Effects of dexmedetomidine on early cognitive function in elderly patients after abdominal surgery: a meta-analysis.

INTRODUCTION: This meta-analysis aims to investigate the effect of dexmedetomidine (Dex) on postoperative cognitive dysfunction (POCD) in elderly patients undergoing abdominal surgery under general anesthesia. EVIDENCE ACQUISITION: Six online databases were searched for studies on the effects of Dex on POCD in elderly patients (≥60 years) who underwent abdominal surgery under general anesthesia. The experimental group was treated with Dex and the control group with normal saline. The retrieval period was from the database's inception to March 2023. Stata 15.0 statistical software was utilized to analyze the data. EVIDENCE SYNTHESIS: In total, 14 studies were entered into this meta-analysis, including 675 patients. On the first, third, and seventh days after surgery, the Mini-Mental State Examination (MMSE) scores in the experimental group were significantly higher than those in the controls (first day: weighted mean difference [WMD] = 2.52, 95% CI: 1.13~3.90, P<0.001; third day: WMD=2.58, 95% CI: 0.76~4.40, P=0.005; seventh day: WMD=1.43, 95% CI: 0.57~2.29, P=0.001). On the first day after surgery, there was a lot less cognitive dysfunction in the Dex group than in the controls (odds ratio [OR] = 0.25, 95% CI: 0.15~0.42, P<0.001). CONCLUSIONS: Dex administered intraoperatively can enhance early cognitive function in elderly patients undergoing abdominal surgery.

Network Pharmacology-Based Approach to Investigate the Active Ingredients and Therapeutic Mechanisms of Jingu Tongxiao Pill against Osteoarthritis.

This study aimed to investigate the active ingredients and therapeutic mechanisms of Jingu Tongxiao Pill (JGTXP), a commonly used Chinese patent medicine, in treating osteoarthritis (OA) via network pharmacology analysis combined with experimental validation. First, we administered JGTXP to rat plasma and identified the candidate active compounds. Next, target prediction, protein-protein interaction, compound-target network construction, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted for JGTXP. Lastly, the network-derived key targets and pathways were validated in vitro and in vivo. Finally, we identified 106 compounds in JGTXP and 24 absorbed compounds in the rat plasma. Network analysis revealed that JGTXP interferes with OA mainly via regulating the inflammatory response, collagen catabolic process, and osteoclast differentiation, and the nuclear factor kappa B (NF-κB) signaling pathway plays a pivotal role in these processes. Experimentally, JGTXP exerted potential protective effects on articular cartilage and inhibited expression of inflammatory mediators and collagen catabolism-related proteins, including interleukin 1 beta (IL-1ß), interleukin 6, tumor necrosis factor alpha (TNF-α), and matrix metalloproteinase (MMP) 3 and MMP13, in a papain-induced OA rat model. Consistently, mRNA expression levels of these factors and nitric oxide release were suppressed by JGTXP in an LPS-induced RAW 264.7 inflammation model. The reporter gene assay showed that JGTXP could reduce the transcriptional activity of NF-κB. Consecutive western blot analysis demonstrated that nuclear NF-κB p65, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) expression were inhibited while cytoplasmic NF-κB p65 was upregulated by JGTXP. Using a combination of chemical profiling, network pharmacology analysis, and experimental validation, we preliminarily clarified the active ingredients of JGTXP intervention for OA and demonstrated that JGTXP ameliorates OA, at least partially, by regulating the NF-κB signaling pathway.

Efficacy and safety of combined Chinese and Western medicine in the treatment of knee osteoarthritis: a prospective, multicenter cohort study.

