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PubMed1992

[Molecular-genetic evaluation of translocation of bcl-2 gene and locus bcl-1 in selected lymphoproliferative changes].

In the work it has been decided to evaluate the occurrence of locus bcl-1 rearrangement in type B chronic lymphatic leukemia and that of gene bcl-2 in non-Hodgkin's lymphoma with diffuse morphology, as well as in reactive lymph nodes. The study material comprised DNA isolated from fragments of lymph nodes sent for routine diagnostic examinations at the Institute of Pathology--Pomeranian Medical Academy. Southern's method was used to examine DNA having been cut with restrictive enzymes, estimating the distribution of gene bcl-2 and locus bcl-1. Resorting to Polymerase Chain Reaction (PCR) translocation t (14;18) was assessed by means of short nucleotides hybridizing with 14 and 18 chromosome sequences restricting this translocation. The amplification product was subsequently studied by Southern's method with probe bcl-2. In 1 out of 18 examined cases of type B chronic lymphocyte leukemia it was disclosed that locus bcl-1 had been rearranged. In 45 cases of non-Hodgkin's lymphoma with diffuse morphology the gen bcl-2 was found to display germline arrangement. Germline position of gen bcl-2 was also revealed in 60 cases of reactive lymph nodes.

Blotting, Southern↗

PubMed2026

A tumor suppressor role of the miR-15b/16-2 cluster in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation drives T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of numerous physiological processes, including cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development using microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated during early pre-T-cell proliferative stages up to the resting stage of immature thymocytes immediately preceding T-cell receptor αβ expression and is subsequently downregulated. We also confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation and demonstrated that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 represses the expression of the genes encoding BCL-2 and cyclin D3, thereby promoting apoptosis and cell cycle dysregulation in T-ALL cells, characterized by an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel tumor-suppressive function for miR-15b/16-2 in T-ALL and highlight its potential as a promising therapeutic target.

MicroRNAs↗

PubMed2025

Fluorescent protein tagging of C. elegans core apoptosis pathway components reveals mitochondrial localization of CED-9 Bcl-2, CED-4 Apaf1 and CED-3 Caspase in non-apoptotic and apoptotic cells.

We used CRISPR-Cas-mediated modification of the genomic loci for C. elegans genes ced-9 Bcl-2, ced-4 Apaf1 and ced-3 Caspase to add the coding sequence for the mNeonGreen (mNG) fluorescent protein to the endogenous open reading frames. In each case, the addition of mNG caused little or no apparent alteration of gene function. We found that tagged versions of CED-9, CED-4 and CED-3 proteins colocalize with mitochondria in all cells of live mid-late stage embryos and are distributed along the entire length of mitochondria. However, CED-4 also exhibits localized puncta of ~4-fold enrichment, and these are preferentially oriented toward the nucleus. We do not observe any shift in the localization pattern of tagged CED-4 in cells that are committing to apoptosis during normal development. However, when egl-1 BH3-only is overexpressed or ced-9 removed by mutation, CED-4::mNG is no longer distributed along the entire length of mitochondria and instead becomes enriched in the bright puncta. Finally, localization of CED-3::mNG to mitochondria is independent of both CED-9 and CED-4. This study represents the first analysis of the distribution and sub-cellular localization of endogenous CED-9 Bcl-2, CED-4 Apaf1 and CED-3 Caspase proteins in live embryos. Our results impact the current model of apoptosis commitment in C. elegans.

Animals↗

PubMed2022

Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism.

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

Cell Differentiation↗

PubMed1992

Selective anti-gene therapy for cancer: principles and prospects.

