S670, an amide derivative of 3-O-acetyl-11-keto-ß-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome.

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

Constructing mesoporous biochar derived from waste carton: Improving multi-site adsorption of dye wastewater and investigating mechanism.

The development of cost-efficient biochar adsorbent with a simple preparation method is essential to constructing efficient wastewater treatment system. Here, a low-cost waste carton biochar (WCB) prepared by a simple two-step carbonization was applied in efficiently removing Rhodamine B (RhB) in aqueous environment. The maximum ability of WCB for RhB adsorption was 222 mg/g, 6 and 10 times higher than both of rice straw biochar (RSB) and broadbean shell biochar (BSB), respectively. It was mainly ascribed to the mesopore structure (3.0-20.4 nm) of WCB possessing more spatial sites compared to RSB (2.2 nm) and BSB (2.4 nm) for RhB (1.4 nm✕1.1 nm✕0.6 nm) adsorption. Furthermore, external mass transfer (EMT) controlled mass transfer resistance (MTR) of the RhB sorption process by WCB which was fitted with the Langmuir model well. Meanwhile, the adsorption process was dominated by physisorption through van der Waals forces and π-π interactions. A mixture of three dyes in river water was well removed by using WCB. This work provides a straightforward method of preparing mesoporous biochar derived from waste carton with high-adsorption capacity for dye wastewater treatment.

Examining the normality assumption of a design-comparable effect size in single-case designs.

What Works Clearinghouse (WWC, 2022) recommends a design-comparable effect size (D-CES; i.e., gAB) to gauge an intervention in single-case experimental design (SCED) studies, or to synthesize findings in meta-analysis. So far, no research has examined gAB's performance under non-normal distributions. This study expanded Pustejovsky et al. (2014) to investigate the impact of data distributions, number of cases (m), number of measurements (N), within-case reliability or intra-class correlation (ρ), ratio of variance components (λ), and autocorrelation (ϕ) on gAB in multiple-baseline (MB) design. The performance of gAB was assessed by relative bias (RB), relative bias of variance (RBV), MSE, and coverage rate of 95% CIs (CR). Findings revealed that gAB was unbiased even under non-normal distributions. gAB's variance was generally overestimated, and its 95% CI was over-covered, especially when distributions were normal or nearly normal combined with small m and N. Large imprecision of gAB occurred when m was small and ρ was large. According to the ANOVA results, data distributions contributed to approximately 49% of variance in RB and 25% of variance in both RBV and CR. m and ρ each contributed to 34% of variance in MSE. We recommend gAB for MB studies and meta-analysis with N ≥ 16 and when either (1) data distributions are normal or nearly normal, m = 6, and ρ = 0.6 or 0.8, or (2) data distributions are mildly or moderately non-normal, m ≥ 4, and ρ = 0.2, 0.4, or 0.6. The paper concludes with a discussion of gAB's applicability and design-comparability, and sound reporting practices of ES indices.

Using random forest to predict antimicrobial minimum inhibitory concentrations of nontyphoidal Salmonella in Taiwan.

Antimicrobial resistance (AMR) is a global health issue and surveillance of AMR can be useful for understanding AMR trends and planning intervention strategies. Salmonella, widely distributed in food-producing animals, has been considered the first priority for inclusion in the AMR surveillance program by the World Health Organization (WHO). Recent advances in rapid and affordable whole-genome sequencing (WGS) techniques lead to the emergence of WGS as a one-stop test to predict the antimicrobial susceptibility. Since the variation of sequencing and minimum inhibitory concentration (MIC) measurement methods could result in different results, this study aimed to develop WGS-based random forest models for predicting MIC values of 24 drugs using data generated from the same laboratories in Taiwan. The WGS data have been transformed as a feature vector of 10-mers for machine learning. Based on rigorous validation and independent tests, a good performance was obtained with an average mean absolute error (MAE) less than 1 for both validation and independent test. Feature selection was then applied to identify top-ranked 10-mers that can further improve the prediction performance. For surveillance purposes, the genome sequence-based machine learning methods could be utilized to monitor the difference between predicted and experimental MIC, where a large difference might be worthy of investigation on the emerging genomic determinants.

Reactive Magnesium Nitride Additive: A Drop-in Solution for Lithium/Garnet Wetting in All-Solid-State Batteries.

Garnet oxides such as Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) are promising solid electrolyte materials for all-solid-state lithium-metal batteries because of high ionic conductivity, low electronic leakage, and wide electrochemical stability window. While LLZTO has been frequently discussed to be stable against lithium metal anode, it is challenging to achieve and maintain good solid-on-solid wetting at the metal/ceramic interface in both processing and extended electrochemical cycling. Here we address the challenge by a powder-form magnesium nitride additive, which reacts with the lithium metal anode to produce well-dispersed lithium nitride. The in situ formed lithium nitride promotes reactive wetting at the Li/LLZTO interface, which lowers interfacial resistance, increases critical current density (CCD), and improves cycling stability of the electrochemical cells. The additive recipe has been diversified to titanium nitride, zirconium nitride, tantalum nitride, and niobium nitride, thus supporting the general concept of reactive dispersion-plus-wetting. Such a design can be extended to other solid-state devices for better functioning and extended cycle life.

