Rituximab has been incorporated into the standard treatment regimen for diffuse large B-cell lymphoma (DLBCL), and induces the death of tumor cells via complement-dependent cytotoxicity (CDC). Unfortunately, the resistance of DLBCL cells to Rituximab limits its clinical usefulness. It remains unclear whether the complement system is related to Rituximab resistance in DLBCL. A Rituximab-resistant DLBCL cell line (Farage/R) was generated under the stress of Rituximab. Constituent proteins of the complement system in wild-type Farage cells (Farage/S) and Farage/R cells were analyzed by qPCR, western blotting, and immunofluorescence. In vitro and in vivo knockdown and overexpression studies confirmed that the complement 1Q subcomponent A chain (C1qA) was a regulator of Rituximab resistance. Finally, the mechanism by which C1qA is regulated by m6A methylation was explored. The reader and writer were identified by pull-down studies and RIP-qPCR. Activity of the complement system in Farage/R cells was suppressed. C1qA expression was reduced in Farage/R cells due to post-transcriptional regulation. Furthermore, in vitro and in vivo results showed that C1qA knockdown in Farage/S cells decreased their sensitivity to Rituximab, and C1qA overexpression in Farage/R cells attenuated the Rituximab resistance of those cells. Moreover, METTL3 and YTHDF2 were proven to be the reader and writer for m6A methylation of C1qA, respectively. Knockdown of METTL3 or YTHDF2 in Farage/R cells up-regulated C1qA expression and reduced their resistance to Rituximab. In summary, the aberrant downregulation of C1qA was related to Rituximab resistance in DLBCL cells, and C1qA was found to be regulated by METTL3- and YTHDF2-mediated m6A methylation. Enhancing the response of the complement system via regulation of C1qA might be an effective strategy for inhibiting Rituximab resistance in DLBCL.
This country report provides a summary of the UK-EU relationship since the UK's entry in 1973. The report explores populist actors in the United Kingdom, with an emphasis on these actors in the period since the global financial crisis in 2008. The report notes that there have been both left and right populist parties active in the UK in this period. It explores key populist actors (George Galloway, Jeremy Corbyn, Nigel Farage) and parties including the Respect Party, UKIP, the Brexit Party, and Reform UK. It examines the basis of these party's euroscepticism, their broader positions on the UK-EU relationship, and how they have mobilised populism and populist ideas. It finds that populist Eurosceptic parties belonging to the Populist Radical Right (PRR) have achieved the most success and influence in the UK context. The report also considers the response of the UK's traditional largest political parties (the Conservative Party, the Labour Party, and the Liberal Democrats) to the rise of Euroscepticism in the UK.
BCL6 is regarded as a promising therapeutic target for diffuse large B-cell lymphoma. However, most of the current BCL6 inhibitors and degraders have demonstrated limited antitumor efficacy when used as monotherapy. We hypothesized that developing multitarget degraders capable of simultaneously degrading multiple lymphoma-driving proteins might yield superior anti lymphoma activity. In this study, based on the BCL6 inhibitor BI3812, we designed and identified a dual-target degrader A5, which effectively degraded both BCL6 and GSPT1. A5 induced the degradation of BCL6 and GSPT1 in a time- and concentration-dependent manner, restored the expression of BCL6-regulated genes, and significantly promoted DNA damage in Farage cells. Consequently, A5 exhibited enhanced antiproliferative activity compared to the BCL6 inhibitor BI3812 and the BCL6 degrader BI3802, along with induction of cell cycle arrest and apoptosis. Furthermore, A5 significantly downregulated BCL6 and GSPT1 protein levels in vivo. Thus, this study provides a solid foundation for the development of novel multitarget BCL6 degraders with improved anti-lymphoma potential.
