Orally Administrated Olsalazine-Loaded Multilayer Pectin/Chitosan/Alginate Composite Microspheres for Ulcerative Colitis Treatment

The pathogenesis of inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn’s disease is extremely cloudy. Maintaining the level of remission lesions in colitis is the default treatment attitude at present. Epithelial barrier restoration is considered as the same important strategy as colonic targeted drug delivery in UC treatment. In this paper, we developed a multilayer natural polysaccharide microsphere (pectin/chitosan/alginate) with pH and enzyme dual sensitivity to reduce the loss of medication in the upper digestive tract and preferentially adhere to exposed epithelial cells in colonic tissues by electrostatic forces for efficiently targeted UC treatment. Olsalazine as an inflammatory drug was efficiently loaded in the chitosan layer and realized a colonic pH-responsive drug release. Furthermore, the multilayer microspheres exhibited excellent capability in suppressing harmful flora and a bio-adhesion effect to extend the duration of local medicine. In the in vivo anti-colitis study, the downregulated levels of pro-inflammatory factors and the increase of tight junction protein indicated the excellent anti-inflammation effect of the olsalazine-loaded microspheres. In summary, these results showed that the multilayer natural polysaccharide microspheres could be a powerful candidate in the targeted drug delivery system for UC therapy

Role of Brassinosteroids in Persimmon (<i>Diospyros kaki</i> L.) Fruit Ripening

Brassinosteroids (BRs) are phytohormones that regulate numerous processes including fruit ripening. In this study, persimmon (<i>Diospyros kaki</i> L.) fruits were treated with 24-epibrassinolide (EBR) or brassinazole (Brz, a BR biosynthesis inhibitor) and then stored at ambient temperature. The results show that endogenous BR contents gradually increased during persimmon fruit ripening. EBR treatment significantly increased both the content of water-soluble pectin and the activities of polygalacturonase, pectate lyase, and endo-1,4-beta-glucanase but significantly reduced the content of acid-soluble pectin and cellulose, resulting in rapid fruit softening. The EBR treatment also promoted ethylene production and respiration rate. In contrast, Brz treatment delayed persimmon fruit ripening. qRT-PCR analysis showed that <i>DkPG1</i>, <i>DkPL1</i>, <i>DkPE2</i>, <i>DkEGase1</i>, <i>DkACO2</i>, <i>DkACS1</i>, and <i>DkACS2</i> were up-regulated (especially a 38-fold increase in <i>DkEGase1</i>) in the fruit of the EBR-treated group. These results suggest that BRs are involved in persimmon fruit ripening by influencing cell-wall-degrading enzymes and ethylene biosynthesis

Biocidal and Rechargeable <i>N</i>‑Halamine Nanofibrous Membranes for Highly Efficient Water Disinfection

There is a critical need for new efficient solutions to purify and disinfect water from source to point-of-use, especially for the water contaminated by pathogenic microbes. Traditional disinfection technologies are chemically intensive and limited, either by biofouling or by the irreversible consumption of disinfectants. Herein, we present a scalable methodology to create biocidal and rechargeable nanofibrous membranes (BNF membranes) by combining <i>N</i>-halamine antimicrobial agent with electrospun nanofibers. Our method allows intrinsically rechargeable <i>N</i>-halamine moieties to covalently incorporate into nanofibers with high biocidal activity and durability. The resulting BNF membranes exhibit integrated properties of high porosity, large surface area, robust mechanical strength, super hydrophilicity, rechargeable chlorination capability (>3000 ppm), and high bactericidal efficacy (99.9999% contact-killing), which enabled the BNF membranes effectively disinfect bacteria-contained water by direct filtration, with promising high durability and fluxes (10000 L m^–2 h^–1). The successful synthesis of BNF membranes also provides a versatile platform for exploring the antimicrobial <i>N</i>-halamine materials in a self-supporting, structurally adaptive, and nanofibrous form

Stability of Illicit Drugs as Biomarkers in Sewers: From Lab to Reality

Systematic sampling and analysis of wastewater samples are increasingly adopted for estimating drug consumption in communities. An understanding of the in-sewer transportation and transformation of illicit drug biomarkers is critical for reducing the uncertainty of this evidence-based estimation method. In this study, biomarkers stability was investigated in lab-scale sewer reactors with typical sewer conditions. Kinetic models using the Bayesian statistics method were developed to simulate biomarkers transformation in reactors. Furthermore, a field-scale study was conducted in a real pressure sewer pipe with the systematical spiking and sampling of biomarkers and flow tracers. In-sewer degradation was observed for some spiked biomarkers over typical hydraulic retention time (i.e., a few hours). Results indicated that sewer biofilms prominently influenced biomarker stability with the retention time in wastewater. The fits between the measured and the simulated biomarkers transformation demonstrated that the lab-based model could be extended to estimate the changes of biomarkers in real sewers. Results also suggested that the variabilities of biotransformation and analytical accuracy are the two major contributors to the overall estimation uncertainty. Built upon many previous lab-scale studies, this study is one critical step forward in realizing wastewater-based epidemiology by extending biomarker stability investigations from laboratory reactors to real sewers

Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid Leukemia

One of the biggest hurdles yet to be overcome for the continued improvement of histone deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The <i>N</i>-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of our lead analogues’ efficacy, selectivity, and toxicity profiles demonstrate that they possess low nanomolar activity against models of acute myeloid leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells

Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

Previously, we designed and synthesized a series of <i>o</i>-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound <b>11a</b> exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using <b>11a</b> as a lead. Representative compound <b>13b</b> showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound <b>13e</b> exhibited low nanomolar IC₅₀s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC₅₀ of <b>13e</b> against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound <b>11a</b>. <i>In vitro</i> responses to <b>13e</b> vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, <b>13e</b> induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, <b>13e</b> caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis

Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status

Previously, we designed and synthesized a series of <i>o</i>-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound <b>11a</b> exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using <b>11a</b> as a lead. Representative compound <b>13b</b> showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound <b>13e</b> exhibited low nanomolar IC₅₀s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC₅₀ of <b>13e</b> against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound <b>11a</b>. <i>In vitro</i> responses to <b>13e</b> vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, <b>13e</b> induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, <b>13e</b> caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis

sj-pdf-2-jcb-10.1177_0271678X231197173 - Supplemental material for Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Supplemental material, sj-pdf-2-jcb-10.1177_0271678X231197173 for Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury by Yue Zhang, Yongfang Zhao, Yana Wang, Jiaying Li, Yichen Huang, Fan Lyu, Yangfan Wang, Pengju Wei, Yiwen Yuan, Yi Fu and Yanqin Gao in Journal of Cerebral Blood Flow & Metabolism</p

sj-pdf-4-jcb-10.1177_0271678X231197173 - Supplemental material for Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Supplemental material, sj-pdf-4-jcb-10.1177_0271678X231197173 for Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury by Yue Zhang, Yongfang Zhao, Yana Wang, Jiaying Li, Yichen Huang, Fan Lyu, Yangfan Wang, Pengju Wei, Yiwen Yuan, Yi Fu and Yanqin Gao in Journal of Cerebral Blood Flow & Metabolism</p

sj-pdf-7-jcb-10.1177_0271678X231197173 - Supplemental material for Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury

Supplemental material, sj-pdf-7-jcb-10.1177_0271678X231197173 for Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury by Yue Zhang, Yongfang Zhao, Yana Wang, Jiaying Li, Yichen Huang, Fan Lyu, Yangfan Wang, Pengju Wei, Yiwen Yuan, Yi Fu and Yanqin Gao in Journal of Cerebral Blood Flow & Metabolism</p