Facile Tandem Copolymerization of O-Carboxyanhydrides and Epoxides to Synthesize Functionalized Poly(ester-b-carbonates).

The synthesis of well-defined degradable block copolymers from mixtures of monomers is one of the foremost challenges in the sustainable plastics industry. For example, the currently available one-pot strategies for preparing poly(ester-co-carbonates)─which combine two commonly used degradable polymers─are energy- and material-intensive, requiring high-pressure CO2 gas and elevated temperatures. Here, we report an atom-economical, scalable method for block copolymerization of O-carboxyanhydrides (OCAs) and epoxides to prepare functionalized poly(ester-b-carbonates) with high molecular weights (MWs) (>200 kDa) and narrow MW distributions (D̵ < 1.1) by using a single Lewis acidic zinc complex at room temperature in the absence of pressurized CO2. Kinetic studies showed that the first stage of the process, ring-opening polymerization of the OCAs, exhibited zero-order kinetics, suggesting that the polymerization rate was independent of monomer concentration and thus allowing for a sharp switch in mechanism without the tapering effect. The obtained degradable poly(ester-b-carbonates) showed better toughness than their corresponding homopolymers and outperformed some commodity polyolefins.

Excellent Li/Garnet Interface Wettability Achieved by Porous Hard Carbon Layer for Solid State Li Metal Battery.

Garnet-type Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) electrolyte is considered as a promising solid electrolyte because of its relatively high ionic conductivity and excellent electrochemical stability. The surface contamination layer and poor Li/LLZTO interface contact cause large interfacial resistance and quick Li dendrite growth. In this paper, a porous hard carbon layer is introduced by the carbonization of a mixed layer of phenolic resin and polyvinyl butyral on the LLZTO surface to improve Li/garnet interfacial wettability. The multi-level pore structure of the hard carbon interlayer provides capillary force and large specific surface area, which, together with the chemical activity of the carbon material with Li, promote the molten Li infiltration with garnet electrolyte. The Li/LLZTO interface delivers a low interfacial resistance of 4.7 Ω∙cm2 at 40 °C and a higher critical current density, which can achieve stable Li+ conduction for over 800 h under current densities of 0.1 and 0.2 mA∙cm-2 . The solid-state battery coupled with Li and LiFePO4 exhibits excellent rate and cycling performance, demonstrating the application feasibility of the hard carbon interlayer for a solid state Li metal battery.

Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy.

Cancer-associated fibroblasts (CAFs) can either suppress or support T lymphocyte activity, suggesting that CAFs may be reprogrammable to an immunosupportive state. Angiotensin receptor blockers (ARBs) convert myofibroblast CAFs to a quiescent state, but whether ARBs can reprogram CAFs to promote T lymphocyte activity and enhance immunotherapy is unknown. Moreover, ARB doses are limited by systemic adverse effects such as hypotension due to the importance of angiotensin signaling outside tumors. To enhance the efficacy and specificity of ARBs in cancer with the goal of revealing their effects on antitumor immunity, we developed ARB nanoconjugates that preferentially accumulate and act in tumors. We created a diverse library of hundreds of acid-degradable polymers and chemically linked ARBs to the polymer most sensitive to tumor pH. These tumor microenvironment-activated ARBs (TMA-ARBs) remain intact and inactive in circulation while achieving high concentrations in tumors, wherein they break down to active ARBs. This tumor-preferential activity enhances the CAF-reprogramming effects of ARBs while eliminating blood pressure-lowering effects. Notably, TMA-ARBs alleviate immunosuppression and improve T lymphocyte activity, enabling dramatically improved responses to immune-checkpoint blockers in mice with primary as well as metastatic breast cancer.

Resilient Poly(α-hydroxy acids) with Improved Strength and Ductility via Scalable Stereosequence-Controlled Polymerization.

Despite the degradability and biocompatibility of poly(α-hydroxy acids), their utility remains limited because their thermal and mechanical properties are inferior to those of commodity polyolefins, which can be attributed to the lack of side-chain functionality on the polyester backbone. Attempts to synthesize high-molecular-weight functionalized poly(α-hydroxy acids) from O-carboxyanhydrides have been hampered by scalability problems arising from the need for an external energy source such as light or electricity. Herein, we report an operationally simple, scalable method for the synthesis of stereoregular, high-molecular-weight (>200 kDa) functionalized poly(α-hydroxy acids) by means of controlled ring-opening polymerization of O-carboxyanhydrides mediated by a highly redox reactive manganese complex and a zinc-alkoxide. Mechanistic studies indicated that the ring-opening process likely proceeded via the Mn-mediated decarboxylation with alkoxy radical formation. Gradient copolymers produced directly by this method from mixtures of two O-carboxyanhydrides exhibited better ductility and toughness than their corresponding homopolymers and block copolymers, therefore highlighting the potential feasibility of functionalized poly(α-hydroxy acids) as ductile and resilient polymeric materials.

