Discovery and preclinical evaluation of KYS202004A, a novel bispecific fusion protein targeting TNF-α and IL-17A, in autoimmune disease models.

The treatment of autoimmune and inflammatory diseases often requires targeting multiple pathogenic pathways. KYS202004A is a novel bispecific fusion protein designed to antagonize TNF-α and IL-17A, pivotal in the pathophysiology of autoimmune and inflammatory diseases. Our initial efforts focused on screening for optimal structure by analyzing expression levels, purity, and binding capabilities. The binding affinity of KYS202004A to TNF-α and IL-17A was evaluated using SPR. In vitro, we assessed the inhibitory capacity of KYS202004A on cytokine-induced CXCL1 expression in HT29 cells. In vivo, its efficacy was tested using a Collagen-Induced Arthritis (CIA) model in transgenic human-IL-17A mice and an imiquimod-induced psoriasis model in cynomolgus monkeys. KYS202004A demonstrated significant inhibition of IL-17A and TNF-α signaling pathways, outperforming the efficacy of monotherapeutic agents ixekizumab and etanercept in reducing CXCL1 expression in vitro and ameliorating disease markers in vivo. In the CIA model, KYS202004A significantly reduced clinical symptoms, joint destruction, and serum IL-6 concentrations. The psoriasis model revealed that KYS202004A, particularly at a 2  mg/kg dose, was as effective as the combination of ixekizumab and etanercept. This discovery represents a significant advancement in treating autoimmune and inflammatory diseases, offering a dual-targeted therapeutic approach with enhanced efficacy over current monotherapies.

Acetylation of ELMO1 correlates with Rac1 activity and colorectal cancer progress.

Acetylation, a critical regulator of diverse cellular processes, holds significant implications in various cancer contexts. Further understanding of the acetylation patterns of key cancer-driven proteins is crucial for advancing therapeutic strategies in cancer treatment. This study aimed to unravel the acetylation patterns of Engulfment and Cell Motility Protein 1 (ELMO1) and its relevance to the pathogenesis of colorectal cancer (CRC). Immunoprecipitation and mass spectrometry precisely identified lysine residue 505 (K505) as a central acetylation site in ELMO1. P300 emerged as the acetyltransferase for ELMO1 K505 acetylation, while SIRT2 was recognized as the deacetylase. Although K505 acetylation minimally affected ELMO1's localization and stability, it played a crucial role in mediating ELMO1-Dock180 interaction, thereby influencing Rac1 activation. Functionally, ELMO1 K505 acetylation proved to be a pivotal factor in CRC progression, exerting its influence on key cellular processes. Clinical analysis of CRC samples unveiled elevated ELMO1 acetylation in primary tumors, indicating a potential association with CRC pathologies. This work provides insights into ELMO1 acetylation and its significance in advancing potentially therapeutic interventions in CRC treatment.

Rhombic dodecahedron nanoframes of PtIrCu with high-index faceted hyperbranched nanodendrites for efficient electrochemical ammonia oxidation via preferred NHx dimerization pathways.

Ammonia has been emerging as a sustainable and environmentally friendly fuel. However, direct electrochemical ammonia oxidation reaction (AOR) in low-temperature fuel cells seriously suffers from high overpotential and deficient durability. Herein, rhombic dodecahedron nanoframe of platinum iridium copper (PtIrCu) with high-index faceted hyperbranched nanodendrites (RDNF-HNDs) was developed using a one-step self-etching solvothermal method. The framework structure with the high-index facets enables the PtIrCu nanocrystals to expose more effective active sites. They exhibit an ultra-low onset potential of 0.33 V vs. RHE and high mass activity of 26.1 A gPtIr-1 at 0.50 V, which is 140 mV lower and 7.5 times higher than that of commercial Pt/C in the AOR. In situ attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy verifies that AOR on PtIrCu RDNF-HNDs prefers to the NHx dimerization pathways, effectively alleviating the poison of Nads and NOx. The theoretical calculation also shows that both introducing Cu atoms into PtIr alloy and increasing the content of Ir in PtIrCu alloy can reduce the reaction energy barrier of electrochemical dehydrogenation from *NH2 to *NH. The specific structure of PtIrCu RDNF-NDs provides a new inspiration to solve the critical issue of electrocatalysts for AOR with low activity and durability.