Purpose: To conduct a real-world evaluation of the efficacy and safety of combined Chinese and Western medicine in treating knee osteoarthritis (KOA). Methods: A multicenter, prospective cohort study design was employed, enrolling 450 KOA patients (Kellgren-Lawrence score of 3 or less). The patients were divided into a Western medicine treatment group (WM group) and a combined Western and traditional Chinese medicine treatment group (WM-CM group). A 6-week treatment plan was administered, and follow-up visits occurred at 2 weeks, 4 weeks, and 6 weeks after initiating treatment. The primary outcome indicator was the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score after 6 weeks of treatment. Secondary outcome indicators included WOMAC subscales for pain, stiffness, and joint function, visual analogue scale (VAS) score, physical component summary (PCS), mental component summary (MCS), and clinical effectiveness. The incidence of drug-related adverse events was used as a safety evaluation indicator. Results: A total of 419 patients were included in the final analysis: 98 in the WM group and 321 in the WM-CM group. The baseline characteristics of the two groups were comparable, except for the incidence of stiffness symptoms and stiffness scores. After 6 weeks of treatment, the WM-CM group exhibited superior results to the WM group in improving the total WOMAC score (24.71 ± 1.38 vs. 16.36 ± 0.62, p < 0.001). The WM-CM group also outperformed the WM group in WOMAC pain and joint function scores, VAS score, PCS score, MCS score, and clinical effectiveness (p < 0.05), which was consistent with the findings of the main evaluation index. Subgroup analysis indicated that the combined Chinese and Western medicine treatment showed more pronounced benefits in patients under 65 years of age and in those with a Kellgren-Lawrence (K-L) classification of 0-I. Throughout the study, no adverse effects were observed in either group. Conclusion: The combination of Chinese and Western medicine demonstrated superiority over Western medicine alone in relieving knee pain symptoms, improving knee function, and enhancing the quality of life for KOA patients with a K-L score of 3 or less. Moreover, the treatment exhibited a good safety profile. Clinical Trial Registration: (https://www.chictr.org.cn/), identifier (ChiCTR1900027175).

Assessment of Ultrasound-Guided Continuous Low Serratus Anterior Plane Block for Pain Management After Hepatectomy: A Randomized Controlled Trial.

Purpose: Adequate postoperative analgesia is a key to earlier recovery from open surgery. This work investigated the pain control and quality of patient recovery after hepatectomy to evaluate the modified continuous serratus anterior plane block (called low SAPB) for postoperative analgesia. Patients and Methods: This single-center, blinded, randomized, controlled study included 136 patients who underwent hepatectomy under general anesthesia. For postoperative analgesia, the patients in the SAPB group were given a continuous low SAPB at the 7th intercostal space in the right mid-axillary line, and the patients in the control group were given continuous intravenous opioid analgesia. The numeric pain rating scale (NPRS) was used for pain assessment. The postoperative assessment focused on the remedial drug consumption, the occurrence of adverse postoperative analgesic reactions, and the quality of patient recovery evaluated with the QoR-15 questionnaire. Results: Compared to the controls, the SAPB patients had significantly lower NPRS scores at 12 h and 24 h at rest and 6 h, 12 h, and 24 h in motion, and a longer time to first use of remedial analgesics at 24 h, and higher overall QoR-15 scores at 24 h [124 (121, 126) vs 121 (120, 124)] and 48 h [129 (126, 147) vs 126 (125, 128)], after surgery. There was no significant difference in the incidence of analgesia-related adverse reactions between the two groups. Conclusion: The continuous low SAPB could achieve superior pain control, especially for motor pain, to intravenous opioid analgesia during the first 24 h post-surgery. Even with no significant difference in the incidence of postoperative adverse reactions, patients with continuous low SAPB appeared to have a higher quality of recovery in the first two days post-surgery than patients with continuous intravenous analgesia.

Recombinant measles virus vaccine rMV-Hu191 exerts an oncolytic effect on esophageal squamous cell carcinoma via caspase-3/GSDME-mediated pyroptosis.

Oncolytic viruses have recently been proven to be an effective and promising cancer therapeutic strategy, but there is rare data about oncolytic therapy in esophageal squamous cell carcinoma (ESCC), especially oncolytic measles virotherapy. Therefore, this study aimed to explore whether the recombinant measles virus vaccine strain rMV-Hu191 has an oncolytic effect against ESCC cells in vitro and in vivo and elucidate the underlying mechanisms. Our results showed that rMV-Hu191 could efficiently replicate in and kill ESCC cells through caspase-3/GSDME-mediated pyroptosis. Mechanistically, rMV-Hu191 triggers mitochondrial dysfunction to induce pyroptosis, which is mediated by BAK (BCL2 antagonist/killer 1) or BAX (BCL2 associated X). Further analysis revealed that rMV-Hu191 activates inflammatory signaling in ESCC cells, which may enhance the oncolytic efficiency. Moreover, intratumoral injection of rMV-Hu191 induced dramatic tumor regression in an ESCC xenograft model. Collectively, these findings imply that rMV-Hu191 exhibits an antitumor effect through BAK/BAX-dependent caspase-3/GSDME-mediated pyroptosis and provides a potentially promising new therapy for ESCC treatment.