Oligodeoxynucleotides can act as antisense complements to target sense sequences of natural mRNAs to selectively regulate gene expression by translation arrest. This is a form of interventional gene therapy. Chemically modified analogs that are nuclease-resistant enable this strategy to be utilized in practice. Of the chemically modified backbone analogs of oligodeoxynucleotides we have used the phosphorothioate (PS) analog, in which a non-bridging phosphate oxygen atom is substituted with a sulfur atom. We have shown that these oligodeoxynucleotide analogs inhibit beta-globin expression in cell free systems, and that they are taken up by cells. Specific sequences have been shown to selectively regulate viral and cellular gene expression, for example the bcl-2 oncogene that is found in ca. 90% of lymphomas. However, the PS analog has certain disadvantages, notably reduced hybridization and non-selective inhibition of translation. We have therefore synthesized a series of (PS-PO) co-polymers and characterized their properties. Other related approaches include catalytic ribozymes, and formation of triplexes by direct interaction of oligomers in the major groove of DNA. In general, a chemically modified oligodeoxynucleotide analog can be regarded as a novel form of informational drug.

Animals↗

PubMed1992

Induction of apoptosis--new targets for cancer chemotherapy.

Many anticancer agents induce an active cell death process, apoptosis, in sensitive tumour cells. Elucidation of molecular mechanisms underlying apoptosis may shed light on why some tumour cells survive chemotherapy, and may identify new targets for anticancer agents whose effects are not tightly linked to proliferative status. The signal transduction events which initiate apoptosis are unclear. A change in cytosolic calcium is generally assumed to be a key signal for apoptosis although the evidence for this is not conclusive. Other putative signal transducers which may modulate apoptosis are protein kinase C and cAMP. Genes which induce apoptosis in response to such signals are largely unidentified, but certain oncogenes, notably bcl-2, act to delay or suppress apoptosis in several cell types.

Apoptosis↗

PubMed1992

Histogenetic correlations between subcategories of small noncleaved cell lymphomas.

To assess the biologic relevance of the morphologic distinctions between subtypes of small noncleaved cell lymphomas (SNCL), ie, the sporadic Burkitt's type (sBT) and the non-Burkitt's type (nBT), we have examined the molecular organization of several lymphomagenic oncogenes (c-myc, bcl-1, bcl-2) and the potential pathogenetic contribution of the Epstein-Barr virus (EBV). Twenty-nine cases of SNCL, not associated with immunodeficiency syndromes, were reviewed and classified as sBT (18 cases) or nBT (11 cases) without knowledge of the clinical or molecular data. Southern blot analysis of 18 sBTs found 17 to contain c-myc rearrangements. Fifteen of these comigrated with an Ig heavy-chain gene segment, indicating t(8;14) translocation. Chromosome 8 breakpoints were clustered in the first exon and the first intron of the c-myc gene. Chromosome 14 breakpoints mapped to the JH locus in three tumors, the S mu locus in nine tumors, and the S alpha locus in the remaining three tumors. Cases involving the S alpha locus appeared to have a more rapid clinical course. All sBTs possessed germline bcl-2 and bcl-1 gene fragments. In contrast, Southern blot analysis of 11 nBTs found none with c-myc rearrangements. Rather, three of 10 evaluable nBTs had bcl-2 rearrangements. The remaining seven showed no evidence of involvement by any of the lymphoma-associated oncogene/breakpoint regions studied. EBV genome was detected in two sBTs and in one nBT, and thus was not a distinguishing feature. These results indicate that the subtle histologic differences that distinguish subcategories of SNCL are significant biologically and reflect distinct molecular mechanisms of lymphomagenesis. Furthermore, the data suggest that the nBTs comprise a heterogeneous group with respect to their molecular genetic composition and confirm the remarkable molecular genetic homogeneity of the sBT group.

Adolescent↗

PubMed1992

The bcl-2 oncogene and apoptosis.

The bcl-2 oncogene is activated as a consequence of the t(14;18) chromosomal translocation in human follicular lymphomas. Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis. The bcl-2 protein is associated with the inner mitochondrial membrane, however, the biochemical function of bcl-2 is unknown. Transgenic mice which overexpress bcl-2 provide evidence for bcl-2's role in memory B cells and thymic education as an intracellular survival factor. Additional regulators of apoptosis, such as the p53 tumor suppressor gene, may be altered in human cancers as one step in tumorigenesis.

Animals↗

PubMed1992

BCL-2 in B-chronic lymphocytic leukemia.

