The crude extract obtained from Cinnamomum macrostemon Hayata regulates oxidative stress and mitophagy in keratinocytes.

Four ethanol fractionated crude extracts (EFCEs [A-D]) purified from the leaves of Cinnamomum macrostemon Hayata were screened for antioxidative effects and mitochondrial function in HaCaT cells. The higher cell viability indicated that EFCE C was mildly toxic. Under the treatment of 50 ng/mL EFCE C, the hydrogen peroxide (H2O2)-induced cytosolic and mitochondrial reactive oxygen species levels were reduced as well as the H2O2-impaired cell viability, mitochondrial membrane potential (MMP), ATP production, and mitochondrial mass. The conversion of globular mitochondria to tubular mitochondria is coincident with EFCE C-restored mitochondrial function. The mitophagy activator rapamycin showed similar effects to EFCE C in recovering the H2O2-impaired cell viability, MMP, ATP production, mitochondrial mass, and also mitophagic proteins such as PINK1, Parkin, LC3 II, and biogenesis protein PGC-1α. We thereby propose the application of EFCE C in the prevention of oxidative stress in skin cells.

Early detection of the initial stages of LED light-triggered non-alcoholic fatty liver disease by wax physisorption kinetics-Fourier transform infrared imaging.

Light-emitting diodes (LEDs), particularly in the blue waveform range, are regarded as a major source of circadian rhythm dysregulation. A circadian rhythm dysregulation induced by blue LEDs is associated with non-alcoholic fatty liver disease (NAFLD). Hepatocellular accumulation of lipids is a key event in the early stages of NAFLD. Kupffer cells (KCs) have been reported to be lost in the early onset of NAFLD followed by an inflammatory reaction that alters the liver response to lipid overload. This study focused on the detection of the initial stages (subpathological stages) of LED light-triggered NAFLD. Mice were exposed to either blue or white LED irradiation for 44 weeks. Synchrotron radiation-based Fourier-transform infrared microspectroscopy (SR-FTIRM) and wax physisorption kinetic-Fourier transform infrared (WPK-FTIR) imaging were used to evaluate the ratio of lipid to protein and the glycosylation of glycoprotein, respectively. Immunohistopathological studies on KCs and circadian-related proteins were performed. Although liver biopsy showed normal pathology, an SR-FTIRM study revealed a high hepatic lipid-to-protein ratio after receiving LED illumination. The results of WPK-FTIR demonstrated that a high inflammation index was found in the high irradiance of the blue LED illumnation group. These groups showed a decrease in KC number and an increase in Bmal1 and Reverbα circadian protein expression. These findings provide explanations for the reduction of KCs without subsequent inflammation. A significant reduction of Per2 and Cry1 expression is correlated with the findings of WPK-FTIR imaging. WPK-FTIR is a sensitive method for detecting initiative stages of NAFLD induced by long-term blue LED illumination.

Autologous Fat Grafting in Female Genital Area Improves Sexual Function by Increasing Collagenesis, Angiogenesis, and Estrogen Receptors.

BACKGROUND: Vulvovaginal laxity, atrophic vaginitis, and orgasmic dysfunction are not only aesthetic but also sexual problems. Autologous fat grafting (AFG) facilitates tissue rejuvenation through the effects of adipose-derived stem cells; the fat grafts serve as soft-tissue filler. However, few studies have reported the clinical outcomes of patients undergoing vulvovaginal AFG. OBJECTIVES: The aim of this study was to describe a new technique, micro-autologous fat transplantation (MAFT), for AFG in the vulvovaginal area. Posttreatment histologic changes in the vaginal canal that imply improved sexual function were assessed. METHODS: This retrospective study enrolled females who underwent vulvovaginal AFG performed through MAFT between June 2017 and 2020. Assessments were based on the Female Sexual Function Index (FSFI) questionnaire and on histologic and immunohistochemical staining. RESULTS: In total, 20 female patients (mean age, 38.1 years) were included. On average, 21.9 mL of fat was injected into the vagina and 20.8 mL in the vulva and mons pubis area. Six months afterwards, the patients' mean total FSFI score (68.6) was significantly higher than that at baseline (43.8; P < .001). Histologic and immunohistochemical staining of vaginal tissues revealed substantially increased levels of neocollagenesis, neoangiogenesis, and estrogen receptors. By contrast, the level of protein gene product 9.5, which is associated with neuropathic pain, was considerably lower after AFG. CONCLUSIONS: AFG performed through MAFT in the vulvovaginal area may help manage sexual function-related problems in females. In addition, this technique improves aesthetics, restores tissue volume, alleviates dyspareunia with lubrication, and reduces scar tissue pain.

