Explore the vast range of titles available.

p-Cymene (p-C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p-C and RA (25–200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4+, CD8+, or CD3+CD4+CD25+) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p-C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p-C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.

Atherosclerosis is a complex pathological process involving macrophages, endothelial cells and vascular smooth muscle cells that can lead to ischemic heart disease; however, the mechanisms underlying cell‐to‐cell communication in atherosclerosis are poorly understood. In this study, we focused on the role of exosomal miRNAs in crosstalk between macrophages and endothelial cells and explored the rarely studied molecular mechanisms involved. Our in vitro result showed that macrophage‐derived exosomal miR‐4532 significantly disrupted human umbilical vein endothelial cells (HUVECs) function by targeting SP1 and downstream NF‐κB P65 activation. In turn, increased endothelin‐1 (ET‐1), intercellular cell adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) and decreased endothelial nitric oxide synthase (eNOS) expression in HUVECs increased attraction of macrophages, exacerbating foam cell formation and transfer of exosomal miR‐4532 to HUVECs. MiR‐4532 overexpression significantly promoted endothelial injury and pretreatment with an inhibitor of miR‐4532 or GW4869 (exosome inhibitor) could reverse this injury. In conclusion, our data reveal that exosomes have a critical role in crosstalk between HUVECs and macrophages. Further, exosomal miR‐4532 transferred from macrophages to HUVECs and targeting specificity protein 1 (SP1) may be a novel therapeutic target in patients with atherosclerosis.

The present study aimed to explore the influence of Polygonatum sibiricum polysaccharides (PSP) on the progression of prostate cancer PC-3 cell xenografts in nude mice, with a specific emphasis on analyzing the regulation of key proteins in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and nuclear factor-kappa B (NF-κB) signaling pathways. An androgen-independent PC-3 prostate cancer cell line was subcutaneously injected into immunocompromised BALB/c nude mice to establish a xenograft model. The mice were randomly allocated into five groups, each comprising six animals. Drug dosages were determined according to the body surface area ratio between humans and nude mice. The control group was given normal saline, whereas the docetaxel (DTX) group received docetaxel at a dosage of 5 mg/(kg·d). The PSP treatment groups were administered PSP at low [100 mg/(kg × d)], medium [200 mg/(kg × d)], and high [400 mg/(kg × d)] doses. Each treatment was delivered via gavage at a volume of 0.2 ml every other day for a 30-day period. Tumor volume and body weight were recorded every 3 days to evaluate the effect of PSP on xenograft growth, with tumor size and overall health status serving as the primary assessment criteria. A total of 4 h after drug administration, tumor volume was measured to calculate the tumor inhibition rate. Subsequently, apoptosis in tumor tissues was evaluated using the TUNEL assay. Immunohistochemistry was conducted to detect the expression levels of PI3K, Akt, NF-κB p65, their phosphorylated forms (p-PI3K, p-Akt and p-NF-κB p65), and caspase-3. At the initial stage of establishing the tumor-bearing nude mouse model of prostate cancer, all groups of nude mice displayed stable mental states, high levels of activity, regular feeding habits and heightened responsiveness to external stimuli. However, as the tumors progressed, a decline in activity, food intake and responsiveness to stimuli was observed across all groups. PSP inhibited the proliferation of PC-3 cells and induced apoptosis in tumor-bearing nude mice, presumably by downregulating PI3K, Akt and NF-κB p65, thereby suppressing the PI3K/Akt and NF-κB signaling pathways. Simultaneously, PSP upregulated the expression of caspase-3, which contributed to its antitumor effects in the PC-3 prostate cancer model.

This study aimed to investigate the cytotoxicity of a cluster of differentiation 70 antibody‐drug conjugate (CD70‐ADC) against ovarian cancer in in vitro and in vivo xenograft models. CD70 expression was assessed in clinical samples by immunohistochemical analysis. Western blotting and fluorescence‐activated cell sorting analyses were used to determine CD70 expression in the ovarian cancer cell lines A2780 and SKOV3, and in the cisplatin‐resistant ovarian cancer cell lines A2780cisR and SKOV3cisR. CD70 expression after cisplatin exposure was determined in A2780 cells transfected with mock‐ or nuclear factor (NF)‐κB‐p65‐small interfering RNA. We developed an ADC with an anti‐CD70 monoclonal antibody linked to monomethyl auristatin F and investigated its cytotoxic effect. We examined 63 ovarian cancer clinical samples; 43 (68.3%) of them expressed CD70. Among patients with advanced stage disease (n = 50), those who received neoadjuvant chemotherapy were more likely to exhibit high CD70 expression compared to those who did not (55.6% [15/27] vs 17.4% [4/23], P < .01). CD70 expression was confirmed in A2780cisR, SKOV3, and SKOV3cisR cells. Notably, CD70 expression was induced after cisplatin treatment in A2780 mock cells but not in A2780‐NF‐κB‐p65‐silenced cells. CD70‐ADC was cytotoxic to A2780cisR, SKOV3, and SKOV3cisR cells, with IC50 values ranging from 0.104 to 0.341 nmol/L. In A2780cisR and SKOV3cisR xenograft models, tumor growth in CD70‐ADC treated mice was significantly inhibited compared to that in the control‐ADC treated mice (A2780cisR: 32.0 vs 1639.0 mm3, P < .01; SKOV3cisR: 232.2 vs 584.9 mm3, P < .01). Platinum treatment induced CD70 expression in ovarian cancer cells. CD70‐ADC may have potential therapeutic implications in the treatment of CD70 expressing ovarian cancer. The immunohistochemical analysis of ovarian cancer specimens revealed that cluster of differentiation 70 (CD70) is expressed in approximately 70% of patients who received platinum‐based neoadjuvant chemotherapy. CD70 is induced in cisplatin‐treated ovarian cancer cells and is strongly expressed in platinum‐resistant cells. The CD70 antibody‐drug conjugate is effective against CD70‐expressing ovarian cancer both in vitro and in vivo. Our translational research indicates that the effectiveness of CD70 antibody‐drug conjugate merits further investigation as a novel therapeutic strategy for women with ovarian cancer.