Recent advances in two-dimensional materials for hydrovoltaic energy technology.

Hydrovoltaic energy technology that generates electricity directly from the interaction of materials with water has been regarded as a promising renewable energy harvesting method. With the advantages of high specific surface area, good conductivity, and easily tunable porous nanochannels, two-dimensional (2D) nanomaterials have promising potential in high-performance hydrovoltaic electricity generation applications. Herein, this review summarizes the most recent advances of 2D materials for hydrovoltaic electricity generation, including carbon nanosheets, layered double hydroxide (LDH), and layered transition metal oxides and sulfides. Some strategies were introduced to improve the energy conversion efficiency and the output power of hydrovoltaic electricity generation devices based on 2D materials. The applications of these devices in self-powered electronics, sensors, and low-consumption devices are also discussed. Finally, the challenges and perspectives on this emerging technology are outlined.

KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2-CXCL10 Axis in Colorectal Cancer.

Poor infiltration of T lymphocytes has been regarded as a crucial mechanism of tumor immune escape. Here, we demonstrate a protective role of KRT17 in colorectal cancer, where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested that KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared with proficient mismatch repair (pMMR) tumors. In a colorectal cancer cohort of 446 cases, KRT17 expression positively correlated with better clinical outcomes. Krt17 overexpression decreased xenograft tumor growth in immune-competent mice. T-cell depletion in a murine model showed that the presence of T lymphocytes was necessary for Krt17-mediated disruption of tumorigenesis. Mass spectrometry and coimmunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found that CXCL10 was the target gene of the N6-methyladenosine (m6A) "reader" YTHDF2. KRT17 synergized with anti-PD-1 for better tumor control in an immunotherapy-resistant murine model. In a cohort of patients with colorectal cancer receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in colorectal cancer to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors.

CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis.

Radiation enteritis (RE) is a prevalent complication of radiotherapy for pelvic malignant tumors, characterized by severe intestinal epithelial destruction and progressive submucosal fibrosis. However, little is known about the pathogenesis of this disease, and so far, there is no specific targeted therapy. Here, we report that CXCL16 is upregulated in the injured intestinal tissues of RE patients and in a mouse model. Genetic deletion of Cxcl16 mitigates fibrosis and promotes intestinal stem cell-mediated epithelial regeneration after radiation injury in mice. Mechanistically, CXCL16 functions on myofibroblasts through its receptor CXCR6 and activates JAK3/STAT3 signaling to promote fibrosis and, at the same time, to transcriptionally modulate the levels of BMP4 and hepatocyte growth factor (HGF) in myofibroblasts. Moreover, we find that CXCL16 and CXCR6 auto- and cross-regulate themselves in positive feedback loops. Treatment with CXCL16 neutralizing monoclonal antibody attenuates fibrosis and improves the epithelial repair in RE mouse model. Our findings emphasize the important role of CXCL16 in the progression of RE and suggest that CXCL16 signaling could be a potential therapeutic target for RE. © 2022 The Pathological Society of Great Britain and Ireland.

Mesoporous hierarchical NiCoSe2-NiO composite self-supported on carbon nanoarrays as synergistic electrocatalyst for flexible lithium-sulfur batteries.

