GATA-3-dependent Gene Transcription is Impaired upon HDAC Inhibition.

PURPOSE: Many peripheral and cutaneous T-cell lymphoma (CTCL) subtypes are poorly responsive to conventional chemotherapeutic agents and associated with dismal outcomes. The zinc finger transcription factor GATA-3 and the transcriptional program it instigates are oncogenic and highly expressed in various T-cell neoplasms. Posttranslational acetylation regulates GATA-3 DNA binding and target gene expression. Given the widespread use of histone deacetylase inhibitors (HDACi) in relapsed/refractory CTCL, we sought to examine the extent to which these agents attenuate the transcriptional landscape in these lymphomas. EXPERIMENTAL DESIGN: Integrated GATA-3 chromatin immunoprecipitation sequencing and RNA sequencing analyses were performed in complementary cell line models and primary CTCL specimens treated with clinically available HDACi. RESULTS: We observed that exposure to clinically available HDACi led to significant transcriptional reprogramming and increased GATA-3 acetylation. HDACi-dependent GATA-3 acetylation significantly impaired both its ability to bind DNA and transcriptionally regulate its target genes, thus leading to significant transcriptional reprogramming in HDACi-treated CTCL. CONCLUSIONS: Beyond shedding new light on the mechanism of action associated with HDACi in CTCL, these findings have significant implications for their use, both as single agents and in combination with other novel agents, in GATA-3-driven lymphoproliferative neoplasms.

Molecular Targets and Mechanisms of Hedyotis diffusa Willd. for Esophageal Adenocarcinoma Treatment Based on Network Pharmacology and Weighted Gene Co-expression Network Analysis.

BACKGROUND: Hedyotis diffusa Willd. (HDW) is a common anticancer herbal medicine in China, and its therapeutic effectiveness has been demonstrated in a range of cancer patients. There is no consensus about the therapeutic targets and molecular mechanisms of HDW, which contains many active ingredients. AIM: To clarify the mechanism of HDW for esophageal adenocarcinoma (EAC), we utilized network pharmacology and weighted gene co-expression network analysis methods (WGCNA). METHODS: The gene modules that were linked with the clinical features of EAC were obtained through the WGCNA method. Then, the potential target genes were retrieved through the network pharmacology method in order to determine the targets of the active components. After enrichment analysis, a variety of signaling pathways with significant ratios of target genes were found, including regulation of trans-synaptic signaling, neuroactive ligand-receptor interaction and modulation of chemical synaptic transmission. By means of protein-protein interaction (PPI) network analysis, we have successfully identified the hub genes, which were AR, CNR1, GRIK1, MAPK10, MAPT, PGR and PIK3R1. RESULT: Our study employed molecular docking simulations to evaluate the binding affinity of the active components with the hub gene. The identified active anticancer constituents in HDW are scopoletol, quercetin, ferulic acid, coumarin, and trans-4-methoxycinnamyl alcohol. CONCLUSION: Our findings shed light on the molecular underpinnings of HDW in the treatment of EAC and hold great promise for the identification of potential HDW compounds and biomarkers for EAC therapy.

Anchoring black phosphorous quantum dots on Bi2WO6 porous hollow spheres: A novel 0D/3D S-scheme photocatalyst for efficient degradation of amoxicillin under visible light.

Reasonable regulation of the micro-morphology of material can significantly enhance the related performance. Herein, bismuth tungstate (Bi2WO6, simplified as BWO) porous hollow spheres with flower-like surface were prepared successfully, and this unique morphology endowed BWO with improved photocatalytic performance by reflecting and absorbing the light multiple times inside the cavity. To inhibit the rapid recombination of photogenerated e--h+ pairs within BWO itself, black phosphorous quantum dots (BPQDs) were anchored onto the nanosheets of BWO sphere closely by a facile self-assembly process, which will not shade the pores of BWO owing to the small size of BPQDs, but the BP nanosheets have the chance to do that. The band gap of BPQDs expanded much after exfoliation due to the quantum confinement effects, which matched the energy band of BWO well to form S-scheme heterojunction, achieving more efficient separation of photogenerated charges. As a result, the BPQDs/BWO exhibited attractive photocatalytic performance in the degradation of amoxicillin (AMX) and other antibiotics. Besides, the operation conditions were optimized, specifically, 94.5 % of AMX (20 mg/L, 200 mL) can be removed in 60 min when 50 mg of 2BPQDs/BWO was used as catalyst with solution pH = 11. Moreover, a possible degradation pathway of AMX was proposed based on the detected intermediates.

