BACKGROUND: Dry eye is a common eye disease. Artificial tears supplements are widely used for the treatment of dry eyes. However, multiple adverse effects have been observed in patients receiving long-term treatment with artificial tears, which may affect the therapeutic effect.
OBJECTIVE: To analyze the characteristics of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels in patients with dry eye and the therapeutic effect of artificial tears combined with cyclosporine A.
METHODS: A total of 124 dry eye patients treated at The First People\'s Hospital of Xining from April 2020 to April 2022 were selected as the observation group, while 20 healthy individuals served as the control group during the same period. Levels of inflammatory markers, including IL-1β, IL-6, and TNF-α, were analyzed. The observation group was further divided into a study group and a control group, each consisting of 62 patients. The control group received artificial tears, whereas the study group received a combination of artificial tears and cyclosporine A. Inflammatory markers, Schirmer\'s test (SIT), tear break-up time (TBUT), corneal fluorescein staining (CFS), National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) scores, and adverse events (AEs) were compared between the two groups.
RESULTS: The observation group exhibited significantly elevated serum levels of IL-1β, IL-6, and TNF-α in comparison to the healthy group. Following treatment, the study group demonstrated substantial reductions in IL-1β, IL-6, and TNF-α levels relative to the control group. Moreover, after treatment, the study group experienced a marked decrease in CFS scores and significant increases in both SIT and BUT levels when compared to the control group. Additionally, significant improvements were observed in the primary symptom of dry eye and secondary symptoms such as photophobia, foreign body sensation, fatigue, red eye, and burning sensation within the study group. Furthermore, post-treatment NEI-VFQ-25 scores across all dimensions exhibited significant enhancements in the study group compared to the control group (P < 0.05). It is noteworthy that significant AEs were reported in both groups throughout the treatment period.
CONCLUSIONS: Cyclosporine A combined with artificial tears is effective in treating dry eye, yielding enhanced outcomes by improving SIT and TBUT levels, reducing CFS scores, and ameliorating vision-related quality of life.

Our previous study has verified that activation of group Ⅰ metabotropic glutamate receptors (mGluRⅠ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR Ⅱ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist β-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than β-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1β in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1β, these effects were reversed by EGLU instead of β-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1β in normal rats, while intrarubral injection of EGLU rather than β-NAAG significantly boosted the expressions of TNF-α and IL-1β. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain.

OBJECTIVE: Bariatric surgery poses an ever-increasing importance in the effective and long-lasting treatment of obesity, a condition strongly associated with inflammation and increased risk of other diseases and health problems. In obesity-related inflammation, maintaining a balance between pro-inflammatory and anti-inflammatory cytokines is crucial. In this study, we examined early effects of laparoscopic sleeve gastrectomy (LSG) on inflammatory and anti-inflammatory cytokines in obese patients, and assessed their effect on postoperative weight loss.
METHODS: This prospective cohort study was conducted from September 2022 till June 2023. Fifty obese adults were enrolled for LSG. All patients underwent assessments of body measurements, as well as levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and TNF-alpha at baseline and 3 months postsurgery. We developed a decision tree model to predict the success of weight loss.
RESULTS: At 3 months postsurgery, patients lost 18.9 ± 6.9 kg of excess body weight. A significant decrease was observed for IL-10 (p < 0.0001), simultaneously with a significant increase in IL-6 (p < 0.0001). We found that high IL-6 (> 1.169 pg/mL) levels could contribute to an effective weight loss among patients with a baseline BMI less than 47.46 kg/m2.
CONCLUSIONS: Study revealed that 3 months after bariatric surgery, inflammation persists, and its markers significantly influence postoperative weight loss, as indicated by BMI range. Distinct behaviors of IL-10 and IL-6 in relation to obesity underline the necessity of considering individual cytokine profiles when evaluating bariatric surgery outcomes.

