Coniferyl ferulate alleviate xylene-caused hematopoietic stem and progenitor cell toxicity by Mgst2.

Xylene exposure is known to induce toxicity in hematopoietic stem and progenitor cells (HSPCs), leading to bone marrow suppression and potential leukemogenesis. However, research on the gene expression profiles associated with xylene-induced toxicity in HSPCs, and effective therapeutic interventions, remains scarce. In our study, we employed single-cell RNA sequencing to capture the transcriptomic shifts within bone marrow HSPCs both prior to and following treatment with coniferyl ferulate (CF) in a mouse model of xylene-induced hematotoxicity. Subsequently, we pinpointed CF as a targeted agent using SPR-LC/MS analysis. This enabled us to confirm the link between the gene Mgst2 and specific cellular subtypes. Our data revealed that CF significantly countered the reduction of both monocyte and neutrophil progenitor cells, which are commonly affected by xylene toxicity. Through targeted analysis, we identified Mgst2 as a direct molecular target of CF. Notably, Mgst2 is preferentially expressed in neutrophil progenitor cells and is implicated in mitochondrial metabolic processes. By selectively inhibiting Mgst2 in bone marrow, we observed amelioration of xylene-induced hematotoxic effects. In summary, our findings suggest that coniferyl ferulate can mitigate the detrimental impact of xylene on hematopoietic stem and progenitor cells by targeting Mgst2, particularly within subpopulations of neutrophil progenitors. This discovery not only advances our comprehension of the cellular response of HSPCs to xenobiotic stressors like xylene but also identifies CF and Mgst2 as potential therapeutic targets for alleviating xylene-induced hematotoxicity.

Human Amniotic Membrane-Derived Mesenchymal Stem Cells Prevent Acute Graft-Versus-Host Disease in an Intestinal Microbiome-Dependent Manner.

Acute graft-versus-host disease (aGVHD) represents a fatal severe complication after allogeneic hematopoietic stem cell transplantation. As a promising cell therapeutic strategy of aGVHD, the mechanism of mesenchymal stem cells (MSC) to ameliorate aGVHD has not been fully clarified, especially in the field of intestinal homeostasis including the intestinal microbiome involved in the pathogenesis of aGVHD. The present study aimed to explore the effect of MSC on intestinal homeostasis including the intestinal barrier and intestinal microbiome and its metabolites, as well as the role of intestinal microbiome in the preventive process of hAMSCs ameliorating aGVHD. The preventive effects of human amniotic membrane-derived MSC (hAMSCs) was assessed in humanized aGVHD mouse models. Immunohistochemistry and RT-qPCR were used to evaluate intestinal barrier function. The 16S rRNA sequencing and targeted metabolomics assay were performed to observe the alternation of intestinal microbiome and the amounts of medium-chain fatty acids (MCFAs) and short-chain fatty acids (SCFAs), respectively. Flow cytometry was performed to analyze the frequencies of T immune cells. Through animal experiments, we found that hAMSCs had the potential to prevent aGVHD. HAMSCs could repair the damage of intestinal barrier structure and function, as well as improve the dysbiosis of intestinal microbiome induced by aGVHD, and meanwhile, upregulate the concentration of metabolites SCFAs, so as to reshape intestinal homeostasis. Gut microbiota depletion and fecal microbial transplantation confirmed the involvement of intestinal microbiome in the preventive process of hAMSCs on aGVHD. Our findings showed that hAMSCs prevented aGVHD in an intestinal microbiome-dependent manner, which might shed light on a new mechanism of hAMSCs inhibiting aGVHD and promote the development of new prophylaxis regimes for aGVHD prevention.

Hypoglossal nerve delineation in nasopharyngeal carcinoma patients may reduce the radiation dose and damage to the nerve.

This study aims to establish a delineation guideline for the contouring of the hypoglossal nerve by dividing the nerve into different segments, and to test the possibility of a radiation dose reduction to the hypoglossal nerve in NPC patients receiving radiotherapy. Twenty NPC patients were selected arbitrarily. The hypoglossal nerves were delineated using anatomic landmarks and divided into the cisternal, intracanalicular, carotid, and transverse segments. The tumor coverage by radiation and dose-volume parameters of the nerve with and without various dose constraints to the hypoglossal nerve were compared. The hypoglossal nerve, which is invisible on CT images, can be delineated accurately with the assistance of several anatomic landmarks. Without a dose constraint to the hypoglossal nerve, the carotid space, intracanalicular, and transverse segments had high radiation dose-volumes. The dose-volume to the nerve, however, can be reduced when the nerve was defined and a dose constraint was given. The delineation of the hypoglossal nerve with its different segments is feasible. The carotid space, intracanalicular, and transverse segments received the highest dose, where the nerve damage was most likely located. The dose to the nerve can be reduced to less than 70 Gy using the intensity-modulated radiotherapy technique.

