Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas.

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.

Pyroptosis-mediator GSDMD promotes Parkinson's disease pathology via microglial activation and dopaminergic neuronal death.

GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.

Rhubarb extract rebuilding the mucus homeostasis and regulating mucin-associated flora to relieve constipation.

In clinical trials, rhubarb extract (Rb) was demonstrated to efficiently alleviate constipation. We would like to find out the underlying mechanism of rhubarb relieving constipation. However, there are few studies on the effects of rhubarb on colonic mucus secretion and constipation. The aim of this study was to investigate the effects of rhubarb on colonic mucus secretion and its underlying mechanism. The mice were randomly divided into four groups. Group I was the control group and Group II was the rhubarb control group, with Rb (24 g/kg body weight [b.w.]) administered through intragastric administration for three days. Group III mice were given diphenoxylate (20 mg/kg b.w.) for five days via gavage to induce constipation. Group IV received diphenoxylate lasting five days before undergoing Rb administration for three days. The condition of the colon was evaluated using an endoscope. Particularly, the diameter of blood vessels in the colonic mucosa expanded considerably in constipation mice along with diminishing mucus output, which was in line with the observation via scanning electron microscope (SEM) and transmission electron microscope (TEM). We also performed metagenomic analysis to reveal the microbiome related to mucin gene expression level referring to mucin secretion. In conclusion, Rb relieves constipation by rebuilding mucus homeostasis and regulating the microbiome.

Reviving Zn0 Dendrites to Electroactive Zn2+ by Mesoporous MXene with Active Edge Sites.

Zinc metal-based aqueous batteries (ZABs) offer a sustainable, affordable, and safe energy storage alternative to lithium, yet inevitable dendrite formation impedes their wide use, especially under long-term and high-rate cycles. How the battery can survive after dendrite formation remains an open question. Here, we pivot from conventional Zn dendrite growth suppression strategies, introducing proactive dendrite-digesting chemistry via a mesoporous Ti3C2 MXene (MesoTi3C2)-wrapped polypropylene separator. Spectroscopic characterizations and electrochemical evaluation demonstrate that MesoTi3C2, acting as an oxidant, can revive the formed dead Zn0 dendrites into electroactive Zn2+ ions through a spontaneous redox process. Density functional theory reveals that the abundant edge-Ti-O sites in our MesoTi3C2 facilitate high oxidizability and electron transfer from Zn0 dendrites compared to their in-plane counterparts. The resultant asymmetrical cell demonstrates remarkable ultralong cycle life of 2200 h at a practical current of 5 mA cm-2 with a low overpotential (<50 mV). The study reveals the unexpected edge effect of mesoporous MXenes and uncovers a new proactive dendrite-digesting chemistry to survive ZABs, albeit with inevitable dendrite formation.

Multiple ossified intracranial and spinal meningiomas: a rare case report and literature review.

Ossified intracranial meningiomas (OIM) and ossified spinal meningiomas (OSM) are rare neoplasms of mesenchymal origin that predominantly manifest in the spinal cord and infrequently in the cranial region, accounting for ~0. 7-5.5% of all meningiomas. It is extremely rare to have multiple intracranial and spinal lesions accompanied by ossification. Herein, we report this rare case for the first time. A 34-year-old woman presented with paresthesia and limb weakness in the right lower limb and gradually worsened. Approximately half a year later, she could only walk with crutches. Magnetic resonance imaging of the brain and spinal cord showed multiple meningiomas, and histopathological examination confirmed multiple OIM and OSM (WHO grade 1). Multiple OIM and OSM are extremely rare with diverse imaging features, and it is easily confused with other tumors. Histopathological examination is the final diagnostic method.

Current perspective on biological properties of plasmacytoid dendritic cells and dysfunction in gut.

Plasmacytoid dendritic cells (pDCs), a subtype of DC, possess unique developmental, morphological, and functional traits that have sparked much debate over the years whether they should be categorized as DCs. The digestive system has the greatest mucosal tissue overall, and the pDC therein is responsible for shaping the adaptive and innate immunity of the gastrointestinal tract, resisting pathogen invasion through generating type I interferons, presenting antigens, and participating in immunological responses. Therefore, its alleged importance in the gut has received a lot of attention in recent years, and a fresh functional overview is still required. Here, we summarize the current understanding of mouse and human pDCs, ranging from their formation and different qualities compared with related cell types to their functional characteristics in intestinal disorders, including colon cancer, infections, autoimmune diseases, and intestinal graft-versus-host disease. The purpose of this review is to convey our insights, demonstrate the limits of existing research, and lay a theoretical foundation for the rational development and use of pDCs in future clinical practice.

