Yueyang Hospital

Pneumonia associated with the 2019 novel coronavirus (2019-nCoV) is continuously and rapidly circulating at present. No effective antiviral treatment has been verified thus far. We report here the clinical characteristics and therapeutic procedure for four patients with mild or severe 2019-nCoV pneumonia admitted to Shanghai Public Health Clinical Center. All the patients were given antiviral treatment including lopinavir/ritonavir (Kaletra®), arbidol, and Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine) and other necessary support care. After treatment, three patients gained significant improvement in pneumonia associated symptoms, two of whom were confirmed 2019-nCoV negative and discharged, and one of whom was virus negative at the first test. The remaining patient with severe pneumonia had shown signs of improvement by the cutoff date for data collection. Results obtained in the current study may provide clues for treatment of 2019-nCoV pneumonia. The efficacy of antiviral treatment including lopinavir/ritonavir, arbidol, and SFJDC warrants further verification in future study.

Cardiac function is determined by the dynamic equilibrium of various cell types and the extracellular matrix that composes the heart. Cardiovascular diseases (CVDs), especially atherosclerosis and myocardial infarction, are often accompanied by cell death and acute/chronic inflammatory reactions. Caspase-dependent pyroptosis is characterized by the activation of pathways leading to the activation of NOD-like receptors, especially the NLRP3 inflammasome and its downstream effector inflammatory factors interleukin (IL)-1β and IL-18. Many studies in the past decade have investigated the role of pyroptosis in CVDs. The findings of these studies have led to the development of therapeutic approaches based on the regulation of pyroptosis, and some of these approaches are in clinical trials. This review summarizes the molecular mechanisms, regulation and cellular effects of pyroptosis briefly and then discusses the current pyroptosis studies in CVD research.

Importance: Electroacupuncture involving the lumbosacral region may be effective for women with stress urinary incontinence (SUI), but evidence is limited. Objective: To assess the effect of electroacupuncture vs sham electroacupuncture for women with SUI. Design, Setting, and Participants: Multicenter, randomized clinical trial conducted at 12 hospitals in China and enrolling 504 women with SUI between October 2013 and May 2015, with data collection completed in December 2015. Interventions: Participants were randomly assigned (1:1) to receive 18 sessions (over 6 weeks) of electroacupuncture involving the lumbosacral region (n = 252) or sham electroacupuncture (n = 252) with no skin penetration on sham acupoints. Main Outcomes and Measures: The primary outcome was change from baseline to week 6 in the amount of urine leakage, measured by the 1-hour pad test. Secondary outcomes included mean 72-hour urinary incontinence episodes measured by a 72-hour bladder diary (72-hour incontinence episodes). Results: Among the 504 randomized participants (mean [SD] age, 55.3 [8.4] years), 482 completed the study. Mean urine leakage at baseline was 18.4 g for the electroacupuncture group and 19.1 g for the sham electroacupuncture group. Mean 72-hour incontinence episodes were 7.9 for the electroacupuncture group and 7.7 for the sham electroacupuncture group. At week 6, the electroacupuncture group had greater decrease in mean urine leakage (-9.9 g) than the sham electroacupuncture group (-2.6 g) with a mean difference of 7.4 g (95% CI, 4.8 to 10.0; P < .001). During some time periods, the change in the mean 72-hour incontinence episodes from baseline was greater with electroacupuncture than sham electroacupuncture with between-group differences of 1.0 episode in weeks 1 to 6 (95% CI, 0.2-1.7; P = .01), 2.0 episodes in weeks 15 to 18 (95% CI, 1.3-2.7; P < .001), and 2.1 episodes in weeks 27 to 30 (95% CI, 1.3-2.8; P < .001). The incidence of treatment-related adverse events was 1.6% in the electroacupuncture group and 2.0% in the sham electroacupuncture group, and all events were classified as mild. Conclusions and Relevance: Among women with stress urinary incontinence, treatment with electroacupuncture involving the lumbosacral region, compared with sham electroacupuncture, resulted in less urine leakage after 6 weeks. Further research is needed to understand long-term efficacy and the mechanism of action of this intervention. Trial Registration: clinicaltrials.gov Identifier: NCT01784172.

