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This study investigates whether Ginkgetin(GK) reverses cisplatin(DDP) resistance in cervical cancer cells by modulating the Nrf2/HO-1 signaling axis to induce ferroptosis, and preliminarily elucidates its underlying mechanisms. DDP-resistant cervical cancer cell line HeLa/DDP was used for in vitro experiments. Cell proliferation was assessed by CCK-8 assay; migration and invasion capabilities were evaluated via wound healing and Transwell assays; colony formation assays measured proliferative capacity. Molecular docking analyzed the binding affinity of GK to Nrf2, HO-1, and GPX4 proteins. Intracellular ROS and Fe 2+ levels were detected using fluorescent probes. Ferroptosis-related indicators including GSH, MDA, SOD, and CAT were measured by biochemical detection. Western blot analyzed expression of key proteins. Mechanistic validation employed the Nrf2 activator sulforaphane (SFN) and ferroptosis inhibitor ferrostatin-1 (Fer-1). An in vivo subcutaneous xenograft mouse model was established to observe the reversal effect of GK on DDP-resistant tumors, combined with histopathological and immunohistochemical analyses of tissue morphology and protein expression. GK significantly inhibited the proliferation of HeLa/DDP cells and enhanced their sensitivity to DDP. Combined treatment of GK and DDP notably suppressed proliferation, migration, invasion, and colony formation abilities of HeLa/DDP cells. Molecular docking revealed strong binding affinity between GK and Nrf2. Combination treatment markedly increased ROS and Fe 2+ levels, reduced antioxidant capacity (GSH, SOD, CAT), induced lipid peroxidation with upregulated ACSL4 expression, and downregulated Nrf2, HO-1, and GPX4 expression. Transmission electron microscopy demonstrated characteristic mitochondrial morphological changes of ferroptosis. In vivo, co-treatment significantly reduced tumor volume of DDP-resistant xenografts, enhanced DDP’s antitumor efficacy, improved histopathological structures, and modulated related protein expression. GK induces ferroptosis by inhibiting the Nrf2/HO-1 signaling pathway, thereby reversing DDP resistance in cervical cancer cells. These findings provide a potential novel therapeutic strategy for clinical management of cervical cancer.

Polydimethylsiloxane (PDMS) is a commonly used insulation/packaging material for implantable neural electrodes. Nevertheless, the PDMS-initiated tissue response would lead to the deterioration of the electrode performances post-implantation, owing to its intrinsic hydrophobic and cell-repellent surface. The conventional physical coatings by hydrophilic hydrogels or bioactive molecules are unable to maintain during the long-term implantation due to their low stability by physical adhesion. In this work, we first anchor both hydrophilic polyethylene glycol (PEG) and bioactive molecule poly-L-lysine (PLL) on the PDMS surface by chemical coupling to change the PDMS surface from hydrophobic and cell-repellent to hydrophilic and cell-adhesive. XPS tests indicate the chemically coupled modification layers are stable on the PDMS surface after experiencing a harsh rinse process. Contact angle measurements show that the use of PEG 600 with the moderate molecular weight results in the highest hydrophilicity for the resulting PDMS-PEG-PLL. PC12 cell evaluation results exhibit that the PDMS-PEG-PLL with PEG 600 leads to significantly larger cell adhesion area, more neurite number, and longer neurite length than the PDMS. The PDMS-PEG-PLL with PEG 600 featuring stable modification layers, high hydrophilicity, and superior cell affinity has great potential in stabilizing the neural electrode-tissue interface for the long-term implantation.

Background:Aldehyde dehydrogenase (ALDH) has been widely used as a marker of cancer stem cells (CSCs). However, the ALDH family includes 19 members, and the most relevant isoforms and their biological functions in cancer biology are still controversial.Methods:We examined ALDH enzyme activity and the mRNA expression of 19 ALDH members in 58 human cell lines. The biological effect and mechanism of knocking down ALDH1A3 with siRNA and shRNA in cell lines were explored. Finally, the relationship between ALDH1A3 and CXCR4 was analysed in a large panel of cell lines.Results:ALDH1A3 is the key isoform that contributed to Aldefluor positivity in cell lines. Knocking down ALDH1A3 in different cancer cells conferred opposite phenotypes due to differential effects on CXCR4 expression. There was a significant negative correlation between ALDH1A3 and CXCR4 in 58 human cell lines.Conclusions:ALDH1A3 was the main contributor to Aldefluor positivity in human cell lines, and its contrasting effects might arise from differences in CXCR4 expression.