Hepatocellular carcinoma (HCC) is a prevalent form of primary liver cancer with a 5-year survival rate of just 18%. Ferulic acid, a natural compound found in fruits and vegetables such as sweet corn, rice bran, and dong quai, is an encouraging drug known for its diverse positive effects on the body, including anti-inflammatory, anti-apoptotic, and neuroprotective properties. Our study aimed to investigate the potential antitumor effects of ferulic acid to inhibit tumor growth and inflammation of HCC in rats. HCC was induced in rats by administering thioacetamide. Additionally, some rats were given 50 mg/kg of ferulic acid three times a week for 16 weeks. Liver function was assessed by measuring serum alpha-fetoprotein (AFP) and examining hepatic tissue sections stained with hematoxylin/eosin or anti-hypoxia induced factor-1α (HIF-1α). The hepatic mRNA and protein levels of HIF-1α, nuclear factor κB (NFκB), tumor necrosis factor-α (TNF-α), mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), cMyc, and cyclin D1 were examined. The results showed that ferulic acid increased the rats\' survival rate by reducing serum AFP levels and suppressing hepatic nodules. Furthermore, ferulic acid ameliorated the appearance of vacuolated cytoplasm induced by HCC, reduced apoptotic nuclei, and necrotic nodules. Finally, ferulic acid decreased the expression of HIF-1α, NFκB, TNF-α, mTOR, STAT3, cMyc, and cyclin D1. In conclusion, ferulic acid is believed to possess antitumor properties by inhibiting HCC-induced hypoxia through the suppression of HIF-1α expression. Additionally, it helps in reducing the expression of mTOR, STAT3, cMyc, and cyclin D1, thereby slowing down tumor growth. Lastly, ferulic acid reduced hepatic tissue inflammation by downregulating NFκB and TNF-α.

OBJECTIVE: Mounting evidence suggests that histone deacetylases (HDAC) inhibitors reduce cartilage destruction in animal models of osteoarthritis (OA). Tumor necrosis factor (TNF)-α-blocking treatment for OA may provide effective joint protection by slowing joint damage. To investigate the effects of intraperitoneal administration of etanercept (a TNF-α inhibitor) on OA development in rats and changes in the nociceptive behavior of rats and expression of HDACs, RUNX2, and MMP13 in cartilage.
METHODS: Induction of OA in Wistar rats was accomplished through anterior cruciate ligament transection (ACLT). One or five milligrams (mg) of etanercept was administered intraperitoneally for 5 consecutive weeks after ACLT to the ACLT + etanercept (1 and 5 mg/kg) groups. Nociceptive behavior and changes in knee joint width were analyzed. Cartilage was evaluated histologically and immunohistochemically.
RESULTS: ACLT + etanercept significantly improved mechanical allodynia and weight-bearing distribution compared to ACLT alone. In OA rats treated with etanercept, cartilage degeneration and synovitis were significantly less pronounced than those in ACLT rats. OA-affected cartilage also showed reduced expression of HDAC 6, 7, RUNX-2, and MMP-13 in response to etanercept but increased expression of HDAC4.
CONCLUSIONS: Our study demonstrated that etanercept therapy (1) attenuated the development of OA and synovitis in rats, (2) reduced nociception, and (3) regulated chondrocyte metabolism, possibly by inhibiting cell HDAC6 and HDAC7, RUNX2, and MMP13 and increasing HDAC4 expression. Based on new evidence, etanercept may have therapeutic potential in OA.

Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

Following the publication of the above paper, it has been drawn to the Editor\'s attention by a concerned reader that the immunohistochemical assay data shown in Fig. 4B on p. 245 were strikingly similar to data appearing in different form in another article written by different authors at different research institutes that had already been published in the journal International Journal of Biological Sciences prior to the submission of this paper to International Journal of Molecular Medicine. In view of the fact that the contentious data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 46: 239-251, 2020; DOI: 10.3892/ijmm.2020.4595].