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Antigens, CD↗

PubMed2025

Targeting anti-apoptosis as a therapeutic strategy in neuroendocrine neoplasms.

BCL-2 is an anti-apoptotic protein expressed by aggressive neuroendocrine neoplasms (NENs). We report a case of a patient with a pancreatic neuroendocrine tumor (pNET) who received venetoclax, a BCL-2-targeting drug for the treatment of chronic lymphocytic leukemia. We further characterized BCL2 expression in NENs from a large multi-institutional patient cohort. Clinical data were abstracted from the records of a patient with a pNET. Next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on 636 NENs of pancreatic (P-NENs), small bowel (SB-NENs), colorectal (CR-NENs), and lung (L-NENs) origin by Caris Life Sciences. Comparisons were performed against site-matched non-NEN cancers. BCL2- or MKI67- high and low cohorts were defined based on the top and bottom quartiles of gene expression. The patient with a pNET who received venetoclax had a partial response in the primary tumor that lasted 30 months. CR-, L-, and P-NENs had significantly higher expression of BCL2 compared to non-NEN counterparts. BCL2 expression was significantly higher in MKI67-high tumors among all NEN subtypes. In P-NENs, there was a higher prevalence of RB1 mutations in BCL2-high vs BCL2-low (40 vs 4.9%, P < 0.005). Patients with BCL2-high P-NENs had significantly decreased overall survival (HR 1.94, 95% CI 1.0-3.76, P = 0.047). Immune checkpoint gene expression and T cells were enriched in BCL2-high tumors across all subtypes. In summary, we report the first known case of a pancreatic NET with response to venetoclax. BCL2 expression correlated with high MKI67 expression, worse survival, and a highly immune-enriched microenvironment.

Aged↗

PubMed2025

Network pharmacology approach to unveiling the mechanism of berberine in the amelioration of morphine tolerance.

OBJECTIVE: To investigate the mechanism underlying the effect of the Huanglian decoction (, HLD) on morphine tolerance (MT), using network pharmacology, and to verify these mechanisms in vitro and in vivo. METHODS: Available biological data on each drug in the HLD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target proteins of MT were retrieved from the GeneCards, PharmGkb, Therapeutic Target Database, DrugBank, and Online Mendelian Inheritance in Man databases. Information regarding MT and the drug targets was compared to obtain overlapping elements. This information was imported into the Search Tool for the Retrieval of Interacting Genes/Proteins platform to obtain a protein-protein interaction network diagram. Then, a "component-target" network diagram was constructed using screened drug components and target information, viaCytoscape (Institute for Systems Biology, Seattle, WA, USA). The database for annotation, visualization, and integrated discovery was used for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways analyses. Pathway information predicted by network pharmacology was verified using animal studies and cell experiments. RESULTS: Network pharmacology analysis identified 22 active compounds of HLD and revealed that HLD partially ameliorated MT by modulating inflammatory, apoptosis, and nuclear factor kappa B (NF-κB) signaling pathways. Berberine (BBR), one of the main components of HLD, inhibited the development of MT in mice. BBR reduced cell viability while increasing B-cell lymphoma 2 (Bcl-2) protein expression and decreasing CD86, NF-κB, Bax, and Caspase-3 protein expression in brain vascular 2 (BV2) mcroglia cells treated with morphine. Additionally, BBR contributed to a reduction in pro-inflammatory cytokine release and apoptotic cell number. CONCLUSIONS: BBR, a key component of HLD, effectively suppressed microglial activation and neuro-inflammation by regulating the NF-κB and apoptosis signaling pathways, thereby delaying MT. This study offers a novel approach to enhance the clinical analgesic efficacy of morphine.

Berberine↗

PubMed2026

Genome mining and metabolomics unveil new napyradiomycin antibiotics from Streptomyces sp. 0H2M.