Manganese salts function as potent adjuvants.

Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2'3'-cGAMP. Herein, we found that Mn2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4+/CD8+ T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.

Modulation of the powder properties of lamotrigine by crystal forms.

The mechanical properties of powders determine the ease of manufacture and ultimately the quality of the oral solid dosage forms. Although poor mechanical properties of an active pharmaceutical ingredient (API) can be mitigated by using suitable excipients in a formulation, the effectiveness of that approach is limited for high dose drugs or multidrug tablets. In this context, improving the mechanical properties of the APIs through solid form optimisation is a good strategy to address such a challenge. This work explores the powder and tableting properties of various lamotrigine (LAM) solid forms with the aim to facilitate direct compression by overcoming the poor tabletability of LAM. The two drug-drug crystals of LAM with nicotinamide and valproic acid demonstrate superior flowability and tabletability over LAM. The improved powder properties are rationalised by structure analysis using energy framework, scanning electron microscopy, and Heckel analysis.

Lab in hydrogel portable kit: On-site monitoring of oxalate.

Oxalate is commonly employed as adjuvant of pesticide agent, causing renal injury of human even in trace residues. Despite the great achievements of the existing point-of-care testing (POCT) technology, accurate on-site screening of oxalate remains a tricky issue. To this aim, we proposed a "lab in a tube" platform which integrated portable hydrogel kit with smartphone for real-time monitoring of oxalate to achieve quantitatively precise analysis. In this work, a stimuli-responsive hydrogel-based kit was constructed via embedding manganese dioxide (MnO2) nanosheets into sodium alginate hydrogel system. Based on the intrinsic oxidase-like activity, MnO2 nanosheets-based nanozyme triggered color reaction by introducing a common sensing probe 3,3',5,5'-tetramethylbenzidine. Meanwhile, the presence of oxalate would decompose MnO2 nanosheets, inducing the decrease of nanozyme activity, which resulted in the color response of portable kit. Coupling with ImageJ software, the image information of kit captured via smartphone could be transduced into the hue intensity, which provided a directly quantitative tool to detect oxalate with a detection limit of 8.0 µmol L-1. This portable smartphone biosensor was successfully applied for screening urine sample within 10 min for high-throughput analysis (twelve samples) without the need for any advanced analytical instruments. Based on the merits of simple operation, cost-efficiency, and good selectivity, the availability of the miniaturized biosensor platform for POCT will achieve the requirements of routine screening and disease prevention.

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy.

CD8+ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8+ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8+ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8+ T cells. Mechanically, Mn2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8+ T cell differentiation, activation and NK cell activation, and increased memory CD8+ T cells. Combining Mn2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.

Gold nano-flowers (Au NFs) modified screen-printed carbon electrode electrochemical biosensor for label-free and quantitative detection of glycated hemoglobin.

Glycated hemoglobin (HbA1c) represents the average glucose level over the past three months and has been considered as the most important biomarker for the diagnosis of Type Ⅱ diabetes (T2D). Herein, a label-free and quantitative electrochemical biosensor based on 4-mercaptophenylboronic acid (4-MPBA) modified gold nano-flowers (Au NFs) substrate was developed for the determination of HbA1c. Under optimal conditions, the linear dynamic ranges of HbA1c (5 µg/mL - 1000 µg/mL) and HbA1c% (2%-20%) by cyclic voltammetry were achieved. The electrochemical biosensor showed great detection specificity towards HbA1c and relatively stability after storage at 4 °C. This method could also be applied in human serum system which holds great potential to be applied to monitor real blood samples of diabetes patients. In human serum system, the recovery rate could reach 103.8% and 99.0%. It could achieve fast detection, the total analysis time was less than 65 min, and the detection time was less than 10 s. Moreover, in terms of fabrication process, operation procedure, detection time and cost, this technique was superior to the current HbA1c detection methods suggesting great promise for the practical clinical use in the future.