Therapeutic Effects of HLA-G5 Overexpressing hAMSCs on aGVHD After Allo-HSCT: Involving in the Gut Microbiota at the Intestinal Barrier.

Background: Acute graft-versus-host disease (aGVHD) initiated by intestinal barrier dysfunction and gut microbiota dysbiosis, remains one of the main obstacles for patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) to achieve good prognosis. Studies have suggested that mesenchymal stem cells (MSCs) can suppress immune responses and reduce inflammation, and human leukocyte antigen-G5 (HLA-G5) plays an important role in the immunomodulatory effects of MSCs, but very little is known about the potential mechanisms in aGVHD. Thus, we explored the effect of HLA-G5 on the immunosuppressive properties of human amnion MSCs (hAMSCs) and demonstrated its mechanism related to the gut microbiota at the intestinal barrier in aGVHD. Methods: Patients undergoing allo-HSCT were enrolled to detect the levels of plasma-soluble HLA-G (sHLA-G) and regulatory T cells (Tregs). Humanized aGVHD mouse models were established and treated with hAMSCs or HLA-G5 overexpressing hAMSCs (ov-HLA-G5-hAMSCs) to explore the mechanism of HLA-G5 mediated immunosuppressive properties of hAMSCs and the effect of ov-HLA-G5-hAMSCs on the gut microbiota at the intestinal barrier in aGVHD. Results: The plasma levels of sHLA-G on day +30 after allo-HSCT in aGVHD patients were lower than those in patients without aGVHD, and the sHLA-G levels were positively correlated with Tregs percentages. ov-HLA-G5-hAMSCs had the potential to inhibit the expansion of CD3+CD4+ T and CD3+CD8+ T cells and promote Tregs differentiation, suppress proinflammatory cytokine secretion but promote anti-inflammatory cytokines release. Besides, ov-HLA-G5-hAMSCs also could reverse the intestinal barrier dysfunction and gut microbiota dysbiosis in aGVHD. Conclusion: We demonstrated that HLA-G might work with Tregs to create a regulatory network together to reduce the occurrence of aGVHD. HLA-G5 mediated hAMSCs to exert higher immunosuppressive properties in vivo and reverse the immune imbalance caused by T lymphocytes and cytokines. Furthermore, HLA-G5 overexpressing hAMSCs could restore gut microbiota and intestinal barriers, thereby ameliorating aGVHD.

Simultaneous analysis of avatrombopag, eltrombopag, and hetrombopag in human plasma by UPLC-MS/MS for therapeutic drug monitoring.

Avatrombopag, eltrombopag, and hetrombopag are three oral thrombopoietin receptor agonists used to treat thrombocytopenia. To investigate the pharmacokinetic properties, a fast and robust UPLC-MS/MS method was developed and validated for simultaneous determination of avatrombopag, eltrombopag, and hetrombopag in human plasma. Chromatographically separation was achieved on an Acquity BEH C18 column using a gradient elution of methanol-water (20:80, v/v) and acetonitrile containing 0.1% formic acid at a flow rate of 0.4 mL/min within 4.5 min. The linearity was assessed over the range of 7.5-1500 ng/mL for avatrombopag, 50-10,000 ng/mL for eltrombopag, and 5-1000 ng/mL for hetrombopag. This method was validated with adequate results in terms of selectivity, precision (intra- and inter-day CV from 4.2% to 12.2%), accuracy (RE from -6.6% to 7.5%), dilution integrity, carryover, recovery, matrix effects, as well as stability of the analytes under various conditions. The developed approach has been successfully applied to the therapeutic drug monitoring of avatrombopag, eltrombopag, and hetrombopag in patients with immune thrombocytopenia.