Napyradiomycins are a family of meroterpenoid natural products known for their promising antibiotic activities. In this study, four new napyradiomycins derivatives were identified, SF2415B4 (1), SF2415B5 (2), SF2415B6 (3), and SF2415B7 (4) from Streptomyces sp. 0H2M, alongside a known molecule, A80915A (5) through the synergy between genome mining and metabolomics analysis. Their structures were elucidated through a combination of spectroscopic and spectrometric analyses, including HRMS-ESI, NMR, and DP4+. Genome sequencing identified a putative biosynthetic gene cluster, and subsequent analyses revealed a distinct biosynthetic pathway with an unprecedented tailoring mechanism mediated by novel hydroxylases and halogenases. Biological assays demonstrated significant activity against Bacillus subtilis, Bacillus cereus and methicillin-resistant Staphylococcus aureus due to perturbation of cell membrane integrity, and minimum inhibitory concentration (MIC) values ranged from 0.24 to 30.7 μM. Additionally, in vitro cytotoxicity experiments indicated that compounds 2-5 very mildly inhibited the viability of human non-small cell lung cancer (NSCLC) cell line A549 in a concentration-dependent manner, with IC50 values of 16.7, 39.1, 65.0, and 32.8 μM, respectively. Moreover, they were shown to induce apoptosis and autophagy in A549 cells, evidenced by increased levels of cleaved PARP, decreased expression of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Survivin), and accumulation of LC3-II. These findings offer new insights into the natural product chemistry in Streptomyces and the pharmacology of napyradiomycin class antibiotics.

Streptomyces↗

PubMed2026

[Aggressive B-cell lymphomas with MYC gene cluster amplification: a clinicopathological analysis of eight cases].

Objective: To investigate the clinicopathological characteristics, molecular genetics, treatments and prognosis of aggressive B-cell lymphomas (ABCL) with MYC gene cluster amplification. Methods: Eight cases of ABCL with MYC gene cluster amplification were collected, including 6 cases from the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and 2 consultation cases from outside hospitals. The histomorphology, immunohistochemical profiles, and molecular genetic characteristics were analyzed. Clinical follow-up and literature review were also conducted. Results: Among the eight patients, six were male and two were female, with an age 71.5 (61.7, 74.2) years. All six in-house patients presented with abdominal pain at onset, without B symptoms. Most cases were classified as Ann Arbor stage Ⅲ-Ⅳ. Extranodal involvement occurred in 5 of the 6 in-house cases, primarily affecting the gastrointestinal tract (4/5). All initial bone marrow biopsies showed no evidence of lymphoma. One patient had a history of immunosuppression following renal transplantation. Two cases exhibited diffuse large B-cell lymphoma (DLBCL) morphology. The other six showed high-grade features, while three of them showed Burkitt lymphoma-like morphology. Except for one case of blastoid variant mantle cell lymphoma, the remaining six cases (6/7) displayed a germinal center B-cell phenotype. None of the in-house cases harbored bcl-2 or bcl-6 rearrangements as shown by fluorescence in situ hybridization. 11q alterations were identified in all but one consultation case, including gain/loss type in five cases and 11q gain in two. 11q telomere loss of heterozygosity by chromosomal microarray analysis was not detected in one of the two cases with 11q gain that was subject to the test. The duration of follow-up ranged from 5.9 to 55.5 months, with 5 patients alive at the end of the study. Conclusions: ABCL with MYC gene cluster amplification often presents high-grade morphology and gastrointestinal involvement, which strongly suggests the alteration of 11q. It seems to have a favorable prognosis.

Humans↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed2026

Overlapping genetic etiology of pediatric and adult germ cell tumors.

