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Significance Diabetic patients often suffer from impaired wound healing, which can develop into nonhealing diabetic ulcers, facilitate bacterial infections, and necessitate amputation. Current strategies for treatment have failed to achieve the anticipated efficacy and do not address the fundamental molecular abnormalities that prevent efficient wound closure. In this work, we introduce a previously unidentified approach to treating diabetic wound healing by using topically delivered spherical nucleic acids to effect the knockdown of ganglioside-monosialic acid 3 (GM3) synthase, a mediator of impaired wound healing, in type 2 diabetic mice. In addition to laying the groundwork for developing a therapy for a debilitating condition, this work also validates the critical role of GM3 in diabetic wound healing. Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nm-diameter gold cores functionalized with densely packed and highly oriented nucleic acids) dispersed in Aquaphor have been shown to penetrate the epidermal barrier of both intact mouse and human skin, enter keratinocytes, and efficiently down-regulate gene targets. ganglioside-monosialic acid 3 synthase (GM3S) is a known target that is overexpressed in diabetic mice and responsible for causing insulin resistance and impeding wound healing. GM3S SNAs increase keratinocyte migration and proliferation as well as insulin and insulin-like growth factor-1 (IGF1) receptor activation under both normo- and hyperglycemic conditions. The topical application of GM3S SNAs (50 nM) to splinted 6-mm-diameter full-thickness wounds in diet-induced obese diabetic mice decreases local GM3S expression by >80% at the wound edge through an siRNA pathway and fully heals wounds clinically and histologically within 12 d, whereas control-treated wounds are only 50% closed. Granulation tissue area, vascularity, and IGF1 and EGF receptor phosphorylation are increased in GM3S SNA-treated wounds. These data capitalize on the unique ability of SNAs to naturally penetrate the skin and enter keratinocytes without the need for transfection agents. Moreover, the data further validate GM3 as a mediator of the delayed wound healing in type 2 diabetes and support regional GM3 depletion as a promising therapeutic direction.

Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNA-NCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are > 100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.

Malignant melanoma is an aggressive and deadly form of skin cancer, and despite recent advances in available therapies, is still lacking in completely effective treatments. Rg3, a monomer extracted from ginseng roots, has been attempted for the treatment of many cancers. It is reported that the expressions of histone deacetylase 3 (HDAC3) and p53 acetylation correlate with tumor cell growth. However, the antitumor effect of Rg3 on melanoma and the mechanism by which it regulates HDAC3 expression and p53 acetylation remain unknown. We found high expression of HDAC3 in human melanoma tissues to be significantly correlated to lymph node metastasis and clinical stage of disease (p<0.05). In melanoma cells, Rg3 inhibited cell proliferation and induced G0/G1 cell cycle arrest. Rg3 also decreased the expression of HDAC3 and increased the acetylation of p53 on lysine (k373/k382). Moreover, suppression of HDAC3 by either siRNA or a potent HDAC3 inhibitor (MS-275) inhibited cell proliferation, increased p53 acetylation and transcription activity. In A375 melanoma xenograft studies, we demonstrated that Rg3 and HDAC3 short hairpin RNA (shHDAC3) inhibited the growth of xenograft tumors with down-regulation of HDAC3 expression and up-regulation of p53 acetylation. In conclusion, Rg3 has antiproliferative activity against melanoma by decreasing HDAC3 and increasing acetylation of p53 both in vitro and in vivo. Thus, Rg3 serves as a potential therapeutic agent for the treatment of melanoma.

The beet armyworm, Spodoptera exigua, is a significant agricultural pest of numerous crops and has caused serious economic losses in China. To effectively control this pest, we analyzed its genetic variation, population genetic structure and demographic history. We used mitochondrial DNA (mtDNA) fragments of the cytochrome oxidase subunit I (COI) and eight nuclear microsatellite loci to investigate genetic diversity and population genetic structure of S. exigua populations at 14 sampling sites in western China. Both mtDNA and microsatellite data indicated low levels of genetic diversity among all populations. A moderate genetic differentiation among some S. exigua populations was detected. Neighbor-joining dendrograms, STRUCTURE, and principal coordinate analysis (PCoA) revealed two genetically distinct groups: the KEL group and the remaining population group. Isolation by distance (IBD) results showed a weak significant correlation between geographic distance and genetic differentiation. Haplotype networks, neutrality testing, and mismatch distribution analysis indicated that the beet armyworm experienced a recent rapid expansion without a recent genetic bottleneck in western China. Thus, the results of this population genetic study can help with the development of strategies for managing this highly migratory pest.