A double-layered gastric floating tablet for zero-order controlled release of dihydromyricetin: Design, development, and in vitro/in vivo evaluation.

Dihydromyricetin (DHM) is an important natural flavonoid. However, most of DHM preparations have shown shortcomings such as low drug loading, poor drug stability, and/or large fluctuations in blood concentration. This study aimed to develop a gastric floating tablet with a double-layered structure for zero-order controlled release of DHM (DHM@GF-DLT). The final product DHM@GF-DLT showed a high average cumulative drug release at 24 h that best fit the zero-order model, and had a good floating ability in the stomach of the rabbit with a gastric retention time of over 24 h. The FTIR, DSC, and XRPD analyses indicated the good compatibility among the drug and the excipients in DHM@GF-DLT. The pharmacokinetic study revealed that DHM@GF-DLT could prolong the retention time of DHM, reduce the fluctuation of blood drug concentration, and enhance the bioavailability of DHM. The pharmacodynamic studies demonstrated that DHM@GF-DLT had a potent and long-term therapeutic effect on systemic inflammation in rabbits. Therefore, DHM@GF-DLT had the potential to serve as a promising anti-inflammatory agent and may develop into a once-a-day preparation, which was favorable to maintain a steady blood drug concentration and a long-term drug efficacy. Our research provided a promising development strategy for DHM and other natural products with a similar structure to DHM for improving their bioavailability and therapeutic effect.

Tunable structural colors in all-dielectric photonic crystals using energetic ion beams.

The modulation of structural color through various methods has attracted considerable attention. Herein, a new modulation method for the structural colors in all-dielectric photonic crystals (PCs) using energetic ion beams is proposed. One type of periodic PC and two different defective PCs were experimentally investigated. Under carbon-ion irradiation, the color variation primarily originated from the blue shift of the optical spectra. The varying degrees of both the reflection and transmission structural colors mainly depended on the carbon-ion fluences. Such nanostructures are promising for tunable color filters and double-sided chromatic displays based on PCs.

"Net" value co-creation: The effect of interactions on consumer citizenship behavior in online travel communities.

Online traveling community is initiated by companies, but its survival is inextricably linked to consumer citizenship behavior (e.g., out-group recommendation, in-group helping, and inward response). The majority of researches have investigated consumer behavior of brand community such as consumer satisfaction, brand loyalty, and purchase intention. A few scholars try to explore consumer behaviors beyond the purchase, like participation, which was concerned as the value co-creation. However, the value co-creation of the community should depend on consumers' citizenship behaviors instead of their pure participation. Therefore, this study empirically examines the effect of consumer interaction on consumer psychology and citizenship behaviors of the online travel community. The findings demonstrated that consumer interaction facilitated participants' self-identity and their perceived social support, which enhanced their community identification and thus their citizenship behaviors. Furthermore, the motivation of participation plays a moderator in this process. Specifically, symbolic motivation moderates the relationship between consumer interaction and their self-identity, while utilitarian motivation moderates the effect of consumer interaction on their perceived social support. These findings contributed to the intervention of consumer citizenship behavior in online traveling community and provide insights into the management of the online travel community from the perspective of the value co-creation.

Interferon regulatory factor 1-triggered free ubiquitin protects the intestines against radiation-induced injury via CXCR4/FGF2 signaling.

Radiation-induced intestinal injury is a serious concern during abdominal and pelvic cancers radiotherapy. Ubiquitin (Ub) is a highly conserved protein found in all eukaryotic cells. This study aims to explore the role and mechanism of free Ub against radiogenic intestinal injury. We found that free Ub levels of irradiated animals and human patients receiving radiotherapy were upregulated. Radiation-induced Ub expression was associated with the activation of interferon regulatory factor 1 (IRF1). Intraperitoneal injection of free Ub significantly reduced the mortality of mice following 5-9 Gy total body irradiation (TBI) through the Akt pathway. Free Ub facilitates small intestinal regeneration induced by TBI or abdominal irradiation. At the cellular level, free Ub or its mutants significantly alleviated cell death and enhanced the survival of irradiated intestinal epithelial cells. The radioprotective role of free Ub depends on its receptor CXCR4. Mechanistically, free Ub increased fibroblast growth factor-2 (FGF2) secretion and consequently activated FGFR1 signaling following radiation in vivo and in vivo. Thus, free Ub confers protection against radiation-induced intestinal injury through CXCR4/Akt/FGF2 axis, which provides a novel therapeutic option.