Lithium-sulfur batteries (LSBs) have enormous application potential in the flexible energy storage field due to their large theoretical specific capacities and high energy densities. However, lithium-sulfur batteries face a notorious shuttle effect problem. To address this challenge, this work reports a three-dimensional (3D) structure of binary transition metal selenides (B-TMSe) hierarchical composites (CC/NiCoSe2-NiO) on carbon cloth as a self-supporting sulfur host for flexible LSBs. According to the density functional theory (DFT) calculations, NiCoSe2can exert a synergetic effect of high affinity with Lithium polysulfides (LiPSs) and electrocatalytic activity to lower the adsorption energy barrier and accelerate the sluggish reaction kinetics of polysulfides. Consequently, the CC/NiCoSe2-NiO-based electrodes realize a large specific capacity of approximately 1363 mAh/g at a current density of 0.1C, excellent rate performance (454.66 mAh/g at 5C) and a reversible specific capacity of 978.9 mAh/g at 1C, along with impressive cycling stability with an attenuation rate of 0.038% per cycle for 1000 cycles. They also achieve a large reversible cycle capacity of 919.43 mAh/g at 0.2C even at a high sulfur loading (3.5 mg/cm2). With a lean electrolyte (E/S ratio 10 µL/mg) and a high sulfur loading of 2.65 mg/cm2, a large capacity of 934.1 mAh/g is retained after 150 cycles at 0.5C. The assembled pouch cells from S@CC/NiCoSe2-NiO electrodes show a high initial discharge capacity of 1039.5 mAh/g at 1C at a sulfur loading of 2.65 mg/cm2 and maintain strong stability under high twisting and buckling.

Transanal total mesorectal excision combined with intersphincteric resection has similar long-term oncological outcomes to laparoscopic abdominoperineal resection in low rectal cancer: a propensity score-matched cohort study.

Background: Transanal total mesorectal excision (taTME) or intersphincteric resection (ISR) has recently proven to be a valid and safe surgical procedure for low rectal cancer. However, studies focusing on the combination of these two technologies are limited. This study aimed to evaluate perioperative results, long-term oncologic outcomes, and anorectal functions of patients with low rectal cancer undergoing taTME combined with ISR, by comparing with those of patients undergoing laparoscopic abdominoperineal resection (laAPR). Methods: After 1:1 propensity score matching, 200 patients with low rectal cancer who underwent laAPR (n = 100) or taTME combined with ISR (n = 100) between September 2013 and November 2019 were included. Patient demographics, clinicopathological characteristics, oncological outcomes, and anal functional results were analysed. Results: Patients in the taTME-combined-with-ISR group had less intraoperative blood loss (79.6 ± 72.6 vs 107.3 ± 65.1 mL, P = 0.005) and a lower rate of post-operative complications (22.0% vs 44.0%, P < 0.001) than those in the laAPR group. The overall local recurrence rates were 7.0% in both groups within 3 years after surgery. The 3-year disease-free survival rates were 86.3% in the taTME-combined-with-ISR group and 75.1% in the laAPR group (P = 0.056), while the 3-year overall survival rates were 96.7% and 94.2%, respectively (P = 0.319). There were 39 patients (45.3%) in the taTME-combined-with-ISR group who developed major low anterior resection syndrome, whereas 61 patients (70.9%) had good post-operative anal function (Wexner incontinence score ≤ 10). Conclusion: We found similar long-term oncological outcomes for patients with low rectal cancer undergoing laAPR and those undergoing taTME combined with ISR. Patients receiving taTME combined with ISR had acceptable post-operative anorectal function.

Surface Functionalization of Graphene Oxide with Hyperbranched Polyamide-Amine and Microcrystalline Cellulose for Efficient Adsorption of Heavy Metal Ions.