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft- versus -host disease (G v HD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

Background Growing evidence has underscored the adverse role of air pollutants in the pathogenesis of sarcopenia, while there lacks knowledge over the relationships between PM 2.5 constituents and sarcopenia. Methods This study included 6666 participants aged 45 years and above from the China Health and Retirement Longitudinal Study in 2011, of which 2538 were followed up until 2015. Average concentrations of PM 2.5 and its constituents (sulfate, nitrate, ammonium, organic matter [OM], black carbon [BC]) were retrieved from Tracking Air Pollution in China (TAP) database. In the cross-sectional analyses, we employed multivariate logistic regression, generalized linear model, and restricted cubic spline function to analyze the individual relationships of air pollutants with sarcopenia prevalence and sarcopenia-related index (SI). A lower SI is generally associated with a greater risk of sarcopenia. Quantile-based g-computation model was used to clarify the joint effect of multiple PM 2.5 components and their relative weights of contributions. Cox proportional hazard model was established to ascertain the longitudinal impacts of air pollutants on sarcopenia incidence. Results For each interquartile range increment of PM 2.5 , sulfate, nitrate, ammonium, OM, and BC, the adjusted ORs for sarcopenia were 1.42 (95% CI, 1,14 to 1.77), 1.42 (95% CI, 1.14 to 1.76), 1.38 (95% CI, 1.09 to 1.75), 1.36 (95% CI, 1.09 to 1.70), 1.35 (95% CI, 1.09 to 1.67), and 1.39 (95% CI, 1.15 to 1.68), respectively. Consistently, we found a negative relationship between air pollutants and SI. Multi-pollutant analyses suggested that sarcopenia risk was linearly associated with exposure mixtures, with sulfate identified as the dominant driver of joint effect. In addition, the findings from concentration-response curves, subgroup analyses, sensitivity analyses, and longitudinal analyses further supported the harm of PM 2.5 and its constituents on sarcopenia development. Conclusion Our study demonstrates a positive association of single and joint exposure to PM 2.5 and its components with sarcopenia risk, offering additional implications on early screening and management of sarcopenia.

Irritable bowel syndrome (IBS) is reported associated with the alteration of gut microbial composition termed as dysbiosis. However, the pathogenic mechanism of IBS remains unclear, while the studies of Chinese individuals are scarce. This study aimed to understand the concept of dysbiosis among Chinese diarrhea-predominant IBS (IBS-D) patients, as a degree of variance between the gut microbiomes of IBS-D population and that of healthy population. The IBS-D patients were recruited (assessed according to the Rome III criteria, by IBS symptom severity score) from the Outpatient Department of Gastroenterology of Peking University Third Hospital, and volunteers as healthy controls (HC) were enrolled, during 2013. The 16S rRNA sequences were extracted from fecal samples. RDP resources, BLAST and SparCC software were used to obtain the phylotype composition of samples and the internal interactions of the microbial community. Herein, the nonparametric test, Wilcoxon rank-sum test was carried out to find the statistical significance between HC and IBS-D groups. All the P values were adjusted to q values to decrease the error rate. The study characterized the gut microbiomes of Chinese IBS-D patients, and demonstrated that the dysbiosis could be characterized as directed alteration of the microbiome composition leading to greater disparity between relative abundance of two phyla, Bacteroidetes (Z = 4.77, q = 1.59 × 10) and Firmicutes (Z = -3.87, q = 5.83 × 10). Moreover it indicated that the IBS symptom features were associated with the dysbiosis of whole gut microbiome, instead of one or several certain genera even they were dominating. Two genera, Bacteroides and Lachnospiracea incertae sedis, were identified as the core genera, meanwhile the non-core genera contribute to a larger pan-microbiome of the gut microbiome. Furthermore the dysbiosis in IBS-D patients was associated with a reduction of network complexity of the interacted microbial community (HC vs. IBS-D: 639 vs. 154). The disordered metabolic functions of IBS-D patients were identified as the potential influence of gut microbiome on the host (significant difference with q < 0.01 between HC and IBS-D). This study supported the view of the potential influence of gut microbiome on the symptom of Chinese IBS-D patients, and further characterized dysbiosis in Chinese IBS-D patients, thus provided more pathological evidences for IBS-D with the further understanding of dysbiosis.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