Background 5-fluorouracil (5-FU)-based chemotherapy regimen has been widely used for the treatment of gastric cancer, but meanwhile the development of chemotherapeutic resistance remains a major clinical challenge. Tumor microenvironment (TME) frequently correlates with the development of chemoresistance in human cancer. As a major component of TME, the role of tumor-associated macrophages (TAMs) in the chemoresistance of gastric cancer has not been fully elucidated. Methods Immunohistochemistry (IHC) was applied to detect the density of TAMs in clinical samples of 103 patients with gastric cancer who had undergone 5-FU-based neoadjuvant chemotherapy. 5-FU-resistant gastric cell lines MKN45-R and HGC27-R were established, macrophages were then separately co-cultured with MKN45-R, HGC27-R cells and their parental cells. The effect of gastric cancer cells on the polarization of macrophages, the biological function of M2-polaried macrophages and the mechanism for promoting 5-FU-resistance were investigated. Then the correlation between the expression of CXC motif chemokine ligand 5 (CXCL5) and the infiltration of hemoglobin scavenger receptor (CD163) positive and mannose receptor (CD206) positive macrophages was analyzed, the prognostic value of CXCL5 expression in clinical samples was further explored. Results The high infiltration of macrophages marked by CD68 in gastric cancer samples was significantly associated with the resistance of gastric cancer to chemotherapy. Gastric cancer cells could modulate macrophages to M2-like polarization through indirect co-culture, and chemoresistant cells were more efficient in inducing macrophages polarization to M2 phenotype. Co-culturing M2-polarized macrophages in turn enhanced 5-FU-resistance of gastric cancer cells, and it was further verified that CXCL5 derived from M2-polarized macrophages promoted chemoresistance through activing the PI3K/AKT/mTOR pathway. Besides, high level of CXCL5 could recruit monocytes to form more M2-polarized macrophages. Clinically, high expression of CXCL5 in gastric cancer samples was associated with the high infiltration of CD163 positive macrophages and CD206 positive macrophages, and patients with high expression of CXCL5 presented lower overall survival (OS) rates than those with low expression of CXCL5. Conclusion Interaction between TAMs and gastric cancer cells promoted chemoresistance in gastric cancer via CXCL5/PI3K/AKT/mTOR pathway. Thus, targeting TAMs and blocking the cell–cell crosstalk between TAMs and gastric cancer cells may represent prospective therapeutic strategies for patients with gastric cancer.

In this case-control study, the main risk factors for atrophic gastritis (AG) were comprehensively analyzed in a real-world environment to identify potential risk factors associated with garlic intake and its effects on AG. Design Upper gastrointestinal endoscopy and pathological examination were performed as part of a gastric cancer screening and health check-up program. The detailed characteristics of both the case group and healthy control group were recorded and analyzed. All participants were fasted for at least 4 h and a urea breath test13C-UBT) was performed in all participants at rest. Both univariate and multivariate logistic regression analyses were performed and presented as the odds ratio (OR) and 95% confidential interval (CI), with additional subgroup analysis stratified by infectious state based on the presence, eradication or absence of H. pylori. Setting Gansu Province in China. Participants 10,035 people from Gansu Province in China were included. Among 7,058 participants, 4,712 (66.8%) had AG. Garlic intake was a significant risk factor for AG in participants currently (infected state) or previously (eradicated state) infected with H. pylori (OR = 1.39, 95% CI: 1.06–1.83; OR = 1.16, 95% CI = 1.01–1.32). Garlic intake was not significantly associated with AG in participants without H. pylori’ s infection (OR = 1.14, 95% CI: 0.88–1.46). The association between garlic intake and AG differed by H. pylori infectious state. People in the infected or eradicated states are at a higher risk for AG associated with garlic intake. Diet may regulate the pathogenic role of H. pylori and intestinal flora.

Given the continuously growing population and decreasing arable land, food shortage is becoming one of the most serious global problems in this century 1 . Grain size is one of the determining factors for grain yield and thus is a prime target for genetic breeding 2 , 3 . Although a number of quantitative trait loci (QTLs) associated with rice grain size have been identified in the past decade, mechanisms underlying their functions remain largely unknown 4 , 5 . Here we show that a grain-length-associated QTL, GL2 , has the potential to improve grain weight and grain yield up to 27.1% and 16.6%, respectively. We also show that GL2 is allelic to OsGRF4 and that it contains mutations in the miR396 targeting sequence. Because of the mutation, GL2 has a moderately increased expression level, which consequently activates brassinosteroid responses by upregulating a large number of brassinosteroid-induced genes to promote grain development. Furthermore, we found that GSK2, the central negative regulator of rice brassinosteroid signalling, directly interacts with OsGRF4 and inhibits its transcription activation activity to mediate the specific regulation of grain length by the hormone. Thus, this work demonstrates the feasibility of modulating specific brassinosteroid responses to improve plant productivity. To understand the mechanisms of grain size control, researchers experimentally reveal that the molecular module miR396/GRF4 regulates rice grain size by activating brassinosteroid signalling. Modulating miR396/GRF4 or brassinosteroid responses can thus be used to improve crop yield.

Abstract RNA interference is an ancient biological defense mechanism against external invasions. Mechanistically, small interfering RNA (siRNA) can specifically bind to any target gene, according to the principle of complementary base pairing, to exert silencing effects. Therefore, siRNA has the potential to serve as an efficient therapeutic agent for various diseases. However, due to their susceptibility to nucleases, off-target effects, and low cellular uptake, the development of siRNA-based drugs remains challenging. Fortunately, with the advancement in chemical modifications and delivery systems, patisiran, the first siRNA therapeutic, was approved for the treatment of hereditary transthyretin amyloidosis by the United States Food and Drug Administration (FDA) in 2018, which represents a crucial milestone in the field of siRNA research. Subsequently, seven other siRNA drugs were introduced to the market. Thus, siRNA drugs are on their way to becoming standard pharmacotherapy tools. This review presents the mechanisms of action, delivery barriers, chemical modifications, and delivery platforms of siRNA. Furthermore, it also summarizes commercialized siRNA drugs and some clinical trials, thereby providing a comprehensive knowledge map of siRNA drug modifications, delivery strategies, action mechanisms, and updated clinical trials.