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The endothelial glycocalyx (EG) is a dynamic, gel-like layer that lines the luminal surface of blood vessels, playing a crucial role in vascular biology. Previously considered a passive barrier, it is now recognized as a key regulator of vascular tone, permeability, inflammation, and coagulation. Composed mainly of proteoglycans, glycoproteins, and glycosaminoglycans, the EG serves as a semipermeable interface between blood and the endothelium, maintaining microvascular flow and modulating nitric oxide (NO) production while protecting against oxidative and inflammatory damage. This review highlights the physiological functions of the EG and its significance in perioperative medicine. It regulates shear-dependent NO release, ensuring adequate vasodilation and tissue perfusion, while its negative charge reduces friction and clot formation. Damage to this layer can lead to vascular dysfunction, particularly in surgical and critical care patients. The review examines the mechanisms of glycocalyx injury in various conditions. Hyperglycemia and diabetes accelerate degradation through reactive oxygen species and enzymes like heparanase. In sepsis, inflammatory mediators disrupt glycocalyx, leading to capillary leak syndrome. Ischemia-reperfusion injury causes rapid shedding of glycocalyx components, impairing vasodilation. Potential therapeutic strategies for preserving glycocalyx integrity include albumin, fresh frozen plasma, and sphingosine-1-phosphate, which stabilize endothelial junctions. Maintaining normovolemia during surgery is crucial, as both excessive fluid and hypovolemia can accelerate glycocalyx breakdown. Overall, the endothelial glycocalyx should be considered in perioperative care as it may influence patient outcome. We outline future avenues for research and clinical intervention.
Gentamicin (GM), an aminoglycoside antibiotic, is associated with neurotoxic effects that result in cognitive and behavioral impairments. Taurine, a sulfur-containing amino acid, has demonstrated neuroprotective properties. This study investigates the potential of taurine to mitigate GM-induced neurotoxicity in Sprague Dawley rats. Thirty-two male rats were randomly assigned to four groups: control, taurine (100 mg/kg/day orally for 15 days), GM (120 mg/kg/day intraperitoneally for 15 days), and taurine + GM (co-administered at the aforementioned doses and routes). Behavioral assessments (open field and Y-maze tests) were conducted to evaluate locomotor activity, anxiety, and memory. Hippocampal tissue was analyzed using histopathology, immunohistochemistry, and biochemical assays. Quantitative analyses via ELISA, RT-qPCR, and immunohistochemical scoring confirmed that GM administration induced anxiety-like behaviors, hippocampal degeneration, oxidative stress (elevated MDA, reduced SOD/CAT), neuroinflammation (elevated NF-ĸB, TNF-α, IL-1β, IL-6), and increased neuronal apoptosis (raised caspase-3, Bax; reduced Bcl-2). Taurine co-treatment effectively reversed these effects, improving behavioral outcomes, preserving neuronal structure, significantly restoring antioxidant enzyme activity and the Nrf2/HO-1 pathway, suppressing NF-ĸB-mediated inflammation, and modulating apoptotic pathways. These findings indicate that taurine provides substantial neuroprotection against GM-induced toxicity by enhancing antioxidant capacity, reducing neuroinflammation, and inhibiting neuronal apoptosis. Future research should explore taurine's dose-response effects, long-term neurobehavioral outcomes, and its molecular interactions with key targets like NF-κB and Nrf2.
To explore the expression and clinical significance of XPO1 in newly diagnosed adult diffuse large B-cell lymphoma (DLBCL), and further investigate its functional mechanism. Immunohistochemical testing was conducted for XPO1 expression in 93 cases of DLBCL and 30 cases of reactive lymphoid hyperplasia. A risk model was construed to find survival related genes in DLBCL patients. Cell proliferation, apoptosis, and cell cycle assays were performed to explore the effect of XPO1 inhibitor (KPT-8602) and XPO1 knockdown. Differential expression gene (DEG) was examined based on the transcriptomes. The expression of XPO1 in DLBCL patients was higher than that of the controls. Compared with XPO1 low-expression group, XPO1 high-expression