Total knee arthroplasty (TKA) is one of the most common surgeries performed to relieve joint pain in patients with end-stage osteoarthritis or rheumatic arthritis of the knee. However, TKA is followed by moderate to severe postoperative pain that affects postoperative rehabilitation, patient satisfaction, and overall outcomes. Historically, opioids have been widely used for perioperative pain management of TKA. However, opioids are associated with undesirable adverse effects, such as nausea, respiratory depression, and retention of urine, which limit their application in daily clinical practice. The aim of this review was to discuss the current postoperative pain management regimens for TKA. Our review of the literature demonstrated that multimodal analgesia is considered the optimal regimen for perioperative pain management of TKA and improves clinical outcomes and patient satisfaction, through a combination of several types of medications and delivery routes, including preemptive analgesia, neuraxial anesthesia, peripheral nerve blockade, patient-controlled analgesia and local infiltration analgesia, and oral opioid/nonopioid medications. Multimodal analgesia provides superior pain relief, promotes recovery of the knee, and reduces opioid consumption and related adverse effects in patients undergoing TKA.

Diabetic foot ulcers (DFU), one of the most serious complications of diabetes, are essentially chronic, nonhealing wounds caused by diabetic neuropathy, vascular disease, and bacterial infection. Given its pathogenesis, the DFU microenvironment is rather complicated and characterized by hyperglycemia, ischemia, hypoxia, hyperinflammation, and persistent infection. However, the current clinical therapies for DFU are dissatisfactory, which drives researchers to turn attention to advanced nanotechnology to address DFU therapeutic bottlenecks. In the last decade, a large number of multifunctional nanosystems based on the microenvironment of DFU have been developed with positive effects in DFU therapy, forming a novel concept of "DFU nanomedicine". However, a systematic overview of DFU nanomedicine is still unavailable in the literature. This review summarizes the microenvironmental characteristics of DFU, presents the main progress of wound healing, and summaries the state-of-the-art therapeutic strategies for DFU. Furthermore, the main challenges and future perspectives in this field are discussed and prospected, aiming to fuel and foster the development of DFU nanomedicines successfully.

Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.

PURPOSE Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non–small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768 ). METHODS Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

Immunotherapy with checkpoint inhibitors has greatly prolonged the overall survival of cancer patients in melanoma and many other cancer types. However, only a subset of patients shows clinical responses from these interventions, which was predicated by the T cell-inflamed tumor microenvironment. T cell-inflamed phenotype is characterized by the infiltration of CD8+ T cells, CD8α/CD103-lineage dendritic cells (DCs), as well as high density of FoxP3+ Regulatory T cells (Tregs) that are associated with the efficacy of immune checkpoint blockade. A number of regulators has been associated with T cell-inflammation in tumor microenvironment, and WNT/β-catenin signaling is one of the best characterized. The tumor-intrinsic WNT/β-catenin signaling activation is frequently associated with poor spontaneous T cell infiltration across most human cancers. In this article, we will review the essential roles of WNT/β-catenin signaling in the T cell-inflamed and non-T cell-inflamed tumor microenvironment, including the development and function of immune cells, activation of immune exclusion of tumor cells, and cancer immunosurveillance. We also discuss the impact of this pathway in driving the non-T cell-inflamed tumor microenvironment in other tumor types. To improve immunotherapy efficacy, we argue that targeting Wnt/β-catenin signaling pathway should be a high priority for combinational cancer therapy to restore T cell infiltration.

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971.

DNA methylation plays an important role in gene silencing in mammals. Two de novo methyltransferases, Dnmt3a and Dnmt3b, are required for the establishment of genomic methylation patterns in development. However, little is known about their coordinate function in the silencing of genes critical for embryonic development and how their activity is regulated. Here we show that Dnmt3a and Dnmt3b are the major components of a native complex purified from embryonic stem cells. The two enzymes directly interact and mutually stimulate each other both in vitro and in vivo. The stimulatory effect is independent of the catalytic activity of the enzyme. In differentiating embryonic carcinoma or embryonic stem cells and mouse postimplantation embryos, they function synergistically to methylate the promoters of the Oct4 and Nanog genes. Inadequate methylation caused by ablating Dnmt3a and Dnmt3b is associated with dysregulated expression of Oct4 and Nanog during the differentiation of pluripotent cells and mouse embryonic development. These results suggest that Dnmt3a and Dnmt3b form a complex through direct contact in living cells and cooperate in the methylation of the promoters of Oct4 and Nanog during cell differentiation. The physical and functional interaction between Dnmt3a and Dnmt3b represents a novel regulatory mechanism to ensure the proper establishment of genomic methylation patterns for gene silencing in development.