Medulloblastoma is a common embryonic malignant tumor in children. Patients with Group 3 medulloblastoma exhibit the poorest prognosis among all subgroups, and approximately 20% of these patients carry an amplification of MYC. Metabolic reprogramming, a hallmark of cancer, includes the pentose phosphate pathway (PPP) as a branch of glucose metabolism, providing cells with ribose-5-phosphate (R5P) and nicotinamide adenine dinucleotide phosphate (NADPH). The role of PPP in medulloblastoma remains unclear. In this study, we utilized transcriptomic data to identify that high expression of transketolase (TKT) correlates with worse overall survival (OS) in Group 3 patients. We found that TKT promotes proliferation of Group 3 medulloblastoma cell line cells both in vitro and in vivo. Additionally, TKT enhances R5P synthesis, increasing the proportion of S-phase cells and promoting proliferation. TKT also facilitates NADPH synthesis, which reduces intracellular reactive oxygen species (ROS) levels, inhibits ROS-induced cell death, and strengthens cellular resistance to ROS-induced injury. Subsequently, we demonstrated that inhibition of MYC leads to decreased TKT protein levels, and MYC promotes cell proliferation and suppresses cell death via TKT. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction (ChIP-qPCR) confirmed that employing the antibody targeting MYC enables the immunoprecipitation of DNA localized to the promoter region of TKT . Using luciferase assay and western blot, we verified that MYC and specificity protein 1 (SP1) co-regulate the transcription of TKT and consequently elevates TKT protein levels. Collectively, our study reports that MYC facilitates the proliferation of Group 3 medulloblastoma cells and mitigates ROS-induced damage through TKT, suggesting TKT as a potential therapeutic target for MYC-driven Group 3 medulloblastoma.

P2X7/NLRP1/caspase-1 mediated neuronal injury plays an important role in diabetic cognitive impairment and eventually inflammatory cascade reaction. Chinese herbal compound Naofucong has been mainly used to treat cognitive disorders in Traditional Chinese Medicine The present study aimed to investigate whether its neuroprotective effects might be related to the inhibition of P2X7R/NLRP1/caspase-1 mediated neuronal injury or not. In this study, high glucose-induced HT22 hippocampal neurons were used to determine Naofucong-containing serum neuronal protective effects. Lentiviruses knock out of TXNIP and P2X7R was used to determine that protective effects of Naofucong was related to inflammatory response and P2X7/NLRP1/caspase-1 mediated neuronal injury. NAC was also used to inhibit oxidative stress, so as to determine that oxidative stress is an important starting factor for neuronal injury of HT22 cells cultured with high glucose. Naofucong decreased apoptosis, IL-1β and IL-18 levels in high glucose-induced HT22 hippocampal neuron cells. Naofucong suppressed NLRP1/caspase-1 mediated neuronal injury, and P2X7 was involved in process. HT22 cells cultured in high glucose had an internal environment with elevated oxidative stress, which could promote neuronal injury. The current study demonstrated that Naofucong could significantly improve high glucose-induced HT22 hippocampal neuron injury, which might be related to suppress P2X7R/NLRP1/caspase-1 pathway, which provides novel evidence to support the future clinical use of Naofucong.

To evaluate the clinical efficacy and safety of transvaginal natural orifice transluminal endoscopic surgery (vNOTES) for treating benign ovarian tumors in obese patients. A retrospective analysis was conducted on the clinical data of 35 obese patients who underwent vNOTES for benign ovarian tumor resection and 41 obese patients who underwent multi-port laparoscopic surgery (MPLS) during the same period from January 2021 to June 2024 at Qinghai Red Cross Hospital. Key parameters such as operative time, intraoperative blood loss, intraoperative and postoperative complications, hospitalization duration, postoperative anal exhaust time, postoperative visual analog scale (VAS) score, and SF-36 score were analyzed. No statistical differences were observed between the two groups regarding baseline characteristics such as age, body mass index (BMI), tumor diameter, parity, and history of pelvic surgery. The vNOTES group exhibited shorter operative times compared to the MPLS group, with no significant differences in tumor pathology, intraoperative blood loss, or tumor rupture rates. Postoperatively, the vNOTES group had shorter hospital stays, fewer postoperative complications, lower 24-hour postoperative VAS scores, and higher three-month postoperative SF-36 scores compared to the MPLS group. No differences were found between the groups concerning anal exhaust time, sexual satisfaction rate, or 24-hour postoperative VAS scores. vNOTES is a safe and feasible surgical method for treating benign ovarian tumors in obese patients, offering advantages such as no abdominal incisions and quicker postoperative recovery.