group had a worse prognosis. The constructed risk model indicated that XPO1 and 14 genes in nucleocytoplasmic transport pathway (NTP) might be potential prediction marker of adverse outcome in DLBCL. Moreover, KPT-8602 as well as the XPO1 knockdown could inhibit cell proliferation, promote apoptosis, and induce cell cycle arrest in two DLBCL cell lines, Farage and SU-DHL-4. Based on the gene expression profiling in the datasets of DLBCL, patients were classified into XPO1 high and XPO1 low expression groups, and the MYBL1 was identified as the down-stream effector of XPO1. Inhibiting the function of XPO1 or reducing its expression can significantly decrease the expression of MYBL1 Conclusion: XPO1 is highly expressed in DLBCL, which is associated with poor prognosis. The oncogenic roles of the new XPO1/MYBL1 signaling are identified in DLBCL and XPO1 inhibitor may be a potential option for newly-diagnosed DLBCL patients. XPO1高表达在弥漫性大B细胞淋巴瘤中的临床意义及机制研究. 探究核输出蛋白1（XPO1）在初发成人弥漫性大B细胞淋巴瘤（DLBCL）中的表达情况及临床意义，并进一步探索其功能机制。. 采用免疫组化方法检测93例DLBCL和30例淋巴结反应增生患者XPO1的表达水平。构建预后风险模型以寻找DLBCL患者生存预后相关基因。通过细胞增殖、凋亡和细胞周期实验，探索XPO1抑制剂（KPT-8602）及XPO1 敲降对DLBCL细胞的影响。通过分析公共数据库转录组测序结果，寻找XPO1 相关差异表达基因（DEG）。. 免疫组化结果表明，XPO1在DLBCL中的表达水平明显高于对照组（P < 0.05）。与XPO1低表组相比，XPO1高表组患者的预后明显更差（P < 0.05）。通过构建预后风险模型发现XPO1 及核浆转运通路（NTP）中的14个基因可能是DLBCL患者的高危预后因素。此外，在两种DLBCL细胞系Farage及SU-DHL-4中，KPT-8602及XPO1 敲降可以抑制DLBCL细胞的增殖、促进凋亡和阻滞细胞周期。基于公共数据库DLBCL转录组测序结果，将患者分为XPO1 高表达和低表达组，分析两组的DEG，提示 MYBL1可能是XPO1的下游信号分子。抑制XPO1功能或者降低XPO1 表达均可以显著降低MYBL1 的表达。. XPO1在DLBCL患者中的表达水平明显增高，且与不良预后相关。XPO1 可能通过激活XPO1/MYBL1 信号通路从而在DLBCL中发挥促肿瘤作用，XPO1抑制剂可能是初发DLBCL患者的一种潜在治疗选择。.
Osteoarthritis (OA) is a leading cause of disability, driven by cartilage degradation, subchondral bone remodeling, and synovial inflammation. Activation of the NF-κB/NLRP3 inflammasome axis contributes to disease progression. This study investigated the chondroprotective and anti-inflammatory effects of intra-articular (IA) metformin (MET) and chlorogenic acid (CGA), alone or in combination, in a rabbit model of OA. OA was induced by monosodium iodoacetate (MIA) injection into the knee joints of male rabbits The rabbits were randomized into six groups: Control, MET + CGA, OA, OA + MET, OA + CGA, and OA + MET + CGA. Disease severity was evaluated via radiography, gross morphology, histopathology, and hematological and synovial fluid analyses. MIA induced OA manifested by joint space narrowing, osteophyte formation, and cartilage erosion, accompanied by elevated serum CRP, increased synovial IL-1β, IL-6, and TNF-α, and upregulation of NF-κB, NLRP3, caspase-1, GSDMD, IRF-1, and cartilage-degrading enzymes. MET or CGA alone significantly attenuated these changes, improving joint architecture, lowering inflammatory cytokines, and suppressing pyroptotic signaling. Combination therapy produced the most pronounced benefits, restoring near-normal cartilage structure, normalizing leukocyte profiles, and reducing molecular markers toward baseline. In silico findings revealed the affinity of CGA to bind with NLRP3 PYD, ASC PYD, IRF-1 and NF-κB p65. In conclusion, IA MET + CGA synergistically ameliorated structural and molecular hallmarks of OA via coordinated inhibition of NF-κB/NLRP3 inflammasome activation and pyroptosis. These findings highlight the translational potential of this dual therapy as a disease-modifying approach for OA management, pending further investigations.
To investigate the effects of Sanguinarine (SAG) on the progression of diffuse large B-cell lymphoma (DLBCL) and to explore its underlying mechanism, this study utilized Epstein-Barr virus (EBV)-positive DLBCL cell lines, FARAGE, and GM12878S. Cell counting kit-8 and bromodeoxyuridine assays were used to assess the effects of SAG on the cell proliferation. Flow cytometry and immunoblotting were employed to analyze cell cycle arrest and apoptosis. Additionally, the molecular mechanism was explored through further immunoblotting analysis of the mechanism. SAG suppressed the growth of EBV-positive DLBCL cells. Furthermore, SAG induced cell cycle arrest and promoted apoptosis in these cells. Mechanistically, SAG suppressed the Wnt/β-catenin pathway, thereby suppressing DLBCL progression in vitro. SAG effectively inhibits cell growth and induces apoptosis in EBV-positive DLBCL via Wnt/β-catenin pathway, offering potential therapeutic insights for this lymphoma subtype.
Partial hepatectomy (PHx) is frequently done for the repair of traumatic liver injury, tumor resection, and donation. The regenerative ability of the residual liver impacts mortality and morbidity. Fisetin is an antioxidant flavonoid that was found to target β-catenin, inducing regeneration in cardiac, nervous, bony tissues, and skin. This study assesses the impact of fisetin on liver regeneration following major PHx. Twenty-four rats were assigned to four groups: sham, fisetin control, 70% PHx, and PHx + Fisetin (10 mg/kg/day) for four days prior to surgery, and two days after surgery. Animals were sacrificed two days following PHx. Serum liver enzymes, AST, ALT, liver oxidative markers, GSH, and MDA, were measured. Immunohistochemical expression of hepatic PCNA, Cyclin D1 (cell proliferation marker), and β-catenin (liver regeneration mediator), as well as mRNA expression for hepatic P53 (senescence marker), TGF-β (regeneration stop inducer), and VEGF (angiogenesis marker), was performed. Fisetin boosted hepatectomy-induced hepatic regeneration, significantly increased relative liver weight, hepatocyte mitotic index, liver PCNA, cyclin D1, and β-catenin, reduced hepatic histopathological injury, serum AST and ALT levels, and liver MDA levels, and increased liver GSH, demonstrating antioxidant status. Fisetin reduced PHx-induced increases in p53, indicating suppression of cell senescence, and in TGF-β, demonstrating the elimination of TGF-β-mediated termination of liver regeneration; however, fisetin didn't show a significant change in PHx-enhanced angiogenesis, as marked by VEGF expression. Fisetin enhances PHx-induced liver regeneration via upregulating β-catenin and suppressing the P53 senescence pathway and TGF-β signaling.
Primary mediastinal B-cell lymphoma (PMBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) that shares features with diffuse large B-cell lymphoma (DLBCL), but also with classical Hodgkin lymphoma (cHL). PMBCL often contains aberrations of genes involved in the immune response such as cREL and PD-L1, whose expression is also influenced by cytokines TNF-α and IFN-γ. In this study, cell lines Farage, U2940, MedB-1 and Karpas1106p were used as PMBCL models and treated with different concentrations of TNF-α and IFN-γ over 24 and 48 h, followed by the quantification of cREL, CXCL10 and PD-L1 expression. Additionally, the expression of TNF-α, IFN-γ, cREL, CXCL10, CXCR3, PD-L1 and PD-1 genes was compared between PMBCL tissue samples and B-cell and T-cell rich zones of non-tumour tonsils. Prolonged exposure to TNF-α increased cREL expression, while IFN-γ strongly induced CXCL10 expression. The change in the expression of PD-L1 in response to the treatments differed across various cell lines. There was no statistically significant difference in the expression of the target genes between tumour and non-tumour patient tissue samples. the obtained results suggest that the immune checkpoints in PMBCL cells are affected by both their genetic profile and tumour microenvironment.
Accumulating research suggests that Epstein-Barr Virus-positive Diffuse Large B-cell Lymphoma (EBV+DLBCL) is associated with immune dysfunction and tumor microenvironment (TME) heterogeneity. While the prognostic role of the TME in EBV-DLBCL is established, its impact on EBV+DLBCL survival remains unclear. Here, we integrated 10X Visium spatial transcriptomics (ST) with single-cell RNA sequencing (scRNA-seq) to map TME heterogeneity in EBV+DLBCL. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified PD-1/PD-L1 signaling as a hallmark of EBV+DLBCL's immunosuppressive TME. Functional validation using the PD-1/PD-L1 inhibitor BMS202 revealed dose-dependent suppression of proliferation and enhanced apoptosis in EBV+Farage cells, with TLR4 emerging as a downstream effector showing EBV-status-dependent regulation. These findings not only link TME-driven PD-1/PD-L1 activation to EBV+DLBCL's poor prognosis but also provide preclinical evidence for PD-1/PD-L1 blockade as a therapeutic strategy.