Dioscin (DIS) is a natural compound derived from Chinese herbal medicine. In recent years, multiple studies have reported that DIS has immunoregulation, anti-fibrosis, anti-inflammation, anti-viral and anti-tumor effects. However, the mechanism by which DIS ameliorates renal fibrosis and inflammation remains to be elucidated. The aim of the present study was to investigate the role of DIS in renal fibrosis and inflammation and to explore its underlying mechanism. It used network pharmacology to predict the targets of DIS for the treatment of renal interstitial fibrosis. The present study was performed using unilateral ureteral obstruction mice and HK-2 cells in vivo and in vitro. The mice were treated with different doses of DIS. Kidney tissues were collected for histopathology staining, western blotting, immunohistochemistry staining and reverse transcription-quantitative (RT-q) PCR. TGF-β1 (2 ng/ml) was used to induce renal fibrosis in the cells. Then, cells were respectively treated with DIS (3.125, 6.25, 12.5 µM) and Bay11-7082 (an inhibitor of NF-κB p65 nuclear transcription, 1 µM) for another 24 h. The expressions of inflammatory factors and NF-κB pathway proteins were detected by immunofluorescence, ELISA, western blotting and RT-qPCR. DIS alleviated renal injury in the UUO mice. Mechanistically, DIS not only decreased the expressions of inflammatory factors including IL-1β, NOD-like receptor thermal protein domain associated protein 3, monocyte chemotactic protein 1, IL-6, TNF-α and IL-18 but also reduced the level of phosphorylation of NF-κB p65 in vivo and in vitro, which was similar to the impact of Bay11-7082. DIS ameliorated renal fibrosis by inhibiting the NF-κB signaling pathway-mediated inflammatory response, which may be a therapeutic pathway for delaying chronic kidney disease.

Background Incontinence‐associated dermatitis (IAD) is a tough problem in clinical settings, not only increasing the risk of complications like catheter‐related urinary tract infections and pressure ulcers in elderly and critically ill patients, but also prolonging hospital stays, raising hospital costs, and possibly leading to medical disputes. This study is aimed to evaluate the therapeutic effect of silicone dressing combined with topical oxygen therapy on IAD in a rat model. Methods An IAD rat model induced by synthetic urine with trypsin was established. Hematoxylin & eosin staining was carried out to examine skin histology. Using immunofluorescence, the microvessel density in the affected skin tissues was determined. ELISA was performed to measure the concentrations of inflammatory cytokines and angiogenic factors in serum. The mRNA expression of EGF, PDGF, and VEGF was detected via qRT‐PCR. Western blotting was employed to determine NF‐κB p65/STAT1 pathway‐related protein levels. Results Compared to single therapy, silicone dressing combined with topical oxygen therapy could significantly reduce the severity of IAD, improve skin histology, inhibit inflammation, and promote angiogenesis in IAD rat models. Additionally, the results showed that relatively speaking, the combined therapy suppressed the NF‐κB p65/STAT1 signaling pathway more effectively. Conclusion These findings indicated that silicone dressing combined with topical oxygen therapy can alleviate IAD through promoting wound healing and inhibiting inflammation via NF‐κB p65/STAT1 signaling pathway in a rat model, which provided a theoretical basis for the prevention and treatment of IAD in clinic.

Chaperone-mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines. In engineered 5-FU-resistant CRC cell lines, a significant elevation of lysosome-associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5-FU resistance and to enhance PLD2 expression through the activation of NF-κB pathway. Accordingly, loss or gain of function of LAMP2A in 5-FU-resistant CRC cells rendered them sensitive or resistant to 5-FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5-FU treatment and anti-CMA therapy may be a novel therapeutic option for patients with CRC.

