB+/- and RhoB-/- mice and upregulated SCFA receptor expression was also observed.CONCLUSIONS: Taken together, a higher level of RhoB is associated with UC, which also contributes to UC development through modulating cell signaling and altering intestinal bacterial composition and metabolites. These observations suggest that RhoB has potential as a biomarker and a treatment target for UC. Video Abstract. <<<

Wen Zhang, Mengze Lyu, Nicholas J Bessman, Zili Xie, Mohammad Arifuzzaman, Hiroshi Yano, Christopher N Parkhurst, Coco Chu, Lei Zhou, Gregory G Putzel, Ting-Ting Li, Wen-Bing Jin, Jordan Zhou, JRI Live Cell Bank, Hongzhen Hu, Amy M Tsou, Chun-Jun Guo, David Artis <<<

Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1 nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with GramClostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1 nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis. <<<

Brent Brown, Vanshika Ojha, Ingo Fricke, Suhaila A Al-Sheboul, Chinua Imarogbe, Tanya Gravier, Michael Green, Lori Peterson, Ivoyl P Koutsaroff, Ayça Demir, Jonatane Andrieu, Chiuan Yee Leow, Chiuan Herng Leow <<<

The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense single-stranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist. Historical pandemics include smallpox and influenza, with efficacious therapeutics utilized to reduce overall disease burden through effectively targeting a competent host immune system response. The immune system is composed of primary/secondary lymphoid structures with initially eight types of immune cell types, and many other subtypes, traversing cell membranes utilizing cell signaling cascades that contribute towards clearance of pathogenic proteins. Other proteins discussed include cluster of differentiation (CD) markers, major histocompatibility complexes (MHC), pleiotropic interleukins (IL), and chemokines (CXC). The historical concepts of host immunity are the innate and adaptive immune systems. The adaptive immune system is represented by T cells, B cells, and antibodies. The innate immune system is represented by macrophages, neutrophils, dendritic cells, and the complement system. Other viruses can affect and regulate cell cycle progression for example, in cancers that include human papillomavirus (HPV: cervical carcinoma), Epstein-Barr virus (EBV: lymphoma), Hepatitis B and C (HB/HC: hepatocellular carcinoma) and human T cell Leukemia Virus-1 (T cell leukemia). Bacterial infections also increase the risk of developing cancer (e.g., ). Viral and bacterial factors can cause both morbidity and mortality alongside being transmitted within clinical and community settings through affecting a host immune response. Therefore, it is appropriate to contextualize advances in single cell sequencing in conjunction with other laboratory techniques allowing insights into immune cell characterization. These developments offer improved clarity and understanding that overlap with autoimmune conditions that could be affected by innate B cells (B1 or marginal zone cells) or adaptive T cell responses to SARS-CoV-2 infection and other pathologies. Thus, this review starts with an introduction into host respiratory infection before examining invaluable cellular messenger proteins and then individual immune cell markers. <<<

Annika Frede, Paulo Czarnewski, Gustavo Monasterio, Kumar P Tripathi, David A Bejarano, Ricardo O Ramirez Flores, Chiara Sorini, Ludvig Larsson, Xinxin Luo, Laura Geerlings, Claudio Novella-Rausell, Chiara Zagami, Raoul Kuiper, Rodrigo A Morales, Francisca Castillo, Matthew Hunt, Livia Lacerda Mariano, Yue O O Hu, Camilla Engblom, Ana-Maria Lennon-Duménil, Romy Mittenzwei, Astrid M Westendorf, Nadine Hövelmeyer, Joakim Lundeberg, Julio Saez-Rodriguez, Andreas Schlitzer, Srustidhar Das, Eduardo J Villablanca <<<

Therapeutic promotion of intestinal regeneration holds great promise, but defining the cellular mechanisms that influence tissue regeneration remains an unmet challenge. To gain insight into the process of mucosal healing, we longitudinally examined the immune cell composition during intestinal damage and regeneration. B cells were the dominant cell type in the healing colon, and single-cell RNA sequencing (scRNA-seq) revealed expansion of an IFN-induced B cell subset during experimental mucosal healing that predominantly located in damaged areas and associated with colitis severity. B cell depletion accelerated recovery upon injury, decreased epithelial ulceration, and enhanced gene expression programs associated with tissue remodeling. scRNA-seq from the epithelial and stromal compartments combined with spatial transcriptomics and multiplex immunostaining showed that B cells decreased interactions between stromal and epithelial cells during mucosal healing. Activated B cells disrupted the epithelial-stromal cross talk required for organoid survival. Thus, B cell expansion during injury impairs epithelial-stromal cell interactions required for mucosal healing, with implications for the treatment of IBD. <<<

Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8 T cells should be pursued to boost anti-tumor immunity. <<<

Shaohua Hu, Hao Xu, Xiaohua Meng, Xiangxiang Bai, Junli Xu, Jinru Ji, Chaoqun Ying, Yunbo Chen, Ping Shen, Yunxiao Zhou, Beiwen Zheng, Yonghong Xiao <<<

is an emerging species and has increasingly been reported to cause life-threatening infections and even outbreaks in humans. Nevertheless, there is little data regarding the geographical distribution, phylogenetic structure, and transmission across the globe, especially in Asia. We utilize whole-genome sequencing (WGS) data to define a global population framework, phylogenetic structure, geographical distribution, and transmission evaluation of pathogens. The geographical distribution diagram revealed the emerging pathogenic bacteria already distributed in various countries worldwide, especially in the USA and China. Strikingly, phylogenetic analysis showed a part of our China original shared the same ancestor with the USA outbreak strain, which implies the possibility of localized outbreaks and global spread. These closer related strains also contained ICEEaI, which might insert into a disrupted DNA repair gene and made the strain more liable to mutation and outbreak infection. BEAST analysis showed that the most recent common ancestor for ICEEaI was dated twelve years ago, and China might be the most likely recent source of this bacteria. Our study sheds light on the potential possibility of causing the large-scale outbreak and rapid global dissemination. Continued genomic surveillance of the dynamics of populations will generate further knowledge for optimizing future prevent global outbreak infections. <<<

The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine. <<<

The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy. <<<

With the aging population trend, there is a great demand for dysphagia diet as the elderly suffering from dysphagia is increasing rapidly. 3D printing is capable of processing mashed and not attractive dysphagia diet into appetizing foods with appealing appearance. Black fungus (Auricularia auricula) illustrates many health-promotion effects, but its elastic texture and great chewing efforts making it unfeasible for the elderly. In this work, we studied the feasibility to develop 3D printed visually appealing texture modified black fungus-based food as potential dysphagia diet, with addition of gums (0.3%, 0.6%, 0.9%, w/w), i.e. k-carrageenan gum (KG), xanthan gum (XG) and arabic gum (AG). Results indicated that KG and XG addition significantly increased the mechanical strength (yield stress and elasticity), viscosity, hardness and gumminess of ink samples by reducing water mobility and facilitating hydrogen bond formation, while AG addition showed an opposite effect. International dysphagia diet standardization initiative (IDDSI) tests indicated that AG and KG containing sample failed the spoon tilt test within IDDSI framework, while XG containing sample could be classified as level 5-minced and moist dysphagia diet. 3D printed samples using control or AG containing ink illustrated poor self-supporting capability. KG containing ink was not easy for extrusion with defective points in printed samples. In contrast, XG-0.9% samples demonstrated high printing precision with great self-supporting capability and smooth surface texture. This work provides insights for the development of visually appealing dysphagia diet using 3D printing. <<<

Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or dietary supplement, its molecular target(s) is debatable. Here, we showed that EPA and its metabolites strongly and reversibly inhibit vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and release of adenosine triphosphate (ATP) in purinergic chemical transmission. In vitro analysis showed that EPA inhibits human VNUT-mediated ATP uptake at a half-maximal inhibitory concentration (IC) of 67 nM, acting as an allosteric modulator through competition with Cl. EPA impaired vesicular ATP release from neurons without affecting the vesicular release of other neurotransmitters. In vivo, mice showed a delay in the onset of neuropathic pain and resistance to both neuropathic and inflammatory pain. EPA potently attenuated neuropathic and inflammatory pain in wild-type mice but not in mice without affecting the basal nociception. The analgesic effect of EPA was canceled by the intrathecal injection of purinoceptor agonists and was stronger than that of existing drugs used for neuropathic pain treatment, with few side effects. Neuropathic pain impaired insulin sensitivity in previous studies, which was improved by EPA in the wild-type mice but not in the mice. Our results showed that VNUT is a molecular target of EPA that attenuates neuropathic and inflammatory pain and insulin resistance. EPA may represent a unique nutrient-based treatment and prevention strategy for neurological, immunological, and metabolic diseases by targeting purinergic chemical transmission. <<<