Correlation between Cancer Stem Cells, Inflammation and Malignant Transformation in a DEN-Induced Model of Hepatic Carcinogenesis.

Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process that is characterised by chronic inflammation and hepatocyte damage, but the correlation between HCC, inflammation and cancer stem cells remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining. We also scored for immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between them. DEN progressively induced inflammation at week 7 (40%, 2/5); week 27 (75%, 6/8); week 33 (62.5%, 5/8); and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5); week 27 (87.5%, 7/8); week 33 (100%, 8/8); and week 50 (100%, 12/12). The obtained data showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5); week 27 (37.5%, 3/8); week 33 (50%, 4/8); and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver, as shown above, as well as applying Spearman's correlation to the data showed that the expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001). There was a significant correlation between the number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.

PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition.

Epigenetic regulation is important for cancer progression; however, the underlying mechanisms, particularly those involving protein acetylation, remain to be fully understood. Here, we show that p300/CBP-associated factor (PCAF)-dependent acetylation of the transcription factor intestine-specific homeobox (ISX) regulates epithelial-mesenchymal transition (EMT) and promotes cancer metastasis. Mechanistically, PCAF acetylation of ISX at lysine 69 promotes the interaction with acetylated bromodomain-containing protein 4 (BRD4) at lysine 332 in tumor cells, and the translocation of the resulting complex into the nucleus. There, it binds to promoters of EMT genes, where acetylation of histone 3 at lysines 9, 14, and 18 initiates chromatin remodeling and subsequent transcriptional activation. Ectopic ISX expression enhances EMT marker expression, including TWIST1, Snail1, and VEGF, induces cancer metastasis, but suppresses E-cadherin expression. In lung cancer, ectopic expression of PCAF-ISX-BRD4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF-ISX-BRD4 axis mediates EMT signaling and regulates tumor initiation and metastasis.

Spinal Irisin Gene Delivery Attenuates Burn Injury-Induced Muscle Atrophy by Promoting Axonal Myelination and Innervation of Neuromuscular Junctions.

Muscle loss and weakness after a burn injury are typically the consequences of neuronal dysregulation and metabolic change. Hypermetabolism has been noted to cause muscle atrophy. However, the mechanism underlying the development of burn-induced motor neuropathy and its contribution to muscle atrophy warrant elucidation. Current therapeutic interventions for burn-induced motor neuropathy demonstrate moderate efficacy and have side effects, which limit their usage. We previously used a third-degree burn injury rodent model and found that irisin-an exercise-induced myokine-exerts a protective effect against burn injury-induced sensory and motor neuropathy by attenuating neuronal damage in the spinal cord. In the current study, spinal irisin gene delivery was noted to attenuate burn injury-induced sciatic nerve demyelination and reduction of neuromuscular junction innervation. Spinal overexpression of irisin leads to myelination rehabilitation and muscular innervation through the modulation of brain-derived neurotrophic factor and glial-cell-line-derived neurotrophic factor expression along the sciatic nerve to the muscle tissues and thereby modulates the Akt/mTOR pathway and metabolic derangement and prevents muscle atrophy.

Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage.