Curcuma's extraction attenuates propranolol-induced psoriasis like in mice by inhibition of keratin, proliferating cell nuclear antigen and toll-like receptor expression.

Curcuma was the dried rhizomes of Curcuma kwangsiensis S.G. Lee et C.F. Liang (Chinese name: e zhu), have been used in China for thousands of years. There are some reports have shown that curcumin, the major component of curcuma, has a good curative effect on psoriasis, but the mechanism is still unknown, so the present study was designed to investigate the effect of curcuma's extraction on psoriasis-like mouse, and to explore the mechanisms of therapy. First, we observed that curcuma's extractions effect on mitosis of mouse vaginal epithelial cells; then making psoriasis like model and measuring the score of skin damage on days 7 and 14; finally, we observed the expression of immune factors (CK14, CK16, CK17, PCNA, TLR-2, TLR-4, TLR-9) in propranolol induced psoriasis like rats. Curcuma's extraction prohibited the mitosis of mouse vaginal epithelial cells; curcuma's extractions have a significantly efficacy and dose dependent inhibition on imiquimod induced psoriasis like rats; and the expression of immune factors (CK14, CK16, CK17, PCNA, TLR-2, TLR-4, TLR-9) was decreasing in the curcuma's extraction treated groups compared with normal groups. Our research proved that curcuma's extractions have a significantly efficacy on psoriasis like rats, thus, curcuma's extractions can be a potential novel treatment for psoriasis. Furthermore, the expression of immune factors was decreasing after treatment with curcuma's extraction suggest us cytokines has strong relation with the mechanism of therapy for psoriasis. Our results contribute towards validation of curcuma in the treatment of psoriasis and other joint disorders.

New Strategies in Cancer Nanomedicine.

We review recent progress in cancer nanomedicine, including stimulus-responsive drug delivery systems and nanoparticles responding to light for phototherapy or tumor imaging. In addition, several new strategies to improve the circulation of nanoparticles in vivo, tumor penetration, and tumor targeting are discussed. The application of nanomedicine in cancer immunology, a relatively new type of cancer therapy, is also highlighted.

Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis.

Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam-functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo-NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.

Outcomes of laparoscopic subtotal colectomy with cecorectal anastomosis for slow-transit constipation: a single center retrospective study.

PURPOSE: To study the safety and efficacy of laparoscopic subtotal colectomy (LASC) with cecorectal anastomosis for slow-transit constipation (STC). METHODS: This study was a retrospective review of all patients undergoing LASC with cecorectal anastomosis for STC between March 2010 and May 2017. The main variables included the operative time, blood loss, length of postoperative hospital stay, complications, and long-term outcomes. RESULTS: In this analysis, 56 patients were included. There were 17 males and 39 females aged between 34 and 80 years old. The mean operative time was 208 ± 21 min, and the mean perioperative blood loss was 116 ± 48 mL. The mean postoperative hospital stay was 7.7 ± 3.5 days, and the incidence of perioperative complications was 19.6%, with no mortality. One patient required reoperation because of intra-abdominal bleeding. During the follow-up period, 26.8% of patients suffered from chronic pain and bloating, with no recurrence of STC. The causes of these symptoms included small bowel obstruction (7.1%), slow transit (10.7%), anastomotic stenosis (5.4%) and gastroptosis (3.6%). Postoperatively, after 12 months, the frequency of defecation was 2-4 times per day. Patients with follow-up of at least 60 months, the mean frequency of defecation was 0.9 ± 0.5 times per day. The percentage of satisfaction was 82.1%. CONCLUSION: LASC with cecorectal anastomosis is a safe and effective surgical approach for STC, with the majority of patients being satisfied with the outcome of surgery.

Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin.

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

A validated LC-MS/MS method for the determination of senkyunolide I in dog plasma and its application to a pharmacokinetic and bioavailability studies.

Senkyunolide I is one of the major bioactive components in the herbal medicine Ligusticum chuanxiong. The aim of this study was to develop and validate a fast, simple and sensitive LC-MS/MS method for the determination of senkyunolide I in dog plasma. The plasma samples were processed with acetonitrile and separated on a Waters Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 µm). The mobile phase consisted of 0.1% formic acid aqueous and acetonitrile was delivered at a flow rate of 0.3 mL min-1 . The detection was achieved in the positive selected reaