Ferrochelatase is the terminal enzyme in heme biosynthesis. Bacillus thuringiensis (Bt) 97-27 contains two ferrochelatases, HemH1 and HemH2, but their regulatory mechanisms and functional differences under virous environmental stimuli remain unclear. This study confirmed that the iron uptake regulator protein (Fur) bound to the promoters of hemH1 and hemH2, with Fe2+ or Fe3+ enhancing this binding. Heterologous expression of HemH1 and HemH2 in Escherichia coli showed that pEH2/BL grew better than pEH1/BL under different 2,2'-Bipyridyl, Fe2+, and Fe3+ concentrations. Under iron limitation, the heme precursor ALA production decreased significantly in both strains. The heme production of pEH2/BL decreased sharply under iron-limited conditions, while that of pEH1/BL decreased significantly under iron-rich conditions. The H2O2 sensitivity experiment revealed that E. coli pEH1/BL was more tolerant to H2O2 than pEH2/BL. In Bt, ΔhemH2 was most sensitive to H2O2 stress, but complementation of hemH1 or hemH2 partially restored H2O2 resistance, with the overexpressed strain pHH2/Bt being most tolerant. β-galactosidase assays indicated that Fur positively regulated hemH1 and negatively regulated hemH2 under normal conditions, but this regulation reversed with 2.5 mM Fe3+. qRT-PCR showed upregulation of genes related to heme synthesis, oxidative stress, and ferrous iron transport. This study reveals the functional differentiation of HemH1 and HemH2 under the joint regulation of Fur and environmental factors, highlighting their synergistic roles in heme synthesis, heavy metal detoxification, and oxidative stress resistance to maintain bacterial physiological homeostasis.

Periodontitis is unanimously accepted to be the sixth complication of diabetes mellitus (DM), while the inverse relationship of causality is still to be deciphered. Among the proposed mechanisms is gut dysbiosis, which is responsible for the systemic release of proinflammatory mediators. In this process, Gram-negative bacteria from the oral cavity enter the general circulation, leading to the emergence of bi-hormonal beta-pancreatic cells that lack the ability to secrete insulin. Additionally, epigenetic and adaptive mechanisms in affected cells may play a role in reducing inflammation. The release of reactive oxygen species, proinflammatory cytokines, and adipokines, such as interleukins, tumor necrosis factor alpha, leptin, prostaglandin E2, C-reactive protein, or matrix metalloproteinases, determine epigenetic changes, such as the methylation of DNA nucleotides or changes in the activity of histone acetylases/deacetylases. The management of periodontitis involves targeting inflammation, and its potential connection to epigenetic modulation observed in other chronic conditions may help to explain its role in preventing DM in affected patients. This review focuses on the key epigenetic changes in periodontitis that might contribute to DM development, and explores the mechanisms and novel multi-drug therapies that could help to prevent these effects.

HIV-1 can establish a lifelong infection by incorporating its proviral DNA into the host genome. Once integrated, the virus can either remain dormant or start active transcription, a process governed by the HIV Tat protein, host transcription factors and the chromatin landscape at the integration site. Histone-modifying enzymes and chromatin-remodeling enzymes play crucial roles in regulating this chromatin environment. Chromatin remodelers, a group of ATP-dependent proteins, collaborate with host proteins and histone-modifying enzymes to restructure nucleosomes, facilitating DNA repair, replication, and transcription. Recent studies have highlighted the importance of chromatin remodelers in HIV-1 latency, spurring research focused on developing small molecule modulators that can either reactivate the virus for eradication approaches or induce long-term latency to prevent future reactivation. Research efforts have primarily centered on the SWI/SNF family, though much remains to be uncovered regarding other chromatin remodeling families. This review delves into the general functions and roles of each chromatin remodeling family in the context of HIV and discusses recent advances in small molecule development targeting chromatin remodelers and the HIV Tat protein, aiming to improve therapeutic approaches against HIV.

Takifugu rubripes is an economically valuable fish species in Asia. The implementation of all-male culture for T. rubripes is highly anticipated in aquaculture. Aromatase inhibitor (AI, letrozole) treatment was found to be an efficient method to induced masculinization in T. rubripes, as reported in our previous study. Here, to further explore the underlying regulation mechanism of AI-induced masculinization, a whole-transcriptome analysis comparing was conducted between AI-induced masculinized XX (AI-XX) gonads and control (Con) gonads in T. rubripes.