Graphene oxide (GO)-based adsorbents have received attention in the removal of heavy metal ions in wastewater due to its large specific surface area and oxygen-containing functional groups, which can enhance the interaction between GO and heavy metal ions. Many researchers are seeking economical and effective strategies to further improve the adsorption capacity of GO. In this study, hyperbranched polymers and cellulose were used to surface functionalize GO for the efficient adsorption of heavy metal ions. First, hyperbranched polyamide-amine (HPAMAM) functionalized GO was fabricated by the formation of an amide bond between the carboxyl group of GO and the amino group of HPAMAM, increasing the active groups on the GO surface and enhancing the affinity with heavy metal ions. Then, dialdehyde cellulose (DAC) obtained through the oxidation of microcrystalline cellulose was grafted onto GO/HPAMAM by forming a Schiff-based structure between the amino group of HPAMAM and aldehyde group of DAC. Interestingly, DAC formed micro/nano bumps on GO, which was beneficial to increase the hydroxyl number and contact area with heavy metal ions. The Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) results confirmed the successful synthesis of GO/HPAMAM/DAC. The obtained GO/HPAMAM/DAC adsorbent exhibited strong adsorption capacity and good cycle stability for heavy metal ions. The maximum adsorption capacities of Pb(II), Cd(II), and Cu(II) were 680.3, 418.4, and 280.1 mg/g at 298 K, which were better than those of most adsorbents reported. A pseudo-second-order kinetic model could well-describe the Pb(II), Cd(II), and Cu(II) adsorption onto GO/HPAMAM/DAC, and the equilibrium data fitted well with the Langmuir isotherm model. The adsorption of Pb(II), Cd(II), and Cu(II) was mainly attributed to the chelation or complexation of nitrogen- and oxygen-containing groups on the GO/HAPAMAM/DAC adsorbent. This study may provide a novel strategy for improving the adsorption performance of GO with hyperbranched polymers and cellulose.

Fibroblast growth factor-21 as a novel metabolic factor for regulating thrombotic homeostasis.

Fibroblast growth factor-21 (FGF-21) performs a wide range of biological functions in organisms. Here, we report for the first time that FGF-21 suppresses thrombus formation with no notable risk of bleeding. Prophylactic and therapeutic administration of FGF-21 significantly improved the degree of vascular stenosis and reduced the thrombus area, volume and burden. We determined the antithrombotic mechanism of FGF-21, demonstrating that FGF-21 exhibits an anticoagulant effect by inhibiting the expression and activity of factor VII (FVII). FGF-21 exerts an antiplatelet effect by inhibiting platelet activation. FGF-21 enhances fibrinolysis by promoting tissue plasminogen activator (tPA) expression and activation, while inhibiting plasminogen activator inhibitor 1 (PAI-1) expression and activation. We further found that FGF-21 mediated the expression and activation of tPA and PAI-1 by regulating the ERK1/2 and TGF-ß/Smad2 pathways, respectively. In addition, we found that FGF-21 inhibits the expression of inflammatory factors in thrombosis by regulating the NF-κB pathway.

Three-year outcomes of transanal total mesorectal excision versus standard laparoscopic total mesorectal excision for mid and low rectal cancer.

INTRODUCTION: Since transanal total mesorectal excision (taTME) was introduced, it has become an important topic in rectal cancer treatment. Many previous studies reported positive relevant short-term results, histopathological results, and associated complications. Recently, concerns regarding the oncological safety of taTME have been raised due to reports showing high local recurrences (LR) rates. Therefore, this study aimed to compare the 3-year outcomes between taTME and laparoscopic total mesorectal excision (laTME) for mid-low rectal cancer. METHODS: A total of 104 patients who underwent taTME were matched with 208 patients treated by laTME. The primary endpoint was 3-year LR rate; secondary endpoints in this matched-cohort study included the perioperative outcomes and histopathological outcomes. RESULTS: taTME was associated with lower permanent ostomy rate (1% vs 13.5%) and lower conversion rate (0% vs 3.4%) compared to laTME. A similar quality of resected specimens was detected for each group. In both groups, the local recurrence rate was 3.8%. Within 3 years after surgery, the disease-free survival (DFS) rates were 78.8% in the taTME group and 76.9% in the laTME group (P = 0.640), while the overall survival (OS) rates were 93.3% in the taTME group and 89.9% in the laTME group (P = 0.327). CONCLUSION: No significant differences regarding 3-year local recurrence rate (3.8%) were observed in the taTME group compared to laTME group.

An immuno-blocking agent targeting IL-1ß and IL-17A reduces the lesion of DSS-induced ulcerative colitis in mice.