Fibroblast-like synoviocytes (FLS) play a pathogenic role in rheumatoid arthritis (RA). STAT3 signaling is activated in FLS of RA patients (RA-FLS), which in turn causes RA-FLS hyperproliferation. RL is a traditional remedy for treating inflammatory diseases in China. It comprises Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. A standardized ethanolic extract of RL (RLE) has been shown to exert anti-arthritic effects in collagen-induced arthritis (CIA) rats. Some constituents of RLE were reported to inhibit JAK2/STAT3 signaling in rat FLS. Here, we determined whether RLE inhibits FLS hyperproliferation, and explored the involvement of STAT3 signaling in this inhibition. In joints of CIA rats, RLE increased apoptotic FLS. In IL-6/sIL-6R-stimulated RA-FLS, RLE reduced cell viability and evoked cell apoptosis. In synovial tissues of CIA rats, RLE lowered the protein level of phospho-STAT3. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited activation/phosphorylation of STAT3 and JAK2, decreased the nuclear localization of STAT3, and downregulated protein levels of Bcl-2 and Mcl-1. Over-activation of STAT3 diminished RLE’s anti-proliferative effects in IL-6/sIL-6R-stimulated RA-FLS. In summary, RLE inhibits hyperproliferation of FLS in rat and cell models, and suppression of STAT3 signaling contributes to the underlying mechanisms. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug.

Atherosclerosis is a chronic inflammatory disease mediated by immune cells. Th22 cells are CD4(+) T cells that secret IL-22 but not IL-17 or IFN-γ and are implicated in the pathogenesis of inflammatory disease. The roles of Th22 cells in the pathophysiologic procedures of acute coronary syndrome (ACS) remain unclear. The purpose of this study is to investigate the profile of Th22, Th17 and Th17/Th1 cells in ACS patients, including unstable angina (UA) and acute myocardial infarction (AMI) patients. In this study, 26 AMI patients, 16 UA patients, 16 stable angina (SA) patients and 16 healthy controls were included. The frequencies of Th22, Th17 and Th17/Th1 cells in AMI, UA, SA patients and healthy controls were examined by flow cytometry. Plasma levels of IL-22, IL-17 and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). Th22, Th17 and Th17/Th1 cells were significantly increased in AMI and UA patients compared with SA patients and healthy controls. Moreover, plasma IL-22 level was significantly elevated in AMI and UA patients. In addition, Th22 cells correlated positively with IL-22 as well as Th17 cells in AMI and UA patients. Our findings showed increased frequencies of both Th22 and Th17 cells in ACS patients, which suggest that Th22 and Th17 cells may play a potential role in plaque destabilization and the development of ACS.

Shifts in the composition of gut microbiota and short-chain fatty acids (SCFAs) levels (the main metabolic products of gut bacteria) can result in the regulation of host immune function, which is essential in the pathogenesis of IBS. [...]whether probiotics or antibiotics can relieve the severity of psychologic comorbidities in IBS, in addition to the effect of antidepressants on the gut microbiota, are still unknown. [...]to investigate the interaction between the gut microbiota and the brain-gut axis, Duloxetine or probiotics were applied on patients with IBS-D with depression to identify the shifts in gut microbiota profiles and fecal SCFA levels, systematic inflammatory responses, and clinical responses of those patients to both therapies to clarify the potential mechanisms of the microbiota-gut-brain axis. Seven fecal SCFAs, including formate, acetate, propionate, butyrate, isobutyrate, valerate, and isovalerate, were assessed using an isotope-labeled chemical derivatization method on ultra-performance liquid chromatography-tandem mass spectrometry with a slightly modified method. See PDF] Of the patients treated with Duloxetine, a decrease in SDS score was noted (39.3 ± 3.5 vs. 64.0 ± 6.8; Z = −2.02, P = 0.043), and the total score of IBS-SSS (98.8 ± 52.4 vs. 282.3 ± 43.1; Z = −2.20, P = 0.028) as well as the component scores, including abdominal pain (4.2 ± 3.3 vs. 26.0 ± 6.0; Z = −2.03, P = 0.042), onset frequency of pain (18.3 ± 16.4 vs. 63.3 ± 14.8; Z = −2.03, P = 0.042), satisfaction with bowel habits (38.3 ± 15.1 vs. 76.7 ± 12.3; Z = −2.03, P = 0.042), and interference with quality of life (28.3 ± 16.4 vs. 78.3 ± 10.8; Z = −2.21, P = 0.027) decreased significantly compared with the pre-treatment values [Figure 1G, 1H, and 1J].