Glucosamine (GlcN) is a common supplement used to alleviate osteoarthritis, but it may dysregulate glucose tolerance and induce insulin resistance, thereby increasing metabolic burden. The liver is a vital organ that modulates the Akt/mTOR/p70S6K signaling pathway in response to growth and metabolism. Fibroblast growth factor 21 (FGF21) is a hepatokine involved in regulating glucose and lipid metabolism. Additionally, increased circulating FGF21 levels have been linked to the prediction of metabolic disorders and type 2 diabetes. However, the regulatory mechanism controlling FGF21 expression by GlcN remains unclear. In the present study, GlcN stimulation led to several outcomes, including an increase in cell content, secretion, and mRNA and protein levels of FGF21 in hepatocytes. Moreover, inhibition of the Akt/mTOR/p70S6K axis resulted in reduced FGF21 expression in response to GlcN. Importantly, GlcN-mediated expression of FGF21 relies on PGC-1α upregulation. These results suggest that GlcN increases FGF21 expression through the activation between Akt/mTOR/p70S6K pathway and PGC-1α dependent manner.

Autism spectrum disorder (ASD) involves a complex neurodevelopmental pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) plays a crucial role in embryonic brain development and neural network stability. This study aimed to investigate the influence of ADAM10 on excitation/inhibition (E/I) balance, autism-like behaviors, and learning and memory dysfunction in rats prenatally exposed to valproic acid (VPA) and determine potential intervention strategies. The VPA-exposed group exhibited increased levels of ADAM10 and secreted amyloid precursor protein-α (sAPPα). Moreover, overexpression of glutamate decarboxylase 1 and N-methyl-D-aspartate receptors was observed. High-performance liquid chromatography-mass spectrometry revealed elevated levels of glutamate, glutamine, and γ-aminobutyric acid, as well as an E/I imbalance in the VPA group. Additionally, narrower synaptic clefts as well as increased postsynaptic density and synaptic vesicles were observed. Remarkably, intraperitoneal administration of ADAM10 inhibitor during the critical period of synaptic development significantly improved ASD-like behavior and learning and memory function in VPA-exposed rats. This intervention effectively reduced abnormally high sAPPα levels in the prefrontal cortex and corrected abnormal E/I balance. Thus, inhibiting ADAM10 overexpression may improve the E/I imbalance, alleviate core symptoms of ASD, and improve learning and memory dysfunction. The use of ADAM10 inhibitor represents a potential therapeutic strategy for treating ASD patients with intellectual disabilities.

Liver metastasis is the most common site of metastasis in colorectal cancer, and the prognosis of colorectal cancer patients with liver metastasis is extremely poor. Revealing the key genes of CLM and implementing targeted interventions is of great significance for colorectal cancer patients. By using the weighted gene co-expression network analysis (WGCNA) algorithm, key gene modules related to metastasis in colorectal cancer were identified. Subsequently, immune-regulating and prognostic-influencing key gene sets were identified from these modules to construct a prognostic model related to colorectal cancer metastasis. Genetic background differences underlying this model were analyzed using colorectal cancer methylation and mutation data, followed by Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) analysis of the relevant biological processes associated with the model. The value of predicting tumor drug response through the model was assessed using drug half maximal inhibitory concentration (IC50) data from colorectal cancer cell lines. Subsequently, utilizing single-cell sequencing data about liver metastasis, the colorectal cancer immune microenvironment reflected in the predictive model was analyzed, and a key gene set of the model was identified. Lastly, experimental validation was conducted to investigate the regulatory effects of photodynamic therapy (PDT) on the key genes of the model, and the cytotoxic effect of PDT on colorectal cancer was confirmed. An immune-related gene prognostic model regulating CLM was constructed, consisting of HSPA1A, ULBP2, RBP7, OXT, SLC11A1, INHBB, and ICOS. This model can predict the clinical response of colorectal cancer patients to Oxaliplatin, Cisplatin, Irinotecan, and 5-Fluorouracil. Single-cell sequencing results demonstrate that the model is associated with an immunosuppressive microenvironment in CLM. The higher the model's riskscore, the weaker the MHC-I, MHC-II, and various tumor immune signaling pathway networks in the colorectal cancer microenvironment. Causal analysis reveals that SLC11A1, ICOS, and HSPA1A play key roles in this model. PDT can kill colorectal cancer cells, inhibit colorectal cancer cell metastasis, significantly influence the expression of genes such as SLC11A1, ICOS, and HSPA1A in these processes, and suppress the infiltration of macrophages in the colorectal microenvironment, inhibiting the immune escape process of PD-1/PD-L1. A prognostic model based on immunity regulated by PDT has been established for assessing the prognosis of CLM patients, as well as clinical responses to chemotherapy drugs and immunotherapy.