In recent decades when biological agents have flourished, a part of patients suffering from inflammatory bowel disease (IBD) have received the treatment of tumor necrosis factor inhibitors or IL-1 antibodies. This study aims to investigate the anti-colitis effects of bispecific antibody (FL-BsAb1/17) targeting IL-1ß and IL-17A comparing with TNF-α soluble receptor medicine etanercept. IBD model in mice was established by drinking 3% DSS (dextran sulfate sodium salt). On the first day of drinking DSS, treatments with etanercept (5 mg/kg) or different doses of FL-BsAb1/17 (1 mg/kg, 5 mg/kg, and 10 mg/kg) were started by intraperitoneal injection every other day. The results demonstrated that FL-BsAb1/17 treatment was more effective than etanercept at the same dose (5 mg/kg) in relieving the typical symptom of ulcerative colitis induced by DSS (such as the severity score and intestinal shortening), and down-regulating the expression of inflammatory factors (IL-17A, IL-6, IL-12, IL-22, IL-1ß, IL-23, TNF-α) in the serum and colon. FL-BsAb1/17 could also reduce the degree of intestinal fibrosis. The same dose of FL-BsAb1/17 (5 mg/kg) performed better than etanercept in down-regulating MDA and up-regulating SOD (superoxide dismutase), CAT (catalase), and T-AOC (total antioxidant capacity) in serum. Both FL-BsAb1/17 and etanercept could reduce the transcription of Bax and increase the transcription of Bcl-2 and slow down apoptosis in colitis colon tissue. We conclude that the blocking of IL-1ß and IL-17A can inhibit DSS-induced ulcerative colitis and FL-BsAb1/17 may have potential to become a new dual-target candidate for colitis treatment.

Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis.

Most cancer-related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate-limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT-qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non-PM primary tumors. Here, we showed that cancer-associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture-induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A-OE in vitro and impaired the survival and growth of organoids derived from CRC-PM. Finally, we found that directly blocking FAO in CAFsCPT1A-OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF-induced colorectal cancer with peritoneal dissemination/metastases.

Transanal Total Mesorectal Excision in Mid-Low Rectal Cancer: Evaluation of the Learning Curve and Comparison of Short-term Results With Standard Laparoscopic Total Mesorectal Excision.