Morin protects glucocorticoid-induced osteoporosis through regulating the mitogen-activated protein kinase signaling pathway.

Our aim is to investigate the potential therapeutic value of morin against osteoporosis and elucidate the mechanism of action. Osteoporosis was induced in rats by a subcutaneous injection of dexamethasone (DEX) for 5 weeks. Body weight was regularly monitored. Body mineral density (BMD) was determined at proximal femurs using dual energy X-ray absorptiometry. Pathological examination was performed by hematoxylin and eosin staining. The relative expression of osteogenic and bone resorption markers was determined by real-time polymerase chain reaction and Western blotting, respectively. Activation of the MAPK signaling pathway was analyzed by Western blotting. Body weight and BMD were both significantly decreased in osteoporotic rats, although BMD was partially restored by intraperitoneal morin administration. Morin treatment also increased the number of trabecular bones in DEX-induced rats. Mechanistically, morin reversed the decrease of osteogenic markers and increase of bone resorption markers, which might eventually be mediated by modulation of MAPK signaling cascades. Here, we uncovered the therapeutic effect of morin against osteoporosis and demonstrated its suppressive action on the MAPK pathway in this disease.

MOXIBUSTION ALLEVIATES GASTRIC PRECANCEROUS LESIONS IN RATS BY PROMOTING CELL APOPTOSIS AND INHIBITING PROLIFERATION-RELATED ONCOGENES.

BACKGROUND: It is well known that gastric mucosa dysplasia and intestinal metaplasia are gastric precancerous lesions (GPL). Moxibustion treatment of Liangmen (ST21) and Zusanli (ST36) alleviated the inflammatory response and dysplasia of gastric mucosa in our previous study. The purpose of this study was to further examine the underlying mechanism of moxibustion treatment of ST21 and ST36 on GPL. MATERIALS AND METHODS: Sixty SD rats were divided into five groups and rats with GPL were treated with either moxibustion (ST), moxibustion (Sham), or vitacoenzyme. B-cell lymphoma 2 (bcl-2), tumor protein p53 (P53) and cellular Myc (C-MYC), which are related to cell apoptosis, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), argyrophilic nucleolar organizer region proteins (Ag-NORs), which are associated with cell proliferation, and cell signaling proteins, nuclear factor kappa B (NF-κB), epidermal growth factor receptor (EGFR) and phosphorylated extracellular signal regulated kinase (p-ERK), were measured after moxibustion treatment. RESULTS: Compared with Control group, gastric mucosa in GPL group showed abnormal mucosal proliferation and pathological mitotic figure, the mRNA expression of bcl-2, P53 and C-MYC increased significantly (P < 0.01), the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-κß as well as EGFR/ERK signaling proteins also increased significantly (P < 0.01). Moxibustion treatment decreased gastric mucosal proliferation and pathological mitotic figure, down-regulated the mRNA expression of bcl-2, P53, C-MYC (P < 0.01), decreased the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-κß as well as EGFR/ERK signaling proteins significantly (P < 0.01). But moxibustion treatment of Sham didn't show the same effect on GPL. CONCLUSION: Moxibustion treatment inhibited cell apoptosis and reduced gastric mucosa dysplasia by inhibiting the expression of bcl-2, P53, C-MYC and decreased the activity of NF-κß as well as EGFR/ERK signaling proteins.

Intraperitoneal injection of (-)-Epigallocatechin-3-gallate protects against light-induced photoreceptor degeneration in the mouse retina.