Poorly differentiated gastric cancer (PDGC) is characterized by high invasiveness, rapid progression, and poor prognosis for patients. Differentiation therapy has long been a promising approach by manipulating the differentiation state of tumor cells to inhibit tumor growth, offering fewer side effects. Decitabine (DAC), is known as an inhibitor of DNA methylation, thus reactivating the transcription of previously methylated silenced genes associated with differentiation to induce a more differentiated state. This study used the differentiation-inducing agents DAC to treat two PDGC cell lines, MKN45 and NUGC4, and explored the impact of DAC on cell proliferation and influence of their sensitivity to Natural Killer cells (NK cells) mediated cytotoxicity. The results demonstrated a significant reduction in cell proliferation, migration, and invasion without affecting cell viability after DAC treatment. Additionally, transcriptomic analysis revealed that DAC-treated PDGC cells upregulated multiple immune-related genes, including the gene encoding for tumor necrosis factor alpha (TNF-α). Co-culture study of NK cells and PDGC cells showed that DAC treatment enhanced the sensitivity of these cancer cells to NK cell-mediated cytotoxicity, and TNF-α played a crucial role in promoting NK cell cytotoxicity. Following the subcutaneous implantation of tumors in nude mice, DAC administration significantly inhibited the growth of PDGC tumors and induced the upregulation of differentiation related genes. In summary, DAC effectively reduces the malignant characteristics of the PDGC cells by promoting their transition towards a higher state of differentiation and enhancing their sensitivity to NK cell-mediated killing, providing new insights for the mechanisms of the antitumor effects of DAC.

PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage repair (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.

Colorectal cancer (CRC) remains an alarming global health concern despite advancements in treatment modalities over recent decades. Among the various factors contributing to CRC, this review emphasizes the critical role of epigenetic mechanisms in its pathogenesis and progression. This review also describes the potential role of natural compounds in altering the epigenetic landscape, focused mainly on DNA methylation, histone modification, and non-coding RNAs. Publications from the previous five years were searched and retrieved using well-known search engines and databases like PubMed, Google Scholar, and ScienceDirect. Keywords like CRC/colorectal cancer, CAC/Colitis associated CRC, inflammasomes, epigenetic modulation, genistein, curcumin, quercetin, resveratrol, anthocyanins, sulforaphane, and epigallocatechin-3-gallate were used in various combinations during the search. These natural compounds predominantly affect pathways such as Wnt/β-catenin, NF-κB, and PI3K/AKT to suppress CRC cell proliferation and oxidative stress and enhance anti-inflammation and apoptosis. However, their clinical use is restricted due to their low bioavailability. However, multiple methods exist to overcome challenges like this, including but not limited to structural modifications, nanoparticle encapsulations, bio-enhancers, and novel advanced delivery systems. These methods improve their potential as supportive therapies that target CRC progression epigenetically with fewer side effects. Current research focuses on enhancing epigenetic targeting to control CRC progression while minimizing side effects, emphasizing improved specificity, bioavailability, and efficacy as standalone or synergistic therapies.

Cervical cancer is the fourth most common malignant tumor among women with high morbidity and mortality. We found the active ingredients, action targets and pathways of Scutellaria Barbata against cervical cancer cells, and verified its effects and mechanisms on the proliferation, migration and apoptosis of cervical cancer cells through cellular experiments.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease closely related to aging with unclear pathogenic mechanisms. This study aims to identify the biomarkers in RA, aging and autophagy using bioinformatics and machine learning and explore the binding stability of taurine to target utilizing computer-aided drug design (CADD).