BACKGROUND: Ever since transanal total mesorectal excision was introduced by Sylla and Lacy in 2010, it has become more popular among colorectal surgeons. However, some surgeons hesitate to use it, because this novel approach differs greatly from laparoscopic total mesorectal excision and requires a long learning curve. OBJECTIVE: This study analyzed the learning curve of transanal total mesorectal excision procedure and compared the different phases of transanal total mesorectal excision with laparoscopic total mesorectal excision. DESIGN: This is retrospective case-control study. SETTINGS: We used data from the approved colorectal cancer database of the Sixth Affiliated Hospital of Sun Yat-sen University. PATIENTS: The patients involved in this study underwent transanal total mesorectal excision performed by a single surgeon (L.K.) or underwent laparoscopic transanal total mesorectal excision performed by experienced surgeons. INTERVENTIONS: Transanal or laparoscopic resection of mid-low rectal cancer was conducted. MAIN OUTCOMES MEASURES: Perioperative complication and resection margin were measured. RESULTS: A total of 342 patients were included in both groups. The learning curve of transanal total mesorectal excision was divided into 3 phases. Data show that demographics and tumor characteristics were not significantly different between the matched groups. Indeed, during phase 1, only operative time was longer than in the laparoscopic group, whereas, during phase 2, results from the transanal group were comparable with the laparoscopic group. Results show that, during phase 3, operative time, intraoperative blood loss, and postoperative hospital stay were all lower than in the laparoscopic group. Local recurrence occurred in 3 patients during phase 1 and in 1 patient during phase 2. LIMITATIONS: This study was a small retrospective study and focused on just 1 surgeon performing transanal total mesorectal excision. CONCLUSIONS: Short-term and histopathologic outcomes are similar compared between a transanal group and matched laparoscopic group. Transanal total mesorectal excision also provided good oncologic outcomes. See Video Abstract at http://links.lww.com/DCR/B450. ESCISIN MESORRECTAL TOTAL TRANSANAL EN EL CNCER DE RECTO MEDIOBAJO EVALUACIN DE LA CURVA DE APRENDIZAJE Y COMPARACIN DE RESULTADOS A CORTO PLAZO CON TME LAPAROSCPICA ESTNDAR: ANTECEDENTES:Desde que Sylla y Lacy introdujeron la escisión mesorrectal total transanal en 2010, se ha vuelto más popular entre los cirujanos colorrectales. Sin embargo, algunos cirujanos dudan en utilizarlo, porque este nuevo método difiere mucho de la escisión mesorrectal total laparoscópica y requiere una larga curva de aprendizaje.OBJETIVO:Este estudio analizó la curva de aprendizaje del procedimiento de escisión mesorrectal total transanal y comparó las diferentes fases de la escisión mesorrectal total transanal con la escisión mesorrectal total laparoscópica.DISEÑO:Este es un estudio retrospectivo de casos y controles.ENTORNO CLINICO:Utilizamos base de datos de cáncer colorrectal aprobada del Sexto Hospital Afiliado de la Universidad Sun Yat-sen (Guangzhou, China).PACIENTES:Los pacientes involucrados en este estudio fueron sometidos a escisión mesorrectal total transanal realizada por un solo cirujano (LK) o se sometieron a escisión mesorrectal total transanal laparoscópica realizada por cirujanos experimentados.INTERVENCIONES:Resección transanal o laparoscópica de cáncer de recto medio-bajo.PRINCIPALES MEDIDAS DE VOLARCION:complicación perioperatoria y margen de resección.RESULTADOS:Se incluyó un total de 342 pacientes en ambos grupos. La curva de aprendizaje de la escisión mesorrectal total transanal se dividió en tres fases. Los datos muestran que las características demográficas y tumorales no fueron significativamente diferentes entre los grupos emparejados. De hecho, durante la fase 1, solo el tiempo operatorio fue más largo que en el grupo laparoscópico. Mientras que durante la fase 2, los resultados del grupo transanal fueron comparables a los del grupo laparoscópico. Los resultados muestran que durante la fase 3, el tiempo operatorio, la pérdida de sangre intraoperatoria y la estancia hospitalaria postoperatoria fueron menores que en el grupo laparoscópico. La recurrencia local ocurrió en 3 pacientes durante la fase 1 y en 1 paciente durante la fase 2.LIMITACIONES:Este estudio fue un estudio retrospectivo pequeño y se centró en un solo cirujano que realizaba la escisión mesorrectal total transanal.CONCLUSIÓN:Los resultados a corto plazo e histopatológicos son similares en comparación entre el grupo transanal y el grupo laparoscópico emparejado. La escisión mesorrectal total transanal también proporcionó buenos resultados oncológicos. Consulte Video Resumen en http://links.lww.com/DCR/B450.

Fibroblast Growth Factor-21 ameliorates hepatic encephalopathy by activating the STAT3-SOCS3 pathway to inhibit activated hepatic stellate cells.

Neurological dysfunction, one of the consequences of acute liver failure (ALF), and also referred to as hepatic encephalopathy (HE), contributes to mortality posing challenges for clinical management. FGF21 has been implicated in the inhibition of cognitive decline and fibrogenesis. However, the effects of FGF21 on the clinical and molecular presentations of HE has not been elucidated. HE was induced by fulminant hepatic failure using thioacetamide (TAA) in male C57BL/6J mice while controls were injected with saline. For two consecutive weeks, mice were treated intraperitoneally with FGF21 (3 mg/kg) while controls were treated with saline. Cognitive, neurological, and activity function scores were recorded. Serum, liver, and brain samples were taken for analysis of CCL5 and GABA by ELISA, and RT qPCR was used to measure the expressions of fibrotic and pro-inflammatory markers. We report significant improvement in both cognitive and neurological scores by FGF21 treatment after impairment by TAA. GABA and CCL5, key factors in the progression of HE were also significantly reduced in the treatment group. Furthermore, the expression of fibrotic markers such as TGFß and Col1 were also significantly downregulated after FGF21 treatment. TNFα and IL-6 were significantly reduced in the liver while in the brain, TNFα and IL-1 were downregulated. However, both in the liver and the brain, IL-10 was significantly upregulated. FGF21 inhibits CXCR4/CCL5 activation and upregulates the production of IL-10 in the damaged liver stimulating the production pro-inflammatory cytokines and apoptosis of hepatic stellate cells through the STAT3-SOCS3 pathway terminating the underlying fibrosis in HE.