Association of human telomerase reverse transcriptase promoter mutation with unfavorable prognosis in glioma: A systematic review and meta-analysis.

Background: Glioma is one of the most malignant and aggressive tumors, with an extremely poor prognosis. Human telomerase reverse transcriptase (hTERT) promoter mutation is regarded as a risk factor in tumor growth. Although the prevalence of hTERT promoter (pTERT) mutation in gliomas has been investigated, the results are inconsistent. This meta-analysis aims to investigate the prognostic value of hTERT in glioma patients and its interaction with other biomarkers. Materials and Methods: We searched 244 citations from four databases: PubMed (2000-2021), Web of Science (2000-2021), Embase (2010-2021), and Cochrane Library (2000-2021) with 28 articles included. Results: We calculated hazard ratios (HRs) using the random effect model and the pooled result suggested that TERT promoter mutation predicted poorer overall survival (HR: 1.53, 95% confidence interval [CI]: 1.34-1.75, P < 0.001, I2: 49.9%, pheterogeneity:0.002) and progression-free survival (HR: 1.55, 95% CI: 1.27-1.88, P < 0.001, I2: 0.0%, pheterogeneity: 0.473). For subgroup analysis, we analyzed multiple factors including iso-citrate dehydrogenase (IDH) genotype, age, diagnosis, pTERT region, so as to locate the sources of heterogeneity. Interestingly, in IDH mutant subgroup, pTERT mutation became a beneficial prognostic factor (HR: 0.73, 95% CI: 0.57-0.93, I2: 22.3%, pheterogeneity: 0.277), which is contrary to the results in pooled analysis. Conclusion: In general, pTERT mutation may result in shorter survival time in glioma patients, but longer survival time when glioma patients are combined with IDH mutation.

Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer.

Targeted therapies in cancer treatment can improve in vivo efficacy and reduce adverse effects by altering the tissue exposure of specific biomolecules. However, there are still large number of target proteins in cancer are still undruggable, owing to the following factors including (1) lack of ligand-binding pockets, (2) function based on protein-protein interactions (PPIs), (3) the highly specific conserved active sites among protein family members, and (4) the variability of tertiary docking structures. The current status of undruggable targets proteins such as KRAS, TP53, C-MYC, PTP, are carefully introduced in this review. Some novel techniques and drug designing strategies have been applicated for overcoming these undruggable proteins, and the most classic and well-known technology is proteolysis targeting chimeras (PROTACs). In this review, the novel drug development strategies including targeting protein degradation, targeting PPI, targeting intrinsically disordered regions, as well as targeting protein-DNA binding are described, and we also discuss the potential of these strategies for overcoming the undruggable targets. Besides, intelligence-assisted technologies like Alpha-Fold help us a lot to predict the protein structure, which is beneficial for drug development. The discovery of new targets and the development of drugs targeting them, especially those undruggable targets, remain a huge challenge. New drug development strategies, better extraction processes that do not disrupt protein-protein interactions, and more precise artificial intelligence technologies may provide significant assistance in overcoming these undruggable targets.

Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas.

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into the activated B-cell (ABC) and germinal center B cell-like (GCB) subtypes. Self-antigen engagement of B-cell receptors (BCR) in ABC tumors induces their clustering, thereby initiating chronic active signaling and activation of NF-κB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR-Cas9 screens to identify regulators of IRF4, a direct transcriptional target of NF-κB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-κB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers. SIGNIFICANCE: DLBCL depends on constitutive BCR activation and signaling. There are currently no therapeutics that target the BCR directly and attenuate its pathologic signaling. Here, we unraveled a therapeutically exploitable, OST-B-dependent glycosylation pathway that drives BCR organization and proximal BCR signaling. This article is highlighted in the In This Issue feature, p. 1749.

Mycophenolate mofetil-associated collagenous ileitis in a kidney transplant recipient: A case report.