Metabolic Profiling Implicates a Critical Role of Cyclooxygenase-2-Mediated Arachidonic Acid Metabolism in Radiation-Induced Esophageal Injury in Rats.

Radiation-induced esophageal injury (RIEI) is a major dose-limiting complication of radiotherapy, especially for esophageal and thoracic cancers. RIEI is a multi-factorial and multi-step process, which is regulated by a complex network of DNA, RNA, protein and metabolite. However, it is unclear which esophageal metabolites are altered by ionizing radiation and how these changes affect RIEI progression. In this work, we established a rat model of RIEI with 0-40 Gy X-ray irradiation. Esophageal irradiation using ≥25 Gy induced significant changes to rats, such as body weight, food intake, water intake and esophageal structure. The metabolic changes and related pathways of rat esophageal metabolites were investigated by liquid chromatography-mass spectrometry (LC-MS). One hundred eighty metabolites showed an up-regulation in a dose-dependent manner (35 Gy ≥ 25 Gy > controls), and 199 metabolites were downregulated with increasing radiation dose (35 Gy ≤ 25 Gy < controls). The KEGG analysis showed that ionizing radiation seriously disrupted multiple metabolic pathways, and arachidonic acid metabolism was the most significantly enriched pathway. 20 metabolites were dysregulated in arachidonic acid metabolism, including up-regulation of five prostaglandins (PGA2, PGJ2, PGD2, PGH2, and PGI2) in 25 or 35 Gy groups. Cyclooxygenase-2 (COX-2), the key enzyme in catalyzing the biosynthesis of prostaglandins from arachidonic acid, was highly expressed in the esophagus of irradiated rats. Additionally, receiver operating characteristic (ROC) curve analysis revealed that PGJ2 may serve as a promising tissue biomarker for RIEI diagnosis. Taken together, these findings indicate that ionizing radiation induces esophageal metabolic alterations, which advance our understanding of the pathophysiology of RIEI from the perspective of metabolism.

Cyclic RGD-Decorated Liposomal Gossypol AT-101 Targeting for Enhanced Antitumor Effect.

INTRODUCTION: (-)-Gossypol (AT-101), the (-)-enantiomer of the natural compound gossypol, has shown significant inhibitory effects on various types of cancers such as osteosarcoma, myeloma, glioma, lung cancer, and prostate cancer. However, the clinical application of (-)-gossypol was often hindered by its evident side effects and the low bioavailability via oral administration, which necessitated the development of suitable (-)-gossypol preparations to settle the problems. In this study, injectable cyclic RGD (cRGD)-decorated liposome (cRGD-LP) was prepared for tumor-targeted delivery of (-)-gossypol. METHODS: The cRGD-LP was prepared based on cRGD-modified lipids. For comparison, a non-cRGD-containing liposome (LP) with a similar chemical composition to cRGD-LP was specially designed. The physicochemical properties of (-)-gossypol-loaded cRGD-LP (Gos/cRGD-LP) were investigated in terms of the drug loading efficiency, particle size, morphology, drug release, and so on. The inhibitory effect of Gos/cRGD-LP on the proliferation of tumor cells in vitro was evaluated using different cell lines. The biodistribution of cRGD-LP in vivo was investigated via the near-infrared (NIR) fluorescence imaging technique. The antitumor effect of Gos/cRGD-LP in vivo was evaluated in PC-3 tumor-bearing nude mice. RESULTS: Gos/cRGD-LP had an average particle size of about 62 nm with a narrow size distribution, drug loading efficiency of over 90%, and sustained drug release for over 96 h. The results of NIR fluorescence imaging demonstrated the enhanced tumor targeting of cRGD-LP in vivo. Moreover, Gos/cRGD-LP showed a significantly enhanced inhibitory effect on PC-3 tumors in mice, with a tumor inhibition rate of over 74% and good biocompatibility. CONCLUSION: The incorporation of cRGD could significantly enhance the tumor-targeting effect of the liposomes and improve the antitumor effect of the liposomal (-)-gossypol in vivo, which indicated the potential of Gos/cRGD-LP that warrants further investigation for clinical applications of this single-isomer drug.