Assessing facial weakness in myasthenia gravis with facial recognition software and deep learning.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease leading to fatigable muscle weakness. Extra-ocular and bulbar muscles are most commonly affected. We aimed to investigate whether facial weakness can be quantified automatically and used for diagnosis and disease monitoring. METHODS: In this cross-sectional study, we analyzed video recordings of 70 MG patients and 69 healthy controls (HC) with two different methods. Facial weakness was first quantified with facial expression recognition software. Subsequently, a deep learning (DL) computer model was trained for the classification of diagnosis and disease severity using multiple cross-validations on videos of 50 patients and 50 controls. Results were validated using unseen videos of 20 MG patients and 19 HC. RESULTS: Expression of anger (p = 0.026), fear (p = 0.003), and happiness (p < 0.001) was significantly decreased in MG compared to HC. Specific patterns of decreased facial movement were detectable in each emotion. Results of the DL model for diagnosis were as follows: area under the curve (AUC) of the receiver operator curve 0.75 (95% CI 0.65-0.85), sensitivity 0.76, specificity 0.76, and accuracy 76%. For disease severity: AUC 0.75 (95% CI 0.60-0.90), sensitivity 0.93, specificity 0.63, and accuracy 80%. Results of validation, diagnosis: AUC 0.82 (95% CI: 0.67-0.97), sensitivity 1.0, specificity 0.74, and accuracy 87%. For disease severity: AUC 0.88 (95% CI: 0.67-1.0), sensitivity 1.0, specificity 0.86, and accuracy 94%. INTERPRETATION: Patterns of facial weakness can be detected with facial recognition software. Second, this study delivers a 'proof of concept' for a DL model that can distinguish MG from HC and classifies disease severity.

Hypoxic Preconditioning Enhances Cellular Viability and Migratory Ability: Role of DANCR/miR-656-3p/HIF-1α Axis in Placental Mesenchymal Stem Cells.

Preeclampsia (PE) is a common complication of pregnancy characterized by new-onset hypertension, albuminuria, or end-stage organ dysfunction, which is seriously harmful to maternal and infant health. Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from extraembryonic mesoderm. They have the potential for self-renewal, multidirectional differentiation, immunomodulation, and tissue regeneration. Several in vivo and in vitro experiments have confirmed that MSCs can delay the pathological progression of PE and improve maternal and fetal outcomes. However, the major limitations in the application of MSCs are their low-survival rates in ischemic and hypoxic disease areas after transplantation and their low rate of successful migration to the diseased regions. Therefore, enhancing cell viability and migration ability of MSCs in both ischemic and anoxic environments is important. This study aimed to investigate the effects of hypoxic preconditioning on the viability and migration ability of placental mesenchymal stem cells (PMSCs) and their underlying mechanisms. In this study, we found that hypoxic preconditioning enhanced the viability and migration ability of PMSCs, increased the expression of DANCR and hypoxia-inducible factor-1α (HIF-1α), and decreased the expression of miR-656-3p in PMSCs. Inhibiting the expression of HIF-1α and DACNR in PMSCs under hypoxia can inhibit the promotive effect of hypoxic preconditioning on viability and migration ability. In addition, RNA pull down and double luciferase assays confirmed that miR-656-3p could directly bind to DANCR and HIF-1α. In conclusion, our study showed that hypoxia could promote the viability and migration ability of PMSCs through the DANCR/miR-656-3p/HIF-1α axis.

System analysis of Huang-Lian-Jie-Du-Tang and their key active ingredients for overcoming CML resistance by suppression of leukemia stem cells.

BACKGROUND: BCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients. PURPOSE: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance. METHODS: Cytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\ Sca-1+ \C-kit+) self-renewal. RESULTS: Treatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo. CONCLUSION: From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.

PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration.

A large proportion of patients with chronic myeloid leukemia (CML; 20%-50%) develop resistance to imatinib in a BCR-ABL1-independent manner. Therefore, new therapeutic strategies for use in this subset of imatinib-resistant CML patients are urgently needed. In this study, we used a multi-omics approach to show that PPFIA1 was targeted by miR-181a. We demonstrate that both miR-181a and PPFIA1-siRNA reduced the cell viability and proliferative capacity of CML cells in vitro, as well as prolonged the survival of B-NDG mice harboring human BCR-ABL1-independent imatinib-resistant CML cells. Furthermore, treatment with miR-181a mimic and PPFIA1-siRNA inhibited the self-renewal of c-kit+ and CD34+ leukemic stem cells and promoted their apoptosis. Small activating (sa)RNAs targeting the promoter of miR-181a increased the expression of endogenous primitive miR-181a (pri-miR-181a). Transfection with saRNA 1-3 inhibited the proliferation of imatinib-sensitive and -resistant CML cells. However, only saRNA-3 showed a stronger and more sustained inhibitory effect than the miR-181a mimic. Collectively, these results show that miR-181a and PPFIA1-siRNA may overcome the imatinib resistance of BCR-ABL1-independent CML, partially by inhibiting the self-renewal of leukemia stem cells and promoting their apoptosis. Moreover, exogenous saRNAs represent promising therapeutic agents in the treatment of imatinib-resistant BCR-ABL1-independent CML.

Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial.

BACKGROUND: Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax combined with azacitidine plus homoharringtonine (VAH) regimen for R/R AML. METHODS: This phase 2 trial was done at ten hospitals in China. Eligible patients were R/R AML (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14) and azacitidine (75 mg/m2 on days 1-7) and homoharringtonine (1 mg/m2 on days 1-7). The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 2 cycles of treatment. The secondary endpoints include safety and survival. RESULTS: Between May 27, 2020, and June 16, 2021, we enrolled 96 patients with R/R AML, including 37 primary refractory AML and 59 relapsed AML (16 relapsed after chemotherapy and 43 after allo-HSCT). The CRc rate was 70.8% (95% CI 60.8-79.2). In the patients with CRc, measurable residual disease (MRD)-negative was attained in 58.8% of CRc patients. Accordingly, overall response rate (ORR, CRc plus partial remission (PR)) was 78.1% (95% CI 68.6-85.4). At a median follow-up of 14.7 months (95% CI 6.6-22.8) for all patients, median overall survival (OS) was 22.1 months (95% CI 12.7-Not estimated), and event-free survival (EFS) was 14.3 months (95% CI 7.0-Not estimated). The 1-year OS was 61.5% (95% CI 51.0-70.4), and EFS was 51.0% (95% CI 40.7-60.5). The most common grade 3-4 adverse events were febrile neutropenia (37.4%), sepsis (11.4%), and pneumonia (21.9%). CONCLUSIONS: VAH is a promising and well-tolerated regimen in R/R AML, with high CRc and encouraging survival. Further randomized studies are needed to be explored. Trial registration clinicaltrials.gov identifier: NCT04424147.

Human Amniotic Mesenchymal Stem Cells Alleviate aGVHD after allo-HSCT by Regulating Interactions between Gut Microbiota and Intestinal Immunity.

Acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation poses one of the most vexing challenges. Gut microbiota dysbiosis can proceed aGVHD and mesenchymal stem cells (MSCs) have promising therapeutic potential for aGVHD. However, whether hAMSCs affect the gut microbiota during aGVHD mitigation remains unknown. Accordingly, we sought to define the effects and underlying mechanisms of human amniotic membrane-derived MSCs (hAMSCs) regulating the gut microbiota and intestinal immunity in aGVHD. By establishing humanized aGVHD mouse models and hAMSCs treatment, we found that hAMSCs significantly ameliorated aGVHD symptoms, reversed the immune imbalance of T cell subsets and cytokines, and restored intestinal barrier. Moreover, the diversity and composition of gut microbiota were improved upon treatment with hAMSCs. Spearman's correlation analysis showed that there was a correlation between the gut microbiota and tight junction proteins, immune cells as well as cytokines. Our research suggested that hAMSCs alleviated aGVHD by promoting gut microbiota normalization and regulating the interactions between the gut microbiota and intestinal barrier, immunity.

Single-cell resolution reveals RalA GTPase expanding hematopoietic stem cells and facilitating of BCR-ABL1-driven leukemogenesis in a CRISPR/Cas9 gene editing mouse model.

BCR-ABL oncogene-mediated Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) is suggested to originate from leukemic stem cells (LSCs); however, factors regulating self-renewal of LSC and normal hematopoietic stem cells (HSCs) are largely unclear. Here, we show that RalA, a small GTPase in the Ras downstream signaling pathway, has a critical effect on regulating the self-renewal of LSCs and HSCs. A RalA knock-in mouse model (RalARosa26-Tg/+) was initially constructed on the basis of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) assay to analyze normal hematopoietic differentiation frequency using single-cell resolution and flow cytometry. RalA overexpression promoted cell cycle progression and increased the frequency of granulocyte-monocyte progenitors (GMPs), HSCs and multipotent progenitors (MPPs). The uniform manifold approximation and projection (UMAP) plot revealed heterogeneities in HSCs and progenitor cells (HSPCs) and identified the subclusters of HSCs and GMPs with a distinct molecular signature. RalA also promoted BCR-ABL-induced leukemogenesis and self-renewal of primary LSCs and shortened the survival of leukemic mice. RalA knockdown prolonged survival and promoted sensitivity to imatinib in a patient-derived tumor xenograft model. Immunoprecipitation plus single-cell RNA sequencing of the GMP population confirmed that RalA induced this effect by interacting with RAC1. RAC1 inhibition by azathioprine effectively reduced the self-renewal, colony formation ability of LSCs and prolonged the survival in BCR-ABL1-driven RalA overexpression CML mice. Collectively, RalA was detected to be a vital factor that regulates the abilities of HSCs and LSCs, thus facilitating BCR-ABL-triggered leukemia in mice. RalA inhibition serves as the therapeutic approach to eradicate LSCs in CML.