A novel bispecific antibody alleviates bleomycin-induced systemic sclerosis injury.

Systemic sclerosis (SSc) is induced by variety of factors and eventually causes multiple organ damage. In recent years, biological agents targeting cytokines and cell surface molecules have gradually come to market. Here, the anti-inflammatory and antifibrotic effects of a novel bispecific antibody (FL-BsAb1/17) targeting interleukin-17A (IL-17A) and interleukin-1ß (IL-1ß) were detected. Bleomycin (BLM) was subcutaneously injected for 21 consecutive days to establish the SSc mouse model, and mice were subsequently treated with etanercept or different doses (1, 5, 10 mg/kg) of FL-BsAb1/17. The results showed that FL-BsAb1/17 treatment (10 mg/kg, 5 mg/kg) significantly attenuated BLM-induced SSc-like inflammation by inhibiting the expression of inflammatory factors (IL-17A, IL-1ß, IL-8, IL-22, IL-23, IL-6) and fibrosis, with specific outcomes of dermis thickening and lung fibrosis, by inhibiting the expression of fibrotic factors (TGF-ß, α-sma, Col-1, Col-3) in the serum, skin and lungs. In addition, FL-BsAb1/17 (10 mg/kg, 5 mg/kg) downregulated protein levels of TGF-ß and phosphorylated Smad2/3 in the skin and lungs and reduced collagen 1 protein levels. This indicated that FL-BsAb1/17 can inhibit the development of fibrosis by inhibiting the TGF-ß/Smad2/3 signaling pathway. FL-BsAb1/17 (10 mg/kg, 5 mg/kg) could also effectively reduce the content of MDA, increase the activity of SOD and CAT, and improve the total antioxidant capacity (T-AOC). In conclusion, FL-BsAb1/17 alleviated BLM-induced SSc by downregulating inflammatory cascades, relieving oxidative stress and inhibiting TGF-ß/Smad2/3 signaling. These data suggest that FL-BsAb1/17 has potential as a novel therapeutic candidate for SSc.

Oral delivery of a Lactococcus lactis strain secreting bovine lactoferricin-lactoferrampin alleviates the development of acute colitis in mice.

Ulcerative colitis (UC) is a chronic relapsing disease. Treatment of UC would benefit from specific targeting of therapeutics to the intestine. Previous studies have demonstrated that bovine lactoferricin and lactoferrampin have bactericidal, anti-inflammatory, and immunomodulatory effects. Here, we investigated whether oral administration of a bovine lactoferricin-lactoferrampin (LFCA)-encoding Lactococcus lactis (LL-LFCA) strain could alleviate experimental colitis. LFCA derived from LL-LFCA inhibited the growth of Escherichia coli and Staphylococcus aureus in vitro. In mice, administration of LL-LFCA decreased the disease activity index and attenuated dextran sulfate sodium (DSS)-induced body weight loss and colon shortening. LL-LFCA treatment also ameliorated DSS-induced colon damage, inhibited inflammatory cell infiltration, significantly decreased myeloperoxidase activity, and ameliorated DSS-induced disruption of intestinal permeability and tight junctions. In addition, 16S rDNA sequencing showed that LL-LFCA reversed DSS-induced gut dysbiosis. The production of proinflammatory mediators in serum and the colon was also reduced by administration of LL-LFCA. In vitro, LFCA derived from LL-LFCA decreased the messenger RNA expression of proinflammatory factors. The underlying mechanisms may involve inhibition of the nuclear factor kappa B (NF-κB) pathway. The results demonstrate that LL-LFCA ameliorates DSS-induced intestinal injury in mice, suggesting that LL-LFCA might be an effective drug for the treatment of inflammatory bowel diseases.