BACKGROUND: Acupuncture has been used for chronic constipation, but evidence for its effectiveness remains scarce. OBJECTIVE: To determine the efficacy of electroacupuncture (EA) for chronic severe functional constipation (CSFC). DESIGN: Randomized, parallel, sham-controlled trial. (ClinicalTrials.gov: NCT01726504). SETTING: 15 hospitals in China. PARTICIPANTS: Patients with CSFC and no serious underlying pathologic cause for constipation. INTERVENTION: 28 sessions of EA at traditional acupoints or sham EA (SA) at nonacupoints over 8 weeks. MEASUREMENTS: The primary outcome was the change from baseline in mean weekly complete spontaneous bowel movements (CSBMs) during weeks 1 to 8. Participants were followed until week 20. RESULTS: 1075 patients (536 and 539 in the EA and SA groups, respectively) were enrolled. The increase from baseline in mean weekly CSBMs during weeks 1 to 8 was 1.76 (95% CI, 1.61 to 1.89) in the EA group and 0.87 (CI, 0.73 to 0.97) in the SA group (between-group difference, 0.90 [CI, 0.74 to 1.10]; P < 0.001). The change from baseline in mean weekly CSBMs during weeks 9 to 20 was 1.96 (CI, 1.78 to 2.11) in the EA group and 0.89 (CI, 0.69 to 0.95) in the SA group (between-group difference, 1.09 [CI, 0.94 to 1.31]; P < 0.001). The proportion of patients having 3 or more mean weekly CSBMs in the EA group was 31.3% and 37.7% over the treatment and follow-up periods, respectively, compared with 12.1% and 14.1% in the SA group (P < 0.001). Acupuncture-related adverse events during treatment were infrequent in both groups, and all were mild or transient. LIMITATIONS: Longer-term follow-up was not assessed. Acupuncturists could not be blinded. CONCLUSION: Eight weeks of EA increases CSBMs and is safe for the treatment of CSFC. Additional study is warranted to evaluate a longer-term treatment and follow-up. PRIMARY FUNDING SOURCE: Ministry of Science and Technology of the People's Republic of China through the Twelfth Five-Year National Science and Technology Pillar Program.

Inflammatory bowel disease (IBD), which mainly includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic bowel diseases that are characterized by abdominal pain, diarrhea, and bloody stools. IBD is strongly associated with depression, and its patients have a higher incidence of depression than the general population. Depression also adversely affects the quality of life and disease prognosis of patients with IBD. The tryptophan-kynurenine metabolic pathway degrades more than 90% of tryptophan (TRP) throughout the body, with indoleamine 2,3-dioxygenase (IDO), the key metabolic enzyme, being activated in the inflammatory environment. A series of metabolites of the pathway are neurologically active, among which kynerunic acid (KYNA) and quinolinic acid (QUIN) are molecules of great interest in recent studies on the mechanisms of inflammation-induced depression. In this review, the relationship between depression in IBD and the tryptophan-kynurenine metabolic pathway is overviewed in the light of recent publications.

Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480-but not a JAK1/JAK3 selective inhibitor, tofacitinib-also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.

Background: Tongue images (the colour, size and shape of the tongue and the colour, thickness and moisture content of the tongue coating), reflecting the health state of the whole body according to the theory of traditional Chinese medicine (TCM), have been widely used in China for thousands of years. Herein, we investigated the value of tongue images and the tongue coating microbiome in the diagnosis of gastric cancer (GC). Methods: From May 2020 to January 2021, we simultaneously collected tongue images and tongue coating samples from 328 patients with GC (all newly diagnosed with GC) and 304 non-gastric cancer (NGC) participants in China, and 16 S rDNA was used to characterize the microbiome of the tongue coating samples. Then, artificial intelligence (AI) deep learning models were established to evaluate the value of tongue images and the tongue coating microbiome in the diagnosis of GC. Considering that tongue imaging is more convenient and economical as a diagnostic tool, we further conducted a prospective multicentre clinical study from May 2020 to March 2022 in China and recruited 937 patients with GC and 1911 participants with NGC from 10 centres across China to further evaluate the role of tongue images in the diagnosis of GC. Moreover, we verified this approach in another independent external validation cohort that included 294 patients with GC and 521 participants with NGC from 7 centres. This study is registered at ClinicalTrials.gov, NCT01090362. Findings: For the first time, we found that both tongue images and the tongue coating microbiome can be used as tools for the diagnosis of GC, and the area under the curve (AUC) value of the tongue image-based diagnostic model was 0.89. The AUC values of the tongue coating microbiome-based model reached 0.94 using genus data and 0.95 using species data. The results of the prospective multicentre clinical study showed that the AUC values of the three tongue image-based models for GCs reached 0.88-0.92 in the internal verification and 0.83-0.88 in the independent external verification, which were significantly superior to the combination of eight blood biomarkers. Interpretation: Our results suggest that tongue images can be used as a stable method for GC diagnosis and are significantly superior to conventional blood biomarkers. The three kinds of tongue image-based AI deep learning diagnostic models that we developed can be used to adequately distinguish patients with GC from participants with NGC, even early GC and precancerous lesions, such as atrophic gastritis (AG). Funding: The National Key R&D Program of China (2021YFA0910100), Program of Zhejiang Provincial TCM Sci-tech Plan (2018ZY006), Medical Science and Technology Project of Zhejiang Province (2022KY114, WKJ-ZJ-2104), Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer (JBZX-202006), Natural Science Foundation of Zhejiang Province (HDMY22H160008), Science and Technology Projects of Zhejiang Province (2019C03049), National Natural Science Foundation of China (82074245, 81973634, 82204828), and Chinese Postdoctoral Science Foundation (2022M713203).