BACKGROUND: Germ cell tumors are heterogeneous neoplasms arising from primordial germ cells. Although genome-wide association studies have identified numerous susceptibility loci for adult testicular germ cell tumors, the heritable basis of pediatric testicular germ cell tumors and germ cell tumors that arise outside the testes remain poorly understood. METHODS: We conducted a multi-ancestry genome-wide association study of pediatric germ cell tumors, including 1927 cases from the Germ Cell Tumor Epidemiology Study and 10 601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) germ cell tumor between the ages of 0 and 19 years. RESULTS: We identified 4 loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chromosome [chr] 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide statistically significant associations were identified in subgroup analyses, including 6 loci for intracranial germ cell tumors (rs2758612 [PMF1/BGLAP], rs9854760 [PLCL2], rs6851498 [KIT], rs11816992 on chromosome 10, rs3830273 [TFAM], and rs13054014 [LZTR1]), 1 locus for testicular germ cell tumor (rs1907702 [KITLG]), and 1 locus for males (rs4610628 [MAD1L1]). After Bonferroni correction, 18 of 78 previously reported testicular germ cell tumor loci were significantly associated with germ cell tumor overall or in at least 1 subgroup with a particularly strong correlation between testicular germ cell tumor and intracranial germ cell tumor effect estimates (rho = 0.63, P = 5.5 × 10-10). Expression quantitative trait locus (QTL) analyses identified candidate genes in the regions identified on chromosome 6 (BAK1, LINC003366, and ITPR3) and chromosome 8 (DEPTOR and RP11-760H22.2). CONCLUSIONS: Our data support a role for germline genetic variation in the development of germ cell tumors in locations outside the testes and highlight shared genetic architecture across age group and tumor location.

Humans↗

PubMed2026

Impact of BCL-2 rs2279115 and rs3943258 variants on protein expression and clinical outcome of urothelial bladder carcinoma.

BACKGROUND: Urothelial bladder carcinoma (UBC) is the ninth most common malignancy worldwide and ranks thirteenth in cancer-related mortality. A significant challenge in managing non-muscle-invasive UBC (NMIBC) is the high recurrence rate, compounded by a paucity of robust prognostic biomarkers. Given that evasion of apoptosis is a hallmark of carcinogenesis, the apoptosis regulator BCL-2 oncogene plays a critical role by negatively regulating the intrinsic apoptotic pathway, often leading to protein overexpression and malignant cell immortalization. METHODS AND RESULTS: This study evaluated the BCL-2 allelic variants rs2279115 (G > T) and rs3943258 (T > C), including their haplotype structures, in association with BCL-2 immunohistochemical expression in UBC patients. Genetic and immunostaining data were analyzed alongside prognostic factors, environmental exposure, and clinical history. Furthermore, we sought to exhibit BCL-2 immunohistochemical staining patterns via immunofluorescence in selected samples. Our findings revealed that the rs2279115 variant is significantly associated with BCL-2 positive expression. Specifically, the TT genotype in the genotypic model (p = 0.035) and the GT genotype in the overdominant model (p = 0.045) were linked to protein status. Additionally, the CT haplotype was independently associated with high-grade tumors. CONCLUSIONS: The presence of the CT haplotype - in either homozygosity or heterozygosity - exerted a risk effect of high-grade (p = 0.020). In conclusion, these findings suggest that BCL-2 variants, haplotype structures, and immunohistochemical expression may offer relevant insights into the molecular characteristics of urothelial bladder cancer. Further prospective validation is needed to determine whether BCL-2 profiling can serve as a useful complementary tool for risk assessment in clinical practice.

Humans↗

PubMed2026

Effects of acute hypoxia followed by reoxygenation on intestinal histomorphology, oxidative stress and hypoxia signaling biomarkers, and microbiota in pikeperch (Sander lucioperca).