Fatal jellyfish stings often cause multi‐organ failure. Until now, these fatal outcomes are attributed to the direct toxic effects of the venom. Here, a mouse model of delayed jellyfish envenomation syndrome (DJES) is established and showed that venom from Nemopilema nomurai jellyfish can trigger a deadly cytokine storm – a severe inflammatory reaction. Mice injected with the venom displayed acute multi‐organ failure and significant upregulation of over 20 pro‐inflammatory cytokines (including IL‐6, TNF‐α, CXCL2, and CCL4) in the heart, liver, and kidneys. Transcriptomic analyses identified NF‐κB p65 subunit activation as central to the cytokine storm induction. Knockdown of p65 in macrophages reduced cytokine production and improved cell viability. Treatment with dexamethasone, an NF‐κB inhibitor, effectively suppressed the cytokine storm, mitigated organ damage, and increased survival rates in mice. The findings present new insights to treat fatal jellyfish stings. N. nomurai is the most important injurious species in the coastal area of China. Model construction, omics analysis, mechanism exploration, and intervention measures of N. nomurai envenomation are performed in the current study, and it suggested that cytokine storm played an important role in pathogenesis. These findings present new insights to treat fatal jellyfish stings.

Hyperglycemia is known to lead to cardiac injury and inflammation through the reactive oxygen species (ROS)-Toll-like receptor 4 (TLR4)-necroptosis pathway. Similarly, angiotensin II (Ang II) activates the TLR4-nuclear factor κB (NF-κB) p65 pathway, while the protein Klotho is known to inhibit this pathway, protecting cardiac cells from Ang II-induced injury. However, there is currently a lack of data on whether necroptosis participates in Ang II-induced cardiac injury and whether the Klotho protein has an effect on this process. The present study aimed to explore whether inhibition of the TLR4/NF-κB p65 necroptosis pathway is involved in the Klotho protein-mediated protection against the Ang II-induced cardiac injury and inflammation. H9c2 cardiac cells were incubated with 0.01 mM Ang II. Western blotting was used to assess the expression of receptor-interacting protein kinase 3 (RIP3), mixed-lineage kinase domain-like protein (MLKL), TLR4 and NF-κB p65. The present study also assessed injury indexes: Inflammatory cytokine expression, mitochondrial membrane potential (ΔΨm), apoptosis, ROS production and cell viability. The expression of TLR4, phosphorylated (p)-NF-κB p65, RIP3 and MLKL were increased by incubation with Ang II in H9c2 cells. The pretreatment of H9c2 cells with necrostatin-1 (Nec-1, an inhibitor of necroptosis) or TAK-242 (a small molecule inhibitor of TLR4) attenuated the upregulation of RIP3 and MLKL caused by Ang II. Klotho protein cotreatment also reversed the Ang II-induced upregulation of TLR4, p-NF-κB p65, RIP3 and MLKL. Furthermore, Ang II decreased cell viability and upregulated the secretion of inflammatory cytokines, ΔΨm loss and ROS generation blocked by pretreatment with Nec-1 or Klotho protein. Thus, it was determined that Klotho can attenuate the Ang II-induced necroptosis of cardiomyocytes through the TLR4/NF-κB p65 pathway, which suggests that Klotho could be a potential therapeutic drug against Ang II-induced cardiotoxicity.

Receptor‐interacting protein kinase 3 (RIPK3) is a key player in necroptosis and an emerging inflammation regulator, whose contribution to podocyte injury in diabetic kidney disease (DKD) remain unclear. Here, podocyte‐specific RIPK3‐knockout (KO) DKD mice and high glucose (HG) cultured mouse podocytes are used to elucidate the protective effects of podocyte RIPK3 deletion on DKD, explore the molecular pathogenic mechanisms of RIPK3 in podocyte injury, and assess pharmacological inhibition of RIPK3 signaling as a therapeutic strategy. The results demonstrated that podocyte‐specific RIPK3‐KO alleviated albuminuria, mesangial matrix proliferation, foot process fusion, and podocyte loss in DKD mice. Additionally, podocyte RIPK3 is upregulated in renal biopsies with DKD and expression is negatively correlated with albuminuria. In vitro, knockdown of RIPK3 using small interfering RNA (siRNA) or inhibition with GSK'872 prevented podocyte injury. RNA sequencing of mouse podocytes revealed that the knockdown of RIPK3 can alleviate HG‐induced activation of the NF‐κB‐related inflammatory pathways. Importantly, pharmacological inhibition of RIPK3 by GSK'872 alleviated podocyte damage, and reduced proteinuria in DKD mice. Overall, these results uncovered a novel role of podocyte RIPK3 in promoting podocyte injury and DKD progression by regulating NF‐κB‐mediated inflammatory signaling independent of necroptosis, offering novel insights and potential therapeutic strategies for DKD management. Prevention and treatment of diabetic kidney disease (DKD) have become a major global public health challenge. This study shed new light on the underlying pathogenic mechanisms of podocyte injury in DKD and highlights the therapeutic potential of mitigating podocyte injury through inhibition of the RIPK3/NF‐κB p65‐mediated inflammatory response as a viable treatment option for DKD.