Several studies reported that Tai Chi showed potential effects for chronic pain, but its role remains controversial. This review assessed the evidence regarding the effects of Tai Chi for chronic pain conditions. 18 randomized controlled trials were included in our review. The aggregated results have indicated that Tai Chi showed positive evidence on immediate relief of chronic pain from osteoarthritis (standardized mean difference [SMD], -0.54; 95% confidence intervals [CI], -0.77 to -0.30; P < 0.05). The valid duration of Tai Chi practice for osteoarthritis may be more than 5 weeks. And there were some beneficial evidences regarding the effects of Tai Chi on immediate relief of chronic pain from low back pain (SMD, -0.81; 95% CI, -1.11 to -0.52; P < 0.05) and osteoporosis (SMD, -0.83; 95% CI, -1.37 to -0.28; P = 0.003). Therefore, clinicians may consider Tai Chi as a viable complementary and alternative medicine for chronic pain conditions.

Autophagy is a conserved feature of lysosome-mediated intracellular degradation. Dysregulated autophagy is implicated as a contributor in neurodegenerative diseases; however, the role of autophagy in retinal degeneration remains largely unknown. Here, we report that the photo-activated visual chromophore, all-trans-retinal, modulated autophagosome formation in ARPE19 retinal cells. Increased formation of autophagosomes in these cells was observed when incubated with 2.5 μM all-trans-retinal, a condition that did not cause cell death after 24 h in culture. However, autophagosome formation was decreased at concentrations, which caused cell death. Increased expression of activating transcription factor 4 (Atf4), which indicates the activation of oxidative stress, was recorded in response to light illumination in retinas of Abca4(-/-)Rdh8(-/-) mice, which showed delayed clearance of all-trans-retinal after light exposure. Expression of autophagosome marker LC3B-II and mitochondria-specific autophagy, mitophagy, regulator Park2, were significantly increased in the retinas of Abca4(-/-)Rdh8(-/-) mice after light exposure, suggesting involvement of autophagy and mitophagy in the pathogenesis of light-induced retinal degeneration. Deletion of essential genes required for autophagy, including Beclin1 systemically or Atg7 in only rod photoreceptors resulted in increased susceptibility to light-induced retinal damage. Increased photoreceptor cell death was observed when retinas lacking the rod photoreceptor-specific Atg7 gene were coincubated with 20 μM all-trans-retinal. Park2(-/-) mice also displayed light-induced retinal degeneration. Ultra-structural analyses showed mitochondrial and endoplasmic reticulum impairment in retinas of these model animals after light exposure. Taken together, these observations provide novel evidence implicating an important role of autophagy and mitophagy in protecting the retina from all-trans-retinal- and light-induced degeneration.

TGFβ1 was initially identified as a potent chemotactic cytokine to initiate inflammation, but the autoimmune phenotype seen in TGFβ1 knockout mice reversed the dogma of TGFβ1 being a pro-inflammatory cytokine to predominantly an immune suppressor. The discovery of the role of TGFβ1 in Th17 cell activation once again revealed the pro-inflammatory effect of TGFβ1. We developed K5.TGFβ1 mice with latent human TGFβ1 overexpression targeted to epidermal keratinocytes by keratin 5. These transgenic mice developed significant skin inflammation. Further studies revealed that inflammation severity correlated with switching TGFβ1 transgene expression on and off, and genome wide expression profiling revealed striking similarities between K5.TGFβ1 skin and human psoriasis, a Th1/Th17-associated inflammatory skin disease. Our recent study reveals that treatments alleviating inflammatory skin phenotypes in this mouse model reduced Th17 cells, and antibodies against IL-17 also lessen the inflammatory phenotype. Examination of inflammatory cytokines/chemokines affected by TGFβ1 revealed predominantly Th1-, Th17-related cytokines in K5.TGFβ1 skin. However, the finding that K5.TGFβ1 mice also express Th2-associated inflammatory cytokines under certain pathological conditions raises the possibility that deregulated TGFβ signaling is involved in more than one inflammatory disease. Furthermore, activation of both Th1/Th17 cells and regulatory T cells (Tregs) by TGFβ1 reversely regulated by IL-6 highlights the dual role of TGFβ1 in regulating inflammation, a dynamic, context and organ specific process. This review focuses on the role of TGFβ1 in inflammatory skin diseases.