In aquatic environments, natural and anthropogenic factors commonly reduce dissolved oxygen (DO) and trigger hypoxia, which threatens the health and survival of aquatic organisms. As an important economic fish species in China, pikeperch (Sander lucioperca) is extremely sensitive to hypoxia. However, there are relatively few reports on how hypoxia and reoxygenation affect its intestinal physiology and microbial community. Three treatment groups were set for pikeperch: normoxia (DO = 8.5 ± 0.5 mg/L), 48 h hypoxia (DO = 2.5 ± 0.1 mg/L), and reoxygenation (48 h hypoxia followed by 6 h reoxygenation at normal DO), to evaluate alterations in intestinal histopathology, tight junction gene expression, oxidative stress, hypoxia signaling molecules and intestinal microbiota composition. The results showed that hypoxia significantly decreased muscularis thickness by approximately 32.5% and reduced the expression of tight junction genes (Occludin, Claudin2, and ZO-2). Moreover, hypoxia significantly increased oxidative stress index levels (GSH-Px, CAT, and MDA), markedly upregulated the expression of Bax, Caspase3, and HIF-1α, while significantly downregulating the expression of Bcl-2, Egln1, and Egln2. Notably, reoxygenation elicited partial compensatory effects against these hypoxia-induced changes. 16S rRNA sequencing analysis revealed that hypoxic stress altered the intestinal microbial community composition of pikeperch and increased its diversity. In the hypoxia group, the abundance of the phylum Bacillota, along with the genera Halomonas and Acinetobacter, was significantly elevated, whereas in the reoxygenation group, the genus Lactobacillus increased approximately 180-fold. The results indicated that hypoxia caused intestinal oxidative damage, cell apoptosis, and intestinal microbiota dysbiosis in pikeperch, while short-term reoxygenation achieved partial recovery from these hypoxia-triggered intestinal injuries. The present research provides valuable references for in-depth exploration of the molecular mechanisms behind the response of pikeperch to acute hypoxia and reoxygenation stress, while also offering a novel perspective to understand the mechanism by which hypoxia impacts intestinal health in fish.

Animals↗

PubMed2026

Active components and potential mechanisms of Wuzhuyu decoction in the treatment of ethanol-induced acute gastric mucosal injury: a network pharmacology and experimental verification.

OBJECTIVE: To investigate the underlying mechanisms and active components of Wuzhuyu decoction (, WD) in alleviating ethanol-induced acute gastric mucosal injury (GMI) using an integrated approach of network pharmacology and experimental verification. METHODS: Sprague-Dawley rats were randomly divided into six groups: control (Con), model (Mod), bismuth potassium citrate (BPC), WD at low (WD-L), medium (WD-M), and high (WD-H) doses. Following seven days of continuous intragastric administration of the respective treatments, an ethanol-induced gastric mucosal injury model was established in all groups except the control group by oral gavage of anhydrous ethanol. The gastric mucosal injury index was evaluated, and pathological changes were assessed viahematoxylin and eosin (HE) staining. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were measured by enzyme-linked immunosorbent assay (ELISA). The chemical composition was identified by ultra-performance liquid chromatography-tandem mass spectrometry. Active compounds were screened using the Swiss-absorption, distribution, metabolism, and excretion database, and their potential targets were predicted using the Swiss Target Prediction database and bioinformatics annotation database for molecular mechanism. Simultaneously, disease targets related to GMI were retrieved from the online mendelian inheritance in man and GeneCards databases. A protein-protein interaction (PPI) network was constructed, and functional enrichment analyses of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the Metascape database. Key predictions from the network pharmacology analysis were subsequently verified through animal experiments. Protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Cleaved Caspase-3, and Cleaved Caspase-9 were analyzed by Western blot. Finally, molecular docking was performed using AutoDock Vina to investigate the interactions between the active components and core targets. RESULTS: WD treatment significantly reduced the gastric mucosal injury index and the levels of TNF-α, IL-1β, MDA, while it increased the activities of SOD and GSH-Px. Histopathological examination revealed marked improvement in gastric tissue morphology. A total of 145 compounds were identified in WD. Network pharmacology analysis identified 440 overlapping targets between WD and GMI. GO and KEGG enrichment analyses highlighted the apoptosis signaling pathway as a key mechanism for WD's protective effect against ethanol-induced GMI. Experimental validation demonstrated that WD treatment reduced the apoptosis of gastric mucosal epithelial cells, promoted the expression of Bcl-2, and inhibited the expression of Bax, Cleaved Caspase-3 and Cleaved Caspase-9. Molecular docking results indicated that dehydroevodiamine, rutaecarpine, evodiamine, hexahydrocurcumin, and isorhamnetin are potential active components in WD that contribute to the inhibition of apoptosis. CONCLUSIONS: WD alleviates ethanol-induced acute GMI, at least in part, by inhibiting the apoptosis. The primary active components responsible for this effect are dehydroevodiamine, rutaecarpine, evodiamine, hexahydrocurcumin, and isorhamnetin.

Drugs, Chinese Herbal↗