Background: Neurological deficits following subarachnoid hemorrhage (SAH) are caused by early or delayed brain injuries. Our previous studies have demonstrated that hyperglycemia induces profound neuronal apoptosis of the cerebral cortex. Morphologically, we found that hyperglycemia exacerbated late vasospasm following SAH. Thus, our previous studies strongly suggest that post-SAH hyperglycemia is not only a response to primary insult, but also an aggravating factor for brain injuries. In addition, mitochondrial fusion and fission are vital to maintaining cellular functions. Current evidence also shows that the suppression of mitochondrial fission alleviates brain injuries after experimental SAH. Hence, this study aimed to determine the effects of mitochondrial dynamic modulation in hyperglycemia-related worse SAH neurological prognosis. Materials and methods: In vitro, we employed an enzyme-linked immunosorbent assay (ELISA) to detect the effect of mitochondrial division inhibitor-1 (Mdivi-1) on lipopolysaccharide (LPS)-induced BV-2 cells releasing inflammatory factors. In vivo, we produced hyperglycemic rats via intraperitoneal streptozotocin (STZ) injections. Hyperglycemia was confirmed using blood-glucose measurements (>300 mg/dL) 7 days after the STZ injection. The rodent model of SAH, in which fresh blood was instilled into the craniocervical junction, was used 7 days after STZ administration. We investigated the mechanism and effect of Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1) to downregulate mitochondrial fission, on SAH-induced apoptosis in a hyperglycemic state, and evaluated the results in a dose−response manner. The rats were divided into the following five groups: (1) control, (2) SAH only, (3) Diabetes mellitus (DM) + SAH, (4) Mdivi-1 (0.24 mg/kg) + DM + SAH, and (5) Mdivi-1 (1.2 mg/kg) + DM + SAH. Results: In vitro, ELISA revealed that Mdivi-1 inhibited microglia from releasing inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. In vivo, neurological outcomes in the high-dose (1.2 mg/kg) Mdivi-1 treatment group were significantly reduced compared with the SAH and DM + SAH groups. Furthermore, immunofluorescence staining and ELISA revealed that a high dose of Mdivi-1 had attenuated inflammation and neuron cell apoptosis by inhibiting Hyperglycemia-aggravated activation, as well as microglia and astrocyte proliferation, following SAH. Conclusion: Mdivi-1, a Drp-1 inhibitor, attenuates cerebral vasospasm, poor neurological outcomes, inflammation, and neuron cell apoptosis following SAH + hyperglycemia.

Chemical Constituents from a Mangrove-Derived Actinobacteria Isoptericola chiayiensis BCRC 16888 and Evaluation of Their Anti-NO Activity.

Cultivation of the actinobacteria strain Isoptericola chiayiensis, a mangrove-derived actinobacteria that was isolated from a mangrove soil collected in Chiayi County, resulted in the isolation of one new 2-furanone derivative, isopterfuranone (1), one new sesquiterpenoid, isopterchiayione (2), one new benzenoid derivative, isopterinoid (3), five new flavonoids, chiayiflavans A-E (4-8), and 4 metabolites isolated for the first time from nature source, methyl 3-(4-methyl-2,5-dioxopyrrolidin-3-yl)propanoate (9), 3-ethyl-4-methylpyrrolidine-2,5-dione (10), chiayiensol (11) and chiayiensic acid (12). Their structures were determined through in-depth spectroscopic and mass-spectrometric analyses. Most of the isolates showed potent inhibitory effects on NO production in LPS-stimulated RAW 264.7 murine macrophages cells with IC50 values ranging from 9.36 to 40.02 µM. Of these isolates, 4 and 5 showed NO inhibitory activity with IC50 values of 17.14 and 9.36 µM, stronger than the positive control quercetin (IC50 =36.95 µM). This is the first report on flavan metabolites from the genus Isoptericola.

Secondary Metabolites with Anti-Inflammatory Activities from One Actinobacteria Amycolatopsis taiwanensis.

Phytochemical investigation and chromatographic separation of extracts from one new actinobacteria strain Amycolatopsis taiwanensis that was isolated from soil of Yilan township, in the north of Taiwan, led to the isolation of nine new compounds, amycolataiwanensins A-I (1-9, resp.), and one new natural product, namely amycolataiwanensin J (10). The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic-data analysis (1D- and 2D-NMR, MS, and UV) and comparison with literature data. The effect of some isolates on the inhibition of NO production in lipopolysaccharide-activated RAW 264.7 murine macrophages was evaluated. Of the isolates, 3, 5, 7 and 8 exhibited potent anti-NO production activity, with IC50 values of 17.52, 12.31, 17.81 and 13.32 µM, respectively, compared to that of quercetin, an iNOS inhibitor with an IC50 value of 35.94 µM. This is the first report on indole metabolite from the genus Amycolatopsis.