Single-cell RNA sequencing reveals the immune microenvironment and signaling networks in cystitis glandularis.

Introduction: Cystitis glandularis (CG) is a rare chronic bladder hyperplastic disease that mainly manifests by recurrent frequent urination, dysuria and gross hematuria. The current lack of unified diagnosis and treatment criteria makes it essential to comprehensively describe the inflammatory immune environment in CG research. Methods: Here, we performed scRNA-sequencing in CG patients for the first time, in which four inflamed tissues as well as three surrounding normal bladder mucosa tissues were included. Specifically, we isolated 18,869 cells to conduct bioinformatic analysis and performed immunofluorescence experiments. Results: Our genetic results demonstrate that CG does not have the classic chromosomal variation observed in bladder tumors, reveal the specific effects of TNF in KRT15 epithelial cells, and identify a new population of PIGR epithelial cells with high immunogenicity. In addition, we confirmed the activation difference of various kinds of T cells during chronic bladder inflammation and discovered a new group of CD27-Switch memory B cells expressing a variety of immunoglobulins. Discussion: CG was regarded as a rare disease and its basic study is still weak.Our study reveals, for the first time, the different kinds of cell subgroups in CG and provides the necessary basis for the clinical treatment of cystitis glandularis. Besides, our study significantly advances the research on cystitis glandularis at the cellular level and provides a theoretical basis for the future treatment of cystitis glandularis.

HIG1 domain family member 1A is a crucial regulator of disorders associated with hypoxia.

Mitochondria play a central role in cellular energy conversion, metabolism, and cell proliferation. The regulation of mitochondrial function by HIGD1A, which is located on the inner membrane of the mitochondria, is essential to maintain cell survival under hypoxic conditions. In recent years, there have been shown other cellular pathways and mechanisms involving HIGD1A diametrically or through its interaction. As a novel regulator, HIGD1A maintains mitochondrial integrity and enhances cell viability under hypoxic conditions, increasing cell resistance to hypoxia. HIGD1A mainly targets cytochrome c oxidase by regulating downstream signaling pathways, which affects the ATP generation system and subsequently alters mitochondrial respiratory function. In addition, HIGD1A plays a dual role in cell survival in distinct degree hypoxia regions of the tumor. Under mild and moderate anoxic areas, HIGD1A acts as a positive regulator to promote cell growth. However, HIGD1A plays a role in inhibiting cell growth but retaining cellular activity under severe anoxic areas. We speculate that HIGD1A engages in tumor recurrence and drug resistance mechanisms. This review will focus on data concerning how HIGD1A regulates cell viability under hypoxic conditions. Therefore, HIGD1A could be a potential therapeutic target for hypoxia-related diseases.

Synergistic Protective Effect of Interactions of Quercetin with Lycopene Against Ochratoxin A-Induced Ulcerative Colitis.

Ulcerative colitis is a type of inflammatory bowel disease responsible for the inflammation of the innermost lining of the colon and rectum. The present study's objective is to determine the potential synergistic impact of quercetin (QR) and lycopene (LP) in ulcerative colitis (UC) induced in rats by ochratoxin A (OTA) by biochemical and morphological alterations. QR and LP were administered alone and in combination with the OTA for 7 days. OTA administration caused UC generation, resulting in significant changes in body weight percentage, disease activity index (DAI), macroscopic evaluation, colon weight/length ratio, and histological score. In addition to the above parameters, it also leads to elevated oxidative stress, i.e. increased malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), and hydroxyproline levels and decreased superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Histological changes in the colon architecture were also observed suggestive of extensive mucosal damage. In addition, a high level of matrix metalloproteinase 7 (MMP7) was observed in immunohistochemistry, and a high level of gene expression of osteopontin (OPN), runt-related transcription factor 2 (RUNX2), MMP-7, and interleukin-6 (IL-6) was observed in OTA administered animals. The combination of QR and LP significantly restored the per cent body weight loss and DAI score and improved macroscopic and histological changes, colon weight/length ratio, and macroscopic damages. It also improved the biochemical parameters to near-normal levels, i.e. reduced MDA, NO, MPO, and hydroxyproline levels and increased SOD and GSH levels. In addition, OPN, Runx2, MMP-7, and IL-6 gene expression decreased compared to the OTA-induced UC group. Outcomes of the present study indicate the potential of QR + LP as anti-inflammatory and immunomodulatory agents against OTA-induced UC in rats.