Ameliorative effects of a fusion protein dual targeting interleukin 17A and tumor necrosis factor α on imiquimod-induced psoriasis in mice.

In recent decades, biological agents such as tumor necrosis factor-α (TNF-α) inhibitors, have revolutionized the treatment of psoriasis. However, inhibition of a single cytokine may not achieve satisfactory therapeutic results. It is against this background that this research was undertaken to investigate the anti-psoriatic effect of a novel fusion protein (DTF) dual targeting TNF-α and interleukin-17 A (IL-17 A). Imiquimod (IMQ) was topically applied to the skin of mice to develop psoriasis-like skin and treated with etanercept or different doses of DTF. Results showed that DTF treatment (1 mg/kg, 3 mg/kg, 5 mg/kg) significantly attenuated IMQ-induced typical psoriasis-like inflammation, severity score, and epidermis thickening in a dose-dependent manner, and was again more efficient than etanercept (3 mg/kg) in alleviating all these parameters at the same dose. Furthermore, DTF was more potent than etanercept in suppressing the expression of inflammatory factors (IL-17 A, IL-6, IL-1ß, IL-23, IL-22 and IL-12) in the serum, spleen and psoriasis-like skin compared with etanercept at the same dose. In addition, DTF was more efficient than etanercept in reducing the expression of keratins, decreasing the mRNA expression of Ly-6 G and Ly-6C, and enhancing the expression of filaggrin and caspase 14 in IMQ-induced psoriasis-like skin. We conclude that DTF alleviates IMQ-induced psoriasis by attenuating inflammatory cascades, reducing keratinocytes proliferation and improving epidermal barrier function through suppressing TNF-α and IL-17 A signal pathways. These data suggest that DTF has potential to be a novel therapeutic candidate for psoriasis.

The novel long noncoding RNA u50535 promotes colorectal cancer growth and metastasis by regulating CCL20.

Long noncoding RNAs (lncRNAs) have been emerging as master regulators of tumor growth and metastasis, but the functions and underlying mechanisms of lncRNAs in colorectal cancer (CRC) still need to be clarified. Here, we found a novel lncRNA u50535, which was greatly overexpressed in CRC tissues and was associated with poor prognosis in CRC patients. Function studies showed that u50535 was an oncogene in CRC both in vitro and in vivo. In mechanism, through RNA sequencing and rescue assay, we found that u50535 activates CCL20 signaling to promote cell proliferation and migration in CRC. Taken together, these findings suggest that u50535 can promote CRC growth and metastasis and may serve as a potential biomarker in CRC.

Preoperative profile of inflammatory factors in aqueous humor correlates with postoperative inflammatory response in patients with congenital cataract.

Purpose: To measure the aqueous humor concentrations of inflammatory factors in patients with congenital cataract and to investigate the relationship between the levels and postoperative inflammatory responses. Methods: Aqueous humor samples were prospectively collected from 65 eyes of children with congenital cataracts from January to June 2015. The levels of 41 inflammation-related cytokines, chemokines, and growth factors in aqueous humor were measured using multiplex bead immunoassay. Data on patient demographics and postoperative inflammatory response evaluation of posterior capsule opacification (EPCO) scores were collected for correlation analysis of short- and long-term postoperative inflammatory responses, respectively. Results: Fifteen inflammatory factors were differentially expressed between congenital cataract and age-related cataract. EGF and IL-3 were positively correlated, whereas IL-8 and MCP-1 were negatively correlated with age. TNFα, IL-17A, IL-3, and sCD40L were preferably expressed in specific morphological types of congenital cataract. One month and 3 months postoperatively, PDGF-AA exhibited a positive correlation with the EPCO scores, whereas IL-1RA exhibited a negative correlation. Macrophage-derived chemokine (MDC) showed a positive correlation with the EPCO scores 1 year postoperatively. Conclusions: This study provided a comprehensive preoperative profile of inflammatory factors and their correlations with postoperative inflammatory responses in patients with congenital cataract. These factors may serve as potential biomarkers to predict the postoperative inflammatory response. These findings will also facilitate the development of anti-inflammatory medications in the perioperative period.