Many diagnostic and interventional procedures are performed in bronchoscopy suites in high-risk patients. Minor impairment in respiratory muscle function caused by incomplete reversal of neuromuscular block can contribute to postoperative pulmonary complications (PPCs). We assessed whether there are fewer serious PPCs after diagnostic or therapeutic bronchoscopy when neuromuscular block is reversed with sugammadex rather than neostigmine. This is a retrospective cohort study for bronchoscopy under general anaesthesia with the use of neuromuscular blockers between July 2016 and June 2022. The primary outcome was a composite of PPCs. The secondary outcome was hypoxaemia. We used inverse probability of treatment weighting (IPTW) to adjust for confounding, fitting weighted outcome regression models to evaluate the association between the treatment and outcomes. We analysed 8557 bronchoscopies across 6123 patients for the primary analysis. Adequate balance was achieved on all potential confounders after IPTW. The unweighted PPC incidence was 85/3830 (2.2%) for sugammadex and 93/4727 (2.0%) for neostigmine. The weighted PPC incidence was 2.7% for sugammadex and 1.9% for neostigmine. Sugammadex was associated with higher odds of experiencing the primary outcome of PPCs (odds ratio [OR]: 1.44; 95% confidence interval [CI]: 1.02-2.05; P=0.038), but not the secondary outcome of hypoxaemia (OR: 0.98; 95% CI: 0.81-1.20; P=0.878). Sugammadex was associated with a higher risk of PPCs than neostigmine. However, the absolute difference observed (0.8%) might not be clinically meaningful. Randomised trials are needed to more accurately determine the effect of neuromuscular block reversal agent selection on respiratory complications.
Hepatic ischemia/reperfusion (Hep I/R) is a great health burden during hepatic transplantation surgery. The present work aimed to examine the mitigative effect of Chlorella vulgaris against Hep I/R and its underlying protective mechanisms. The animals in the present research were classified into four equal experimental groups (n=6): the sham group, sham+Chlorella vulgaris group, Hep I/R group, and Hep I/R+Chlorella vulgaris group. Hepatic ischemia results in liver impairment, as evidenced by elevated liver enzyme levels and altered liver histology. It also reduced antioxidant enzyme levels and increased lipid peroxidation. Additionally, the Hep I/R group displayed significant suppression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 pathway. There was a marked elevation in the expression of inflammatory markers, including nuclear factor kappa beta (NF-κB), tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and myloperoxidase, and NOD-like receptor protein 3 (NLRP3) and caspase-1. Furthermore, the levels of apoptotic markers such as caspase-3 and Bax were greater than those in the sham groups. Pretreatment with Chlorella vulgaris significantly protected against Hep I/R by reversing these effects. Rats pretreated with Chlorella vulgaris exhibited a hepatoprotective effect against Hep I/R through its inhibition of the NF-κB and NLRP3 cascades and Nrf2 stimulation.
Currently, the use of contrast agents in interventional procedures and imaging has been increasing. Icariin, an active component of Epimedium, offers beneficial biological activities such as antioxidation and anti-inflammation. Therefore, our study aimed to investigate the protective role of icariin and its underlying mechanisms against contrast-induced nephropathy (CIN). We divided twenty-four rats into four groups (n = 6 each): control group icariin-only treated group, contrast-induced nephropathy (CIN) group, and CIN+Icariin group, with six rats in each group. We performed renal function tests (serum creatinine and blood urea nitrogen (BUN) and histological evaluations. Additionally, we measured malondialdehyde (MDA) and superoxide dismutase (SOD) levels in renal supernatant and used ELISA to quantify caspase-8, caspase-9, cytochrome c, Bcl-2 associated protein x (Bax), and B cell lymphoma/leukemia 2 protein (Bcl-2) levels. We assessed nuclear factor kappa beta (NF-κB) and interleukin-1 beta (IL-1β) gene expression and evaluated immunoexpression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), CD68, and caspase-3. Icariin showed nephroprotective effects against CIN, demonstrated by reduced creatinine and BUN; decreased MDA, IL-6, NF-κB, TNF-α, IL-1β, CD68, caspase-8, caspase-9, Bax, and cytochrome c; and increased SOD and Bcl-2 levels. Renal histology improved in the CIN+Icariin group compared to CIN group. Oral administration of 100 mg/kg icariin exhibited renoprotective effects against contrast-induced renal injury through anti-inflammatory, anti-apoptotic, and antioxidant mechanisms.
Poretti-Boltshauser Syndrome (PBS) is a rare neuro-ophthalmological disorder with autosomal recessive inheritance. It is characterized by non-progressive cerebellar ataxia, delay in neuropsychomotor development, intellectual disability, and vision abnormalities. PBS is caused by mutations in the LAMA1 gene, resulting in cerebellar abnormalities, including cerebellar cysts in most cases. We present two siblings with LAMA1 mutations and distinct phenotypic presentation, with one of them showing no evidence of cerebellar cysts on magnetic resonance imaging (MRI). This study highlights intrafamilial variability in patients with Poretti-Boltshauser Syndrome (PBS). Patient 1 exhibits more pronounced cerebellar dysplasia (with cysts) and oculomotor apraxia, while Patient 2 shows milder cerebellar dysplasia (without cysts) and a macular hole. These findings underscore the importance of comprehensive evaluation and genetic testing for accurate diagnosis and management of PBS.