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to prevent the progression of diabetic kidney disease (DKD). However, their impact on renal fibrosis remains largely uninvestigated. This study aimed to explore the effect of SGLT2 inhibitor empagliflozin on renal fibrosis in DKD patients and DKD models, and the molecular mechanisms involved.

Some natural compounds derived from medicinal plants show anti-tumor activity with high efficacy and safety, low toxicity and residual levels etc. The aim of this study was to select natural compounds and biomarkers having high inhibitory effects against A549 adenocarcinoma cells. A total of eight natural compounds having pure plant origin were initially screened, purchased, and their potential anti-cancer activities were comprehensively and systematically evaluated against A549 lung adenocarcinoma cells. The maximum non-cytotoxic concentration (MNTC) and 50% cytotoxic concentration (CC50) of the eight compounds against A549 cells were obtained by cytopathological and MTT assays, respectively. Using Cisplatin as a positive control, the effect of selected compounds were elucidated on the proliferation, migration and invasion of A549 cells by MTT, wound healing and invasion assays, respectively. AnnexinV-FITC/PI, JC-1, ROS and Cell Cycle Kits were used to detect the pro-apoptotic mechanism of A549 cells induced by the tested compounds. qRT-PCR and RNA-seq were used to investigate the effective biomarkers involved in the inhibition process. The results showed that Curcumin, Osthole, Paeonol, Cepharanthine and Cisplatin significantly reduced the proliferation, migration and invasion abilities of A549 cells in a dose-dependent manner. Post 48 h of treatment, Osthole inhibited the metastatic ability of A549 cells by regulating mitochondrial apoptosis, arresting A549 cell in G1-phase and inhibiting release of ROS, while Curcumin, Paeonol and Cepharanthine did not showed the same response. It was therefore elucidated that Osthole was the optimal natural compound showing powerful anti-inhibitory properties against A549 cells. Moreover, the expressions of EGF, IL-2 and IL-10 genes were significantly decreased in Osthole treated group, while IL-6 gene was significantly increased. This study suggested that EGF gene has the potential to be used as a biomarker for Osthole treatment against A549 cells, involved in mitochondrial apoptosis and ROS down-regulation, inhibiting proliferation and epithelial mesenchymal transition (EMT), inflammation and immune processes in A549 cells providing a foundation to develop Osthole as a potential target drug to prevent the occurrence and development of lung adenocarcinoma.

Galangin is an extract of traditional Chinese medicine with anti-cancer effect. Exosomes (Exo) contain RNA, peptides, or proteins and communicate between cells through a bio-genesis pathway. In the present study, Gastric cancer (GC) cell exosomes containing galangin were obtained. MicroRNAs (miRNAs) in exosomes containing galangin (galangin-Exo) were screened by RNA-seq. GC cells were treated with galangin-Exo and the changes of cell proliferation were analyzed. Besides, the mouse model of GC was established to verify the effect of galangin-Exo in vivo. The results showed that galangin-Exo inhibited the growth of AGS and BGC823 cells. Additionally, RNA-seq data showed that miR-10b-5p was differentially expressed in exosomes. The reduced expression of miR-10b-5p which increased the expression of P53 inhibited the growth and induced apoptosis of GC cells. The in vivo results confirmed that exosomes can inhibit tumor growth by delivering galangin. In conclusion, our results suggest that galangin-Exo have anti-cancer effect on GC and can be used as a potential therapeutic strategy.

The Glucocorticoid-induced posterior subcapsular cataracts (GIC) is a common complication of patients received glucocorticoid treatment in clinic. We find that dexamethasone (DEX) induces lens epithelial cells' ferroptosis. DEX treatment increases intracellular ferroptosis signatures in lens epithelial cell line in vitro as well as in rat lens in vivo. The inhibition of ferroptosis by liproxstatin-1 reduces the incidence of DEX-induced rat GIC. Experimental evidence and expression profiling showed that DEX induces ferroptosis through upregulating tetraspanin CD82- controlled P53 expression. DEX-activated glucocorticoid receptors directly bind to the CD82 promoter, driving its transcriptional upregulation. CD82 expression is upregulated in the anterior capsular epithelium of GIC patients as well as in the DEX-treated rat lens and caused the cell death of anterior capsule. DEX treatment and Overexpression of CD82 in cells recapitulated ferroptotic signatures through P53 activation and GPX4/SLC7A11 suppression. Taken together, GIC is closely associated with the upregulation of CD82-P53-GPX4/SLC7A11 axis-mediated ferroptosis.