PURPOSE: (-)-epigallocatechin-3-gallate (EGCG), a major catechin component of green tea, is reported to delay or prevent certain forms of cancer, arthritis, cardiovascular disease, and neurodegenerative disorders. In this study, we determined if systemically administered EGCG could protect the retina against light damage (LD) in mice. METHODS: BALB/cJ mice were treated with either EGCG or saline via intraperitoneal (IP) injection, and then placed under constant cool white light-emitting diode (LED) light (10,000 lux) for 5 h. Retinal structure and function were evaluated using optical coherence tomography (OCT), histology, and electroretinography (ERG) 7 days after LD. In addition, the mRNAs of several oxidative stress genes were quantified by qPCR before LD and 24 h after LD. RESULTS: OCT and photomicrographs of mouse retinas showed morphologic protection of photoreceptors. Mice in the EGCG group had significantly higher ERG amplitudes for all three wave types compared with mice in the saline control group, which indicated that EGCG protected retinal function. Furthermore, qPCR results showed that EGCG administration can increase the mRNA level of the antioxidant gene Sod2 before LD and 24 h after LD. CONCLUSIONS: The IP injection of EGCG attenuated the detrimental effects of bright light on the retinas of BALB/cJ mice by protecting the structure and function of the retina.

Solid-state characterization of optically pure (+)Dihydromyricetin extracted from Ampelopsis grossedentata leaves.

Dihydromyricetin (DMY) is a natural flavanol compound isolated from a traditional Chinese medicine, Ampelopsis grossedentata. Despite that optically pure (+)DMY is desired for treating chronic pharyngitis and alcohol use disorders, only DMY racemate is commercially available due to prolonged exposure time to high temperature and the presence of metal ions during industrial extraction, which cause racemization of the homochiral (+)DMY. We have developed an extraction method for successfully obtain optically pure (+)DMY. We have further assessed the physicochemical properties of the two phases using PXRD, DSC, TGA, FTIR, and moisture sorption. Among them, PXRD and FT-IR are suitable for quickly distinguishing homochiral (+)DMY from racemic (±)DMY. Lastly, with the aid of cocrystallization with theophylline, the absolute configuration of homochiral (+)DMY was identified to be (2R, 3R).

[Effects of moxibustion on cell proliferative factors in gastric mucosa in rats with precancerous lesions of chronic atrophic gastritis].

OBJECTIVE: To explore the molecular mechanism of moxibustion at stomach meridian acupoints for precancerous lesions of chronic atrophic gastritis (CAG). METHODS: Fifty male SD rats were randomly divided into a normal group, a model group, a stomach meridian group, a control point group and a vitacoenzyme group, 10 rats in each group. The CAG precancerous lesion model was made in all the groups except the normal group. The rats in the normal group and model group were bundled for 30 min per day; the rats in the stomach meridian group and control point group were bundled and treated with moxibustion at stomach meridian acupoints or control points for 30 min per day; the rats in the vitacoenzyme group were treated with intragastric administration of vitacoenzyme, once per day. All the treatment was given for 20 weeks. The pathological morphological change of gastric mucosa was observed under optical microscope; the expression of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), vascular endothelial growth factor (VEGF), gastric mucosal proliferatig cell nuclear antigen (PCNA), argyrophilic protein of nucleolar organizer regions (Ag-NORs) in gastric mucosal cells were detected by enzyme linked immuno sorbent assay (ELISA). RESULTS: Compared with the normal group, in the model group the gastric mucosal cells showed dysplasia and the expression of EGF, TGF-alpha, PCNA, VEGF, Ag-NORs in gastric mucosa cells in the model group was increased significantly (all P < 0.05). Compared with the model group, the gastric mucosa lesion gradually recovered and the expression of EGF, TGF-alpha, PCNA, VEGF, Ag-NORs in gastric mucosal cells was gradually decreased in the stomach meridian group, control point group and vitacoenzyme group, in which the stomach meridian group had the most significant effects (all P < 0.05). CONCLUSION: Moxibustion at stomach meridian acupoints can obviously decrease the expression of cell proliferative factors in gastric mucosa in rats with CAG precancerous lesions, inhibit the gastric mucosal cell dysplasia, and promote the recovery of gastric mucosa.