Cheater viruses cannot replicate on their own yet replicate faster than the wild type (WT) when the 2 viruses coinfect the same cell. Cheaters must possess dual genetic features: a defect, which leads to their inability to infect cells on their own, and a selective advantage over WT during coinfection. Previously, we have discovered 2 point-mutant cheaters of the MS2 bacteriophage. Here, we set out to discover the possible repertoire of cheater MS2 viruses by performing experimental evolution at a very high multiplicity of infection. Our results revealed a third point-mutant cheater that arose in 8 biological replicas. Each of the 3 primary cheaters disrupts the fine balance necessary for phage replication, in different ways that create a defect + advantage. We found that over time, the point-mutant cheaters accumulate additional secondary mutations, which alter other stages of the viral replication cycle, complementing the disruptions created by the original cheater. Intriguingly, cheater and secondary mutations almost always reside in very close proximity on the genome. This region encodes for multiple functions: overlapping reading frames as well as overlapping RNA structures critical for transitioning from one stage to another in the viral replication cycle. This region of overlap explains the dual functions of cheaters, as one mutation can have pleiotropic effects. Overall, these findings underscore how viruses, whose dense genomes often have overlapping functions, can easily evolve point-mutant cheaters, and how cheaters can evolve to alter the intricate balance of the viral replication cycle.
Monosodium glutamate is a food additive and flavour enhancer in processed foods and soups that is considered to affect testicular histology. The aim of this research was to investigate the impact of monosodium glutamate (MSG) on testicular structure in rats and explore the potentially protective effects of resveratrol. Four experimental groups involved in our study contained 10 rats in each. The first group was a control group; in the second group (the resveratrol group) control rats received 20 mg/kg of resveratrol via oral gavage; in the third group (the MSG group) rats received monosodium glutamate (MSG) at a dose of 60 mg/kg body weight daily, via a gastric tube. The fourth group we called the MSG + resveratrol group. Serum levels of testosterone, FSH, and LH were measured. Testicular specimens were prepared for measurement of oxidative stress markers, and gene expression of NLRP3, caspase-3, and GSK-3b. Moreover, paraffin blocks contained testicular tissue used for histological and immunohistochemical examination. Additionally, seminal smears from epididymis were examined. MSG administration adversely affected testosterone production, hormonal levels, and sperm parameters, Histological examination revealed marked testicular degeneration, and oxidative stress assessments indicated an elevated level of MDA, a lipid peroxidation marker, and decreases in SOD and CAT, two antioxidant enzymes. Moreover, MSG induced apoptotic and pyroptotic markers and its gene expressions. Importantly, the administration of resveratrol reversedthese detrimental effects of MSG, demonstrating its corrective influence on hypothalamic-pituitary-gonadal axis disruption, the improvement of sperm parameters, the attenuation of oxidative stress, and anti-apoptotic activity and anti-pyroptotic effects. The expression of Ki-67 as a cell proliferation marker further supported the positive response to spermatogenesis dysfunction upon resveratrol treatment. This article sheds light on the protective effect of resveratrol against MSG-induced testicular damage, with an exploration of its mechanistic role.
Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous non-Hodgkin lymphoma that is extremely aggressive and has an intermediate to high malignancy. Some patients still experience treatment failure, relapse, or resistance to rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) therapy. Therefore, there is an urgent need for further research on new agents for the treatment of DLBCL. AP-48 is an aaptamine alkaloid analog with potent anti-tumor effects that originates from marine natural products. In this study, we found that AP-48 exhibits dose-dependent cytotoxicity in DLBCL cell lines. Flow cytometry showed that AP-48 induced cell cycle arrest in the G0/G1 phase in SU-DHL-4 and Farage cells and in the S phase in WSU-DLCL-2 cells. AP-48 also accelerated apoptosis via the caspase-3-mediated intrinsic apoptotic pathway. Further experiments demonstrated that AP-48 exerted its anti-DLBCL effects through the PI3K/AKT/mTOR pathway, and that the PI3K agonist YS49 partially alleviated the inhibition of cell proliferation and apoptosis induced by AP-48. Finally, in a tumor xenograft model, AP-48 inhibited tumor growth and promoted apoptosis in tumor tissues, indicating its therapeutic potential in DLBCL.