BACKGROUND: Silicosis has been topping the list of high-incidence occupational diseases in developing countries and cannot be completely cured. Recent advances in stem cell research have made possible the treatment of various diseases including lung fibrosis. The application of stem cell therapy in occupational diseases, in particular the use of adipose-derived mesenchymal stem cells (AD-MSCs) in treatment of silicosis, has not yet been reported. The aim of the study is to explore the intervening effect of silica-induced lung fibrosis in rats. METHODS: In this study, we investigated the anti-pulmonary fibrosis effects of the transplantation of AD-MSCs in rats in which lung fibrosis was induced by oral tracheal intubation with silica suspension. Twenty rats were divided into four groups: control group (n = 5), exposure group (n = 5), vehicle group (n = 5) and treatment group (n = 5). AD-MSCs were given to rats after exposure to silica for 24 h. Twenty-eight days after AD-MSC transplantation, we examined the organ coefficient, inflammatory cytokines, apoptosis, pathological and fibrotic changes in lung tissue. RESULTS: Results showed that exposure to silica for 28 days induced an increase of the lung coefficient with significant pulmonary fibrosis. Treatment with AD-MSC transplantation led to a remissive effect on pulmonary fibrosis. We found that after AD-MSC transplantation the inflammatory response decreased and Caspase-3 protein expression significantly decreased with a significant increase of the Bcl-2/Bax ratio. CONCLUSIONS: Anti-inflammatory and anti-apoptosis of AD-MSCs may play important roles in their anti-pulmonary fibrosis effect. Our data suggest that transplantation of AD-MSCs holds promise for potential interference in the formation of silicosis through regulating inflammatory and apoptotic processes.

Abstract Psoriasis is a common inflammatory disease of especially high recurrence rate (90%) which is suffered by approximately 3% of the world population. The overexpression of reactive oxygen species (ROS) plays a critical role in psoriasis progress. Here we show that biomimetic iron single-atom catalysts (FeN 4 O 2 -SACs) with broad-spectrum ROS scavenging capability can be used for psoriasis treatment and relapse prevention via related gene restoration. FeN 4 O 2 -SACs demonstrate attractive multiple enzyme-mimicking activities based on atomically dispersed Fe active structures, which are analogous to those of natural antioxidant enzymes, iron superoxide dismutase, human erythrocyte catalase, and ascorbate peroxidase. Further, in vitro and in vivo experiments show that FeN 4 O 2 -SACs can effectively ameliorate psoriasis-like symptoms and prevent the relapse with augmented efficacy compared with the clinical drug calcipotriol. Mechanistically, estrogen receptor 1 (ESR1) is identified as the core protein upregulated in psoriasis treatment through RNA sequencing and bioinformatic analysis. Together, this study provides a proof of concept of psoriasis catalytic therapy (PCT) and multienzyme-inspired bionics (MIB).

Natural killer (NK) cells are enriched within the liver. Apart from conventional NK (cNK) cells, recent studies identified a liver-resident NK (LrNK) subset, which constitutes about half of hepatic NK cells and exhibits distinct developmental, phenotypic, and functional features. However, it remains unclear whether and how LrNK cells, as well as cNK cells, participate in the development of hepatocellular carcinoma (HCC) individually. Here, we report that both LrNK and cNK cells are significantly decreased in HCC. The T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was significantly upregulated in both tumor-infiltrating LrNK and cNK cells and suppressed their cytokine secretion and cytotoxic activity. Mechanistically, phosphatidylserine (PtdSer) engagement promoted phosphorylation of Tim-3, which then competed with PI3K p110 to bind p85, inhibiting downstream Akt/mTORC1 signaling and resulting in malfunctioning of both NK-cell subsets. Tim-3 blockade retarded HCC growth in a NK-cell-dependent manner. These studies for the first time report the presence and dysfunction of LrNK cells in HCC and show that Tim-3-mediated PI3K/mTORC1 interference is responsible for the dysfunction of both tumor-infiltrating cNK and LrNK cells, providing a new strategy for immune checkpoint-based targeting. SIGNIFICANCE: Tim-3 enhances hepatocellular carcinoma growth by blocking natural killer cell function.