We report a case of mycophenolate mofetil-induced collagenous ileitis in a kidney transplant patient. A 38-year-old Chinese man who had received a kidney transplant 3 years earlier was admitted to our department for severe diarrhea and rapid weight loss. Infection studies were negative, and tumors were ruled out, so drug-induced factors were suspected. He had been taking mycophenolate mofetil for immunosuppression, which was then suspended, and he had a rapid resolution of diarrhea. Pathological findings of gastrointestinal endoscopy biopsy showed the presence of thickened collagen bands in the subepithelium of the terminal ileum. This is the first report of collagenous ileitis caused by mycophenolate mofetil in a patient with a kidney transplantation, adding another reversible cause to this rare condition. It is important for clinicians to recognize and treat it promptly.

The self-powered electrochemical biosensing platform with multi-amplification strategy for ultrasensitive detection of microRNA-155.

A self-powered biosensor (SPB) was constructed for the ultra-sensitive detection of microRNA-155 (miR-155) by combining a capacitor/enzymatic biofuel cell (EBFC), a strategy of rolling circle amplification (RCA) and a digital multimeter (DMM). The experimental results show that the sensitivity of the assembled EBFC-SPB can reach 15.85 µA/pM with the action of matching capacitor, which is 513% of that without capacitor (3.09 µA/pM). This achieves the first signal amplification. Furthermore, when the target miR-155 triggers RCA, electrons are continuous generated and flow to the biocathode through the external circuit to catalyze the reduction of oxygen and release [Ru(NH3)6]3+ electron acceptor. This achieves the second signal amplification. Finally, DMM is used to convert the signal into instantaneous current and amplify it for real-time reading. This achieves the third signal amplification. Therefore, the limit of detection (LOD) of the developed biosensor is as low as 0.17 fM (S/N = 3), and the linear range is between 0.5 fM and 10,000 fM, indicating that the EBFC-SPB has a broad application prospect for cancer marker of miR-155 with ultrasensitive detection.

Corrigendum: Endoplasmic reticulum stress of gut enterocyte and intestinal diseases.

[This corrects the article DOI: 10.3389/fmolb.2022.817392.].

Insight into the Role of Psychological Factors in Oral Mucosa Diseases.

With the development of psychology and medicine, more and more diseases have found their psychological origins and associations, especially ulceration and other mucosal injuries, within the digestive system. However, the association of psychological factors with lesions of the oral mucosa, including oral squamous cell carcinoma (OSCC), burning mouth syndrome (BMS), and recurrent aphthous stomatitis (RAS), have not been fully characterized. In this review, after introducing the association between psychological and nervous factors and diseases, we provide detailed descriptions of the psychology and nerve fibers involved in the pathology of OSCC, BMS, and RAS, pointing out the underlying mechanisms and suggesting the clinical indications.

The function of nuclear hormone receptor 4A signaling in the human reproductive system: A review.

AIM: This review aims to summarize the research focused upon the functions of nuclear hormone receptor 4A (NR4A) in the human reproductive system. The research questions addressed are to decipher what role the NR4A subfamily plays in the regulation of the human reproductive system and effects upon fertility issues through regulation of the expression of the NR4A subfamily. METHODS: The electronic database PubMed was searched for studies published before November 2021. Keywords included "NR4A," "trophoblast," "decidualization," "folliculogenesis," "estrogen," "pregnancy," "Leydig cells," "fertility," and "reproductive." Relevant references from retrieved manuscripts and review articles were also searched manually. RESULTS: NR4A subfamily are involved in trophoblast differentiation, endometrial decidualization, embryo adhesion, secretion of related hormones, and regulation of spontaneous term labor. Besides, many studies have provided strong evidence that they play critical roles in spermatogenesis. Furthermore, Multiple mechanisms can affect the expression of NR4As. Broadly, NR4A family receptors affect the human reproductive system in multiple ways. CONCLUSIONS: Further research is needed to specifically dissect the functions and regulatory mechanisms of these receptors and their pharmaceutical antagonists and agonists. The connection between the NR4A subfamily and a variety of reproductive disorders needs to be proven experimentally such that further examination of human tissue is required to assess the role of these receptors in human reproductive diseases.

Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases.