Saccharpiscinols A-C: Flavans with Potential Anti-Inflammatory Activities from One Actinobacteria Saccharomonospora piscinae.

Phytochemical investigation and chromatographic separation of extracts from the actinobacteria strain Saccharomonospora piscinae that was isolated from dried fishpond sediment of Kouhu township, in the south of Taiwan, led to the isolation of three new compounds, saccharpiscinols A-C (1-3, respectively), and three new natural products, namely (2S)-5,7,3',4'-tetrahydroxy-6,8-dimethylflavanone (4), methyl-4-hydroxy-2-methoxy-6-methylbenzoate (5), and (±)-7-acetyl-4,8-dihydroxy-6-methyl-1-tetralone (6). Compounds 4-6 were reported before as synthesized products, herein, they are reported from nature for the first time. The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic data analysis (1D- and 2D-NMR, MS, and UV) and comparison with literature data. The effect of some isolates on the inhibition of NO production in lipopolysaccharide-activated RAW 264.7 murine macrophages was evaluated. Saccharpiscinol A showed inhibitory activities against LPS-induced NO production.

YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance by suppressing caspase-mediated apoptosis.

The objective of this study was to characterize the oncogenic actions of a recently identified cancer-associated gene YWHAZ (also named as 14-3-3 ζ/δ) in urothelial carcinomas of the urinary bladder (UCUB). A genome-wide study revealed YWHAZ to be involved in the amplicon at 8q22.3, and its genetic amplification was detected predominantly in muscle-invasive bladder cancer (MIBC). Immunohistochemical staining confirmed the association of YWHAZ overexpression with higher tumor stages, lymph node/vascular invasion, and mitotic activity. Univariate and multivariate analyses further indicated the prognostic potential of YWHAZ for more aggressive cancer types. Both gene set enrichment analysis and STRING network studies suggested involvement of YWHAZ in regulating caspase-mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low endogenous YWHAZ levels boosted cell resistance to doxorubicin and cisplatin, as well as to ionizing radiation. Conversely, YWHAZ-knockdown using specific shRNA in cells with high endogenous YWHAZ levels diminished survival activity, suppressing cell growth and increasing cell death. Our findings confirm the essential role played by YWHAZ in sustaining cell proliferation during chemo/radiotherapy. Treatments based on anti-YWHAZ strategies may thus be beneficial for UCUB patients overexpressing YWHAZ. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Erythropoietin Alleviates Burn-induced Muscle Wasting.

Background: Burn injury induces long-term skeletal muscle pathology. We hypothesized EPO could attenuate burn-induced muscle fiber atrophy. Methods: Rats were allocated into four groups: a sham burn group, an untreated burn group subjected to third degree hind paw burn, and two burn groups treated with weekly or daily EPO for four weeks. Gastrocnemius muscle was analyzed at four weeks post-burn. Results: EPO attenuated the reduction of mean myofiber cross-sectional area post-burn and the level of the protective effect was no significant difference between two EPO-treated groups (p=0.784). Furthermore, EPO decreased the expression of atrophy-related ubiquitin ligase, atrogin-1, which was up-regulated in response to burn. Compared to untreated burn rats, those receiving weekly or daily EPO groups had less cell apoptosis by TUNEL assay. EPO decreased the expression of cleaved caspase 3 (key factor in the caspase-dependent pathway) and apoptosis-inducing factor (implicated in the caspase-independent pathway) after burn. Furthermore, EPO alleviated connective tissue overproduction following burn via transforming growth factor beta 1-Smad2/3 pathway. Daily EPO group caused significant erythrocytosis compared with untreated burn group but not weekly EPO group. Conclusion: EPO therapy attenuated skeletal muscle apoptosis and fibrosis at four weeks post-burn. Weekly EPO may be a safe and effective option in muscle wasting post-burn.

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction.

Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

An observational study of patho-oncological outcomes of various surgical methods in total mesorectal excision for rectal cancer: a single center analysis.

BACKGROUND: Total mesorectal excision (TME) with or without neoadjuvant concurrent chemoradiotherapy (CCRT) is the treatment for rectal cancer (RC). Recently, the use of conventional laparoscopic surgery (LS) or robotic-assisted surgery (RS) has been on a steady increase cases. However, various oncological outcomes from different surgical approaches are still under investigation. METHODS: This is a retrospective observational study comprising 300 consecutive RC patients who underwent various techniques of TME (RS, n = 88; LS, n = 37; Open surgery, n = 175) at a single center of real world data to compare the pathological and oncological outcomes, with a median follow-up of 48 months. RESULTS: Upon multivariate analysis, histologic grade (P = 0.016), and stage (P < 0.001) were the independent factors of circumferential resection margin (CRM) involvement. The Kaplan-Meier survival analysis determined RS, early pathologic stage, negative CRM involvement, and pathologic complete response to be significantly associated with better overall survival (OS) and disease-free survival (DFS) (all P < 0.05). Multivariable analyses observed the surgical method (P = 0.037), histologic grade (P = 0.006), and CRM involvement (P = 0.043) were the independent factors of DFS, whereas histologic grade (P = 0.011) and pathologic stage (P = 0.022) were the independent prognostic variables of OS. CONCLUSIONS: This study determined that RS TME is feasible because it has less CRM involvement and better oncological outcomes than the alternatives have. The significant factors influencing CRM and prognosis depended on the histologic grade, tumor depth, and pre-operative CCRT. RS might be an acceptable option owing to the favorable oncological outcomes for patients with RC undergoing TME.

CHD4-mediated loss of E-cadherin determines metastatic ability in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is a subtype of cancer with aggressive behaviors (high recurrence and metastasis rate) and poor prognosis. Therefore, studying the determining factors that lead to malignant TNBCs is necessary to develop personalized therapy and improve survival rates. In this study, we first analyzed levels of chromodomain helicase DNA binding protein 4 (CHD4) in 60 TNBC patients by immunohistochemical staining. We then clarified the role of CHD4 in TNBC and non-TNBC cell lines. Our clinical data indicated that higher CHD4 expression is positively correlated with metastatic stage, tumor recurrence, and survival status. Consistent with the clinical analytical data, our in vitro data also indicated that high level of CHD4 is positively correlated with malignant behaviors in TNBC cells, such as cell motility and mortality. For further analyses, we found that E-cadherin, N-cadherin and fibronetin are involved in CHD4-mediated epithelial-mesenchymal transition (EMT). Silencing of CHD4 also increased drug sensitivity to cisplatin and PARP1 inhibitor, especially in TNBC cells. Altogether, our findings showed that CHD4 is not only a potential prognostic biomarker for TNBC patient survival, but is also a powerful candidate in the development of new anti-cancer agents in TNBC.

Dose-Dependent Effect of Hyperbaric Oxygen Treatment on Burn-Induced Neuropathic Pain in Rats.

Hyperbaric oxygen treatment (HBOT) has been used to reduce neuropathic pain. Melatonin and opioid receptors are involved in neuropathic pain, but it is not known if HBOT works through these pathways to achieve its antinociceptive effect. We divided anesthetized rats into two treatment and three sham groups. The two treatment groups received third-degree burns on their right hind paws, one treated in a hyperbaric chamber for a week and the other for two weeks. We evaluated the mechanical paw-withdrawal threshold (MWT) and expression of melatonin receptor 1 (MT1), melatonin receptor 2 (MT2), µ (MOR) and κ (KOR) opioid receptor, brain-derived neurotrophic factor (BDNF), Substance P, and calcitonin gene-related peptide (CGRP) in cuneate nucleus, dorsal horn, and hind paw skin by immunohistochemical, immunofluorescence assays and real-time quantitative polymerase chain reaction (RT-PCR). The group receiving one-week HBOT had increased expressions of MT1, MT2, MOR and KOR and decreased expressions of BDNF, Substance P, and CGRP. Their mechanically measured pain levels returned to normal within a week and lasted three weeks. This anti-allodynia effect lasted twice as long in those treated for two weeks. Our findings suggest that increasing the duration of HBOT can reduce burn-induced mechanical allodynia for an extended period of time in rats. The upregulation of melatonin and opioid receptors observed after one week of HBOT suggests they may be partly involved in attenuation of the mechanical allodynia. Downregulation of BDNF, substance P and CGRP may have also contributed to the overall beneficial effect of HBOT.