Transcriptome- and metabolome-based candidate mechanism of BCR-ABL-independent resistance to olverembatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Olverembatinib represents the third-generation breakpoint cluster region protein-Abelson-murine leukemia 1 (BCR-ABL1) tyrosine kinase inhibitor with oral bioavailability, which can be used to overcome the T315I mutation in Philadelphia chromosome-positive (Ph +) leukemia. BCR-ABL-independent resistance to olverembatinib has been reported among patients in various clinical cases. However, the mechanism of olverembatinib resistance has rarely been reported. This study has illustrated bone marrow cell transcriptome and metabolome profiles among Ph + acute lymphoblastic leukemias (ALL) cases pre- and post-olverembatinib resistance. The transcriptome studies demonstrated that PI3K/AKT, purine metabolism, and other signaling pathways could play a vital role in olverembatinib resistance. As suggested by metabolomics, olverembatinib resistance in Ph + ALL was associated with purine metabolism alterations. Subsequently, high-performance liquid chromatography along with real-time quantitative PCR was utilized to measure purine metabolism-related mRNA levels and metabolism expression levels between olverembatinib resistance and sensitive cell lines. Our results elucidate the mechanism of olverembatinib resistance in Ph + ALL at transcriptome and metabolome levels, which facilitate a better understanding of olverembatinib resistance and hence may prove crucial in identifying novel drugs to tackle this conundrum.

Glochodpurnoid B from Glochidion puberum Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Colorectal Cancer Cells.

Glochidpurnoids A and B (1 and 2), two new coumaroyl or feruloyl oleananes, along with 17 known triterpenoids (3-19) were obtained from the stems and twigs of Glochidion puberum. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, and single crystal X-ray diffraction. All compounds were screened for cytotoxicity against the colorectal cancer cell line HCT-116, and 2, 3, 5, 6, 11, and 17 showed remarkable inhibitory activities (IC50: 0.80-2.99 µM), being more active than the positive control 5-fluorouracil (5-FU). The mechanistic study of 2, the most potent compound, showed that it could induce endoplasmic reticulum (ER) stress-mediated apoptosis and improve the sensitivity of HCT-116 cells to 5-FU.

A prognostic model based on prognosis-related ferroptosis genes for patients with acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder with an unpredictable prognosis. Ferroptosis, the iron-dependent cell death program, could serve as an alternative for overcoming drug resistance. However, its effect on AML remains largely unclear. Methods: We collected RNA sequencing data and relevant clinical information of AML patients from The Cancer Genome Atlas to construct a prognosis prediction model. Risk score was calculated with eight prognosis-related ferroptosis genes (PRFGs) discovered through univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. A nomogram was constructed by incorporating LASSO risk score, age, and cytogenetic risk based on univariate/multivariate Cox regression. Results: Of the 33 AML PRFGs identified from the TCGA-derived dataset, 8 genes were used to construct a gene signature to predict AML prognosis. Principal component analysis and heatmap showed significant differences between the low and high risk score groups. Next, LASSO risk score, age, and cytogenetic risk were incorporated into the nomogram to predict the overall survival (OS) of AML patients. According to survival analysis, patients with a low risk score had markedly increased OS as compared to those with a high risk score. Based on the results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, the differences between the two risk groups showed a close relationship with immune-related pathways and membrane transportation. The analysis of tumor-infiltrating immune cells and immune checkpoints revealed that the immunosuppressive tumor microenvironment possibly facilitated different prognostic outcomes between the two groups. Gene expression analyses showed that the mRNA expression levels of PARP1 and PARP3 (PARPs) were closely related to the different clinical subgroups and the analyzed OS in AML patients. Finally, the PARP inhibitor talazoparib and the ferroptosis inducer erastin exerted a synergistic anti-proliferative effect on AML cells. Conclusion: We constructed a nomogram by incorporating PRFGs, and the constructed nomogram showed a good performance in AML patient stratification and prognosis prediction. The combination of PARP inhibitors with ferroptosis inducers could be a novel treatment strategy for treating AML patients.