Omnidirectional photonic bandgap in one-dimensional photonic crystals containing hyperbolic metamaterials.

We theoretically and experimentally investigate the angle-dependent omnidirectional photonic bandgap (PBG) in one-dimensional photonic crystals (PCs) comprising hyperbolic metamaterials (HMMs) for TM polarization, which is different from blue-shifted PBG in conventional all-dielectric photonic crystals. The frequency range of PBG increases when the incident angles increase, owing to the red-shift and blue-shift of the long-wavelength and short-wavelength band edges, respectively. The red-shifted band edge originates from the phase-variation compensation mechanism between the HMMs and dielectric material. The experimental values are in good agreement with the simulation results. These nanostructures are ideal for fabricating photonic devices such as omnidirectional reflectors.

Transplantation of the Stromal Vascular Fraction (SVF) Mitigates Severe Radiation-Induced Skin Injury.

Severe radiation-induced skin injury is a complication of tumor radiotherapy and nuclear accidents. Cell therapy is a potential treatment for radiation-induced skin injury. The stromal vascular fraction (SVF) is a newer material in stem cell therapy that is made up of stem cells harvested from adipose tissue, which has been shown to promote the healing of refractory wounds of different causes. In this study, SVF was isolated from patients with radiation-induced skin injury. Adipose-derived stem cells (ADSCs) accounted for approximately 10% of the SVF by flow cytometry. Compared with the control group of rats, administration with SVF attenuated the skin injury induced by electron beam radiation. The effect of SVF on the human skin fibroblast microenvironment was determined by proteomic profiling of secreted proteins in SVF-co-cultured human skin fibroblast WS1 cells. Results revealed 293 upregulated and 1,481 downregulated proteins in the supernatant of SVF-co-cultured WS1 cells. WS1 co-culture with SVF induced secretion of multiple proteins including collagen and MMP-1. In the clinic, five patients with radiation-induced skin injury were recruited to receive SVF transfer-based therapy, either alone or combined with flap transplantation. Autogenous SVF was isolated and introduced into a multi-needle precision electronic injection device, which automatically and aseptically distributed the SVF to the exact layer of the wound in an accurate amount. After SVF transfer, wound healing clearly improved and pain was significantly relieved. The patients' skin showed satisfactory texture and shape with no further wound recurrence. Our findings suggest that transplantation of SVF could be an effective countermeasure against severe radiation-induced skin injury.

Regulation of alveolar type 2 stem/progenitor cells in lung injury and regeneration.

The renewal of lung epithelial cells is normally slow unless the lung is injured. The resident epithelial stem cells rapidly proliferate and differentiate to maintain lung structure and function when the lung is damaged. The alveolar epithelium is characterized by alveolar type 1 (AT1) and alveolar type 2 (AT2) cells. AT2 cells are the stem cells for alveoli, as they can both self-renew and generate AT1 cells. Abnormal proliferation and regulation of AT2 cells will lead to serious lung diseases including cancers. In this review, we focused on the alveolar stem/progenitor cells, the key physiological function of AT2 cells in lung homeostasis and the complicated regulation of AT2 cells in the repairing processes after lung injury.

Factors influencing clinical outcomes in patients with diabetic macular edema treated with intravitreal ranibizumab: comparison between responder and non-responder cases.

Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus. A retrospective study was conducted to investigate the factors influencing the clinical outcomes in 73 patients (94 eyes) with DME treated with intravitreal ranibizumab therapy. Baseline demographic, systemic, and ocular data were assessed for the association with visual and anatomic outcomes after treatment. The mean best corrected visual acuity (BCVA) improved from 0.92 ± 0.45 to 0.61 ± 0.43 logarithm of the minimum angle of resolution (LogMAR) (p < 0.001) after treatment. The mean central subfield macular thickness (CST) decreased from 425.2 ± 127.4 to 328.6 ± 99.4 µm (p < 0.001). The treatment response was significantly influenced by Age (p = 0.003) and baseline BCVA (p = 0.001). In addition, glycosylated hemoglobin (HbA1c) (p = 0.013) and proliferative diabetic retinopathy (PDR) (p = 0.019) were the prognostic factors for the visual outcome in the responders and non-responders, respectively. Moreover, baseline CST was the strongest predictor of anatomic outcome in all subjects (p < 0.001). Intravitreal ranibizumab for DME resulted in significant improvement in clinical outcomes. Younger age and better baseline BCVA were associated with better visual outcome after the treatment. In addition, glycemic control in the treatment of patients with DME is crucial to achieve better visual outcomes, especially in the responders to ranibizumab treatment.