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128.

The NuRD complex-mediated p21 suppression facilitates chemoresistance in BRCA-proficient breast cancer.

The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex play a role in silencing gene expression. CHD4, the core component of the NuRD complex, which cooperates with histone deacetylase in reducing tumor suppressor genes (TSGs). To dissect the mechanisms underlying cancer promotion, we clarify the role of CHD4 in cyclin-dependent kinase inhibitor protein p21. Here, our data indicates that CHD4 deficiency impairs the recruitments of HDAC1 to the p21 promoter. ~ 300bp proximal promoter region is responsible for CHD4-HDAC1 axis-mediated p21 transcriptional activity. For identifying the role of anti-cancer drug response, knockdown of p21 overcomes cisplatin and poly-(ADP-ribose) polymerase (PARP) inhibitor-mediated growth suppression in CHD4-depleted cells. Consistent with in vitro data, tissue of patients and bioinformatics approach also showed positive correlation between CHD4 and p21. Overall, our findings not only identify that CHD4 deficiency preferentially impairs cell survival via increasing the level of p21, but also establishes targeting CHD4 as a potential therapeutic implication in BRCA-proficient breast cancer treatment.

Platelet-Rich Plasma Injection in Burn Scar Areas Alleviates Neuropathic Scar Pain.

Objective: No effective treatments have yet been developed for burn-induced neuropathic pain. Platelet-rich plasma (PRP) has been reported to ameliorate various types of inflammation pain. However, the effect of PRP on burn-induced neuropathic pain is unclear. Methods: Burn-induced neuropathic pain Sprague-Dawley rat model was confirmed using a mechanical response test 4 weeks after the burn injuries were sustained, following which PRP was injected in the scar area. The rats were divided into four groups (n = 6) as following: Group A, Sham; Group B, Sham + PRP; Group C, Burn; and Group D, Burn + PRP. Four weeks after the PRP injection, the animals were subjected to behavior tests and then sacrificed; specimens were collected for inflammation tests, Masson's trichrome stain and chromosome 10 (PTEN) in the injured skin; and PTEN, phosphorylated mammalian target of rapamycin (p-mTOR), p38, nuclear factor κB (NFκB), chemokine (CC motif) ligand 2 (CCL2), and CCL2 cognate receptor (CCR2) in spinal cord dorsal horns through immunohistochemistry and immunofluorescence staining. Results: PRP significantly alleviated allodynia in burn-induced neuropathic pain 4 weeks after treatment, and PTEN expression in the skin and spinal cord were significantly increased in group D compared with the group C. p-PTEN, p-mTOR, and CCL2 expression in neuron cells; p-p38 and p-NFκB expression in microglia; and p-JNK and p-NFκB activation in spinal astrocytes decreased significantly in the group D compared with the group C. Conclusions: PRP is effective in treating burn-induced neuropathic pain and may be used in clinical practice.

Early Hyperbaric Oxygen Treatment Attenuates Burn-Induced Neuroinflammation by Inhibiting the Galectin-3-Dependent Toll-Like Receptor-4 Pathway in a Rat Model.

Hyperbaric oxygen (HBO) treatment has been proven to decrease neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague-Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment; (2) sham burn with HBO treatment; (3) burn with one-week sham HBO treatment; (4) burn with two-week sham HBO treatment; (5) burn with one-week HBO treatment; and (6) burn with two-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting. A behavior test was also conducted, which revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared to the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor α (TNF-α) and interleukin 1 beta (IL-1ß) levels in the dorsal horn of the spinal cord and the skin significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis showed that the expression of Gal-3, TLR-4, CD68 and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia and macrophage activation in a rat model.