There is limited understanding of the phenomenon of reversible drug resistance, which is characterized by tumor cells regaining sensitivity when the drug is changed or withdrawn after a period of drug resistance. This phenomenon is usually not associated with genetic alterations of tumor cells. In this study, reversible resistant state was induced by alectinib in EML4-ALK mutant lung cancer cell. By performing RNA sequencing on reversible drug-resistant cell line to examine changes in transcriptional profile, significant change in CCN1 was detected after withdrawal and repeated administration of alectinib. Targeting CCN1 resulted in inhibition of tumor cell proliferation and angiogenesis, and restoration of sensitivity to alectinib in reversible drug-resistant cells. Further studies revealed that CCN1 could affect the expression of VEGFA by affecting AKT phosphorylation, and the change of NF-κB could impact the activation of CCN1-AKT-VEGFA pathway. Suppressing NF-κB or CCN1 receptor could improve the sensitivity to alectinib, further suggesting that NF-κB and CCN1 might play a key role in overcoming reversible drug resistance.

Enzalutamide (Enz) is employed in the management of castration-resistant prostate cancer (CRPC). However, a substantial subset of patients may develop resistance to Enz, thereby reducing its therapeutic effectiveness. The underlying mechanisms contributing to the development of Enz resistance in PCa, whether arising from androgen deprivation or the burden of Enz treatment, remain inadequately understood. OPRK1 plays a key role in Enz resistance through ferroptosis inhibition, which is detected by the analysis of Gene Expression Omnibus (GEO) databases. Silencing OPRK1 via small interfering RNA (siRNA) resulted in the activation of ferroptosis signaling in LNCaP cells. These findings indicate that OPRK1 significantly contributes to Enz resistance in PCa and may serve as a promising therapeutic target for resistant patients.

Plant responses to biotic and abiotic stresses are complex processes. Previous studies have shown that the LBD gene family plays important roles in plant growth and development as well as in plant defense against biotic and abiotic stresses. The expression of LBD genes was investigated in walnuts under biotic and abiotic stresses, revealing that LBD38-1 may be a key gene in the plant stress response. This study provides new insights into the roles of LBD genes in plant responses to biotic stress.

Pancreatic cancer (PC) is one of the most tremendously malignant cancers with a poor prognosis, especially when it advances to metastasis. Besides, PC patients have encountered resistance to recent therapeutic approaches. In recent work, we effectively determined ANKRD22 by re-analyzing RNA-seq datasets from cell lines and human tissues deriving from PC. We demonstrated that ANKRD22 expression was remarkably high in the PC group compared to the normal group at both gene expression and protein levels. ANKRD22 resulted in a worse overall survival (OS) rate of PC patients (HR = 1.7, p = 0.0082). Intriguingly, ANKRD22 was statistically highly expressed in the mutated KRAS group relative to the wildtype group (p < 0.05). Similarly, compared to the wildtype TP53, in the mutated TP53, ANKRD22 also significantly expressed (p < 0.05); their concurrent expression, ANKRD22 and KRAS; ANKRD22 and TP53 exacerbated the survival outcome relative to the co-expression of low ANKRD22 and unaltered genes (p < 0.001; HR > 2.6). We explored the potential pathways and biological processes ANKRD22 might not only contribute to promoting PC, including cell-cycle regulation, E2F1 targets, and apoptosis but also foster the dissemination of PC by involve in invasion and migration processes. In the investigation of drugs that might target ANKRD22, we figured out fostamatinib. Molecular docking and molecular dynamic simulation (MDs) techniques provided extensive insights into the binding mode of ANKRD22 and fostamatinib. ANKRD22 exhibited strong binding affinity (ΔG = -7.0 kcal/mol in molecular docking and ∆Gbind = -38.66 ± 6.09 kcal/mol in MDs). Taken together, ANKRD22 could be a promising theragnostic target that might be inhibited by fostamatinib, thereby suppressing PC growth.