Treatment of tumors with vitamin E suppresses myeloid derived suppressor cells and enhances CD8+ T cell-mediated antitumor effects.

Vitamin E has been shown to have strong anticarcinogenic properties, including antioxidant characteristics, making it an ideal candidate for use in combination with immunotherapies that modify the tumor microenvironment. The tumor microenvironment contains immunosuppressive components, which can be diminished, and immunogenic components, which can be augmented by immunotherapies in order to generate a productive immune response. In the current study, we employ the α-tocopherol succinate isomer of vitamin E to reduce immunosuppression by myeloid derived suppressor cells (MDSCs) as well as adoptive transfer of antigen-specific CD8+ T cells to generate potent antitumor effects against the HPV16 E7-expressing TC-1 tumor model. We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice. We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism. Additionally, treatment with vitamin E reduces the percentage of MDSCs in tumor loci, and induces a higher percentage of T cells, following T cell adoptive transfer. Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice. Our data provide additional evidence that vitamin E has anticancer properties and that it has promise for use as an adjuvant in combination with a variety of cancer therapies.

Salvia miltiorrhiza extracts protect against retinal injury in a rat glaucoma model.

Glaucoma is a serious progressive degenerative disorder of the eye that leads to the continuous loss of retinal ganglion cells. Traditional Chinese medicine provides an important source for new drug screening and identification. The present study used Salvia miltiorrhiza (Danshen) extracts to examine the potential neuroprotective effects for the eye in a rat model of experimental glaucoma. The results of the study indicated that Salvia miltiorrhiza extracts were unable to prevent intraocular pressure increase in the laser-induced glaucoma model, but the treatment did reduce cell loss during glaucoma progression. Therefore, the results provide the basis for the development of a novel therapeutic agent that exhibits neuroprotective effects against glaucoma. In the future, further studies are required to purify the extracts and determine the effective bioactive components of Salvia miltiorrhiza.

Nexrutine inhibits survival and induces G1 cell cycle arrest, which is associated with apoptosis or autophagy depending on the breast cancer cell line.

Breast cancers that are estrogen receptor (ER) negative or are ER negative with ErbB2/HER-2 overexpression have a poor prognosis, which emphasizes the importance of developing compounds for preventing breast cancer. Nexrutine, an herbal extract from the plant Phellodendron amurense, has been used for centuries in Asian medicine to treat inflammation, gastroenteritis, abdominal pain, and diarrhea. In this study we investigated the anticancer effects of Nexrutine on ER negative breast cancer cell lines that are positive or negative for HER-2. Nexrutine decreased the activities of 2 potential targets of breast cancer, cyclooxygenase (COX)-2, and peroxisome proliferators activated receptor gamma (PPARγ). The antiinflammatory effects of Nexrutine were evident with decreased prostaglandin (PG)E2 production, protein expression of microsomal PGE2 synthase (mPGES), and PPARγ. Nexrutine decreased cell survival and induced a G1 cell cycle arrest in SkBr3 and MDA-MB 231 cells, which were associated with reduced protein expression of Cyclin D1 and cdk2 along with increased protein expression of p21 and p27. The growth-inhibitory effect of Nexrutine was associated with apoptosis in SkBr3 cells and autophagy in MDA-MB231 cells. Based on these findings, we propose that Nexrutine may provide a novel approach for protection against breast cancer.

[Application of "disharmony of stomach leads to insomnia" theory in acupuncture treatment for insomnia].

When looking back to the literature regarding insomnia, it is believed that "disharmony of stomach leads to insomnia" is an important mechanism for the attack of insomnia. This theory is widely accepted in clinical practices by ancient and modern acupuncturists, thus the method treating insomnia from the stomach is developed. But deeper research on its mechanism is still lacking. Through correlation between stomach meridian and heart meridian, spleen and stomach being the pivot of rise and decline of qi movement and yin-yang and being the pivot of five zang-viscera housing spirit, modern abdomen-brain theory and experimental research, the mechanism of treating insomnia from the stomach is discussed in this paper, so as to be better to guide clinical acupoint-selection and treatment.