OBJECTIVE: To explore the mechanism of Tongyangxiao Lotion (TYX) for promoting wound healing following surgery for anal fistula.
METHODS: The active ingredients and drug targets of TYX were explored using TCMSP and BATMAN databases, and the targets associated with wound healing were screened using GeneCards and OMIM databases; the intersecting drug and wound-related targets were analyzed with protein-protein interaction (PPI) analysis and GO and KEGG enrichment analyses. In 25 SD rat models with simulated anal fistula surgery, the effect of wound dressing with TYX at low, medium and high doses (once daily for 14 days) on wound healing were assessed in comparison with potassium permanganate (PP) solution. The granulation tissues collected from the wounds were examined for pathological changes with HE staining and for TNF-α expression using immunohistochemistry. The expressions of 1β, TNF-α, IL-6 mRNA and proteins in the granulation tissue were detected using RT-qPCR, Western blotting or ELISA.
RESULTS: Network pharmacology analysis yielded 156 common targets between TYX and wound healing, and among them IL-1β, TNF- α, and IL-6 were identified as potential targets of TYX for promoting wound healing. Six core components of TYX were capable of binding to IL-1β, TNF-α, and IL-6 with binding energies all below -6.0 Kcal/mol. In the rat models, the wounds with TYX and PP solution dressing showed significantly reduced inflammatory cell infiltration and increased fibroblasts and collagen deposition. TYX at the 3 doses and PP solution all significantly reduced the expressions of IL-6, IL-1β, TNF-α mRNA and IL-6 protein in the granulation tissues, but TYX at the medium and high doses produced significantly stronger effects than PP solution for lowering TNF-α protein expression and mRNA expressions of TNF- α and IL-6.
CONCLUSIONS: TYX accelerates wound healing by down-regulating the inflammatory factors and reducing inflammation in the wounds.

Tumor necrosis factor-α (TNFα) is a master cytokine which induces expression of chemokines and adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), in endothelial cells to initiate the vascular inflammatory response. In this study, we identified neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, as a modulator of TNFα-induced inflammatory response of endothelial cells. NRP1 shRNA expression suppressed TNFα-stimulated leukocyte adhesion and expression of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVECs). Likewise, it reduced TNFα-induced phosphorylation of MAPK p38 but did not significantly affect other TNF-induced signaling pathways, such as the classical NFκB and the AKT pathway. Immunofluorescent staining demonstrated co-localization of NRP1 with the two receptors of TNF, TNFR1 and TNFR2. Co-immunoprecipitation further confirmed that NRP1 was in the same protein complex or membrane compartment as TNFR1 and TNFR2, respectively. Modulation of NRP1 expression, however, neither affected TNFR levels in the cell membrane nor the receptor binding affinities of TNFα. Although a direct interface between NRP1 and TNFα/TNFR1 appeared possible from a protein docking model, a direct interaction was not supported by binding assays in cell-free microplates and cultured cells. Furthermore, TNFα was shown to downregulate NRP1 in a time-dependent manner through TNFR1-NFκB pathway in HUVECs. Taken together, our study reveals a novel reciprocal crosstalk between NRP1 and TNFα in vascular endothelial cells.

Jack bean (JB), Canavalia ensiformis (L.) DC, is a commonly cultivated legume in Indonesia. It is rich in protein, which can be hydrolyzed, making it potentially a good source of bioactive peptides. Intestinal inflammation is associated with several diseases, and the production of interleukin-8 (IL-8) in intestinal epithelial cells induced by tumor necrosis factor (TNF)-α has an important role in inflammatory reaction. The present study investigated the anti-inflammatory effects of peptides generated from enzymatic hydrolysis of JB protein on human intestinal Caco-2BBe cells. Additionally, in silico approaches were used to identify potential bioactive peptides. JB protein hydrolysate (JBPH) prepared using pepsin and pancreatin reduced the IL-8 expression at protein and mRNA levels in Caco-2BBe cells stimulated with TNF-α. Immunoblot analysis showed that the JBPH reduced the TNF-α-induced phosphorylation of c-Jun-NH(2)-terminal kinase, nuclear factor kappa B (NF-κB), and p38 proteins. Anti-inflammatory activity was observed in the 30% acetonitrile fraction of JBPH separated on a Sep-Pak C18 column. An ultrafiltration method revealed that relatively small peptides (< 3 kDa) had a potent inhibitory effect on the IL-8 production. Purification of the peptides by reversed-phase and anion-exchange high performance chromatography produced three peptide fractions with anti-inflammatory activities. A combination of mass spectrometry analysis and in silico approaches identified the potential anti-inflammatory peptides. Peptides derived from JB protein reduces the TNF-α-induced inflammatory response in Caco-2BBe cells via NF-κB and mitogen-activated protein kinase signaling pathways. Our results may lead to a novel therapeutic approach to promote intestinal health.