Influence Factors of the Pharmacokinetics of Herbal Resourced Compounds in Clinical Practice.

Herbal medicines have been used to prevent and cure diseases in eastern countries for thousands of years. In recent decades, these phytotherapies are becoming more and more popular in the West. As being nature-derived is the essential attribute of herbal medicines, people believe that taking them for diseases treatment is safe enough and has no side-effects. However, the efficacy of herbal resourced compounds (HRC) depends on the multiple constituents absorbed in the body and their pharmacokinetics. Thus, many factors will influence the clinical practice of HRC, i.e., their absorption, distribution, metabolism, and excretion (ADME). Among these factors, herb-drug interaction has been widely discussed, as these compounds may share the same drug-metabolizing enzymes and drug transporters. Meanwhile there are many other potential factors that can also change the ADME of HRC, including herb pretreatment, herb-herb interactions, pathological status, gender, age of patient, and chemical and physical modification of certain ingredients. With the aim of ensuring the efficacy of HRC and minimizing their clinical risks, this review provides and discusses the influence factors and artificial improvement of the pharmacokinetics of HRC.

Loss of VGLL4 suppresses tumor PD-L1 expression and immune evasion.

Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models. VGLL4 deficiency reduces PD-L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability through inhibiting proteasome-mediated protein degradation. Loss of IRF2BP2 results in persistent binding of IRF2, a transcriptional repressor, to PD-L1 promoter. In addition, YAP inhibits IFNγ-inducible PD-L1 expression partially through suppressing the expression of VGLL4 and IRF1 by YAP target gene miR-130a. Our study identifies VGLL4 as an important regulator of PD-L1 expression and highlights a central role of VGLL4 and YAP in the regulation of tumor immunity.

Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation.

Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1ß, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.

MEKK2 and MEKK3 suppress Hedgehog pathway-dependent medulloblastoma by inhibiting GLI1 function.

Hedgehog (Hh) pathway plays a pivotal role in diverse aspects of development and postnatal physiology. Perturbation of Hh signaling and activation of GLI1 (glioma-associated oncogene 1), a dedicated transcription factor for Hh pathway, are highly associated with several cancers, such as medulloblastoma and basal cell carcinoma. Dynamic and precise control of GLI1 activity is thus important to ensure proper homeostasis and tumorigenesis. Here we show that MEKK2 (MAP3K2) and MEKK3 (MAP3K3) inhibit GLI1 transcriptional activity and oncogenic function through phosphorylation on multiple Ser/Thr sites of GLI1, which reduces GLI1 protein stability, DNA-binding ability, and increases the association of GLI1 with SUFU. Interestingly, MEKK2 and MEKK3 are responsible for FGF2-mediated inhibition on Hh signaling. Moreover, expression of MEKK2 and MEKK3 inhibits medulloblastoma cell proliferation and negatively correlates with Hh pathway activity in medulloblastoma clinical samples. Together, these findings reveal a novel noncanonical GLI1 regulation and provide a potential therapeutic target for the treatment of cancers with aberrant Hh pathway activation, such as medulloblastoma.

The LIS1/NDE1 Complex Is Essential for FGF Signaling by Regulating FGF Receptor Intracellular Trafficking.

Intracellular transport of membranous organelles and protein complexes to various destinations is fundamental to signaling transduction and cellular function. The cytoplasmic dynein motor and its regulatory proteins LIS1 and NDE1 are required for transporting a variety of cellular cargos along the microtubule network. In this study, we show that deletion of Lis1 in developing lung endoderm and limb mesenchymal cells causes agenesis of the lungs and limbs. In both mutants, there is increased cell death and decreased fibroblast growth factor (FGF) signaling activity. Mechanistically, LIS1 and its interacting protein NDE1/NDEL1 are associated with FGF receptor-containing vesicles and regulate FGF receptor intracellular trafficking and degradation. Notably, FGF signaling promotes NDE1 tyrosine phosphorylation, which leads to dissociation of LIS1/NDE1 complex. Thus, our studies identify the LIS1/NDE1 complex as an important FGF signaling regulator and provide insights into the bidirectional regulation of cell signaling and transport machinery for endocytosis.