The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.

Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis.

Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, however, the underlying mechanisms remain elusive. Here, we uncover that Fusobacterium nucleatum (F. nucleatum) induces a dramatic decline of m6A modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulation of an m6A methyltransferase METTL3, contributing to inducation of CRC aggressiveness. Mechanistically, we characterized forkhead box D3 (FOXD3) as a transcription factor for METTL3. F. nucleatum activates YAP signaling, inhibits FOXD3 expression, and subsequently reduces METTL3 transcription. Downregulation of METTL3 promotes its target kinesin family member 26B (KIF26B) expression by reducing its m6A levels and diminishing YTHDF2-dependent mRNA degradation, which contributes to F. nucleatum-induced CRC metastasis. Moreover, METTL3 expression is negatively correlated with F. nucleatum and KIF26B levels in CRC tissues. A high expression of KIF26B is also significantly correlated with a shorter survival time of CRC patients. Together, our findings provide insights into modulating human m6A epitranscriptome by gut microbiota, and its significance in CRC progression.

Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis.

Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and Fusobacterium nucleatum (F. nucleatum) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of F. nucleatum in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that F. nucleatum enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that F. nucleatum induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of F. nucleatum in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.

MicroRNA-34a in coronary heart disease: Correlation with disease risk, blood lipid, stenosis degree, inflammatory cytokines, and cell adhesion molecules.

BACKGROUND: MicroRNA-34a (miR-34a) plays an essential role in regulating blood lipid, inflammation, cell adhesion molecules, and atherosclerosis, the latter factors are closely involved in the etiology of coronary heart disease (CHD). However, the clinical value of miR-34a in CHD patients' management is rarely reported. Hence, this study aimed to assess the correlation of miR-34a with disease risk, blood lipid, coronary artery stenosis, inflammatory cytokines, and cell adhesion molecules of CHD. METHODS: A total of 203 CHD patients and 100 controls were recruited in this study, then their plasma samples were collected to detect the miR-34a by reverse transcription quantitative polymerase chain reaction. Furthermore, serum samples from CHD patients were obtained for inflammatory cytokines and cell adhesion molecule measurement by enzyme-linked immunosorbent assay. RESULTS: MiR-34a was elevated in CHD patients compared to controls (p < 0.001) and it disclosed a good diagnostic value of CHD (area under curve: 0.899, 95% confidence interval: 0.865-0.934). Besides, miR-34a positively correlated with triglyceride (p < 0.001), total cholesterol (p = 0.022) and low-density lipoprotein cholesterol (p = 0.004), but not with high-density lipoprotein cholesterol (p = 0.110) in CHD patients. Moreover, miR-34a associated with Gensini score in CHD patients (p < 0.001). As to inflammation-related indexes and cell adhesion molecules, MiR-34a expression was positively linked with C-reactive protein (p < 0.001), tumor necrosis factor alpha (p = 0.005), interleukin (IL)-1ß (p = 0.020), IL-17A (p < 0.001), vascular cell adhesion molecule-1 (p < 0.001), and intercellular adhesion molecule-1 (p = 0.010) in CHD patients, but not with IL-6 (p = 0.118) and IL-10 (p = 0.054). CONCLUSION: MiR-34a might serve as a biomarker in assistance of diagnosis and management of CHD.

The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer.

DGC is a particular aggressive malignancy with poor prognosis. Recent omics studies characterized DGC with CDH1/E-cadherin loss and EMT-signatures. However, the underlying mechanisms for maintaining the aggressive behavior and molecular features of DGC remain unclear. Here, we find that intermediate filaments KRT17 is significantly lower in DGC tissues than that in intestinal gastric cancer tissues and associated with poor prognosis of DGC. We demonstrate that downregulation of KRT17 induces E-cadherin loss, EMT changes, and metastasis behaviors of GC cells. Mechanistically, the loss of intermediate filaments KRT17 induces reorganization of cytoskeleton, further activates YAP signaling, and increases IL6 expression, which contributes to the enhanced metastasis ability of GC cells. Together, these results indicate that KRT17/YAP/IL6 axis contributes to maintaining E-cadherin loss, EMT feature, and metastasis of DGC, providing a new insight into the role of aberrant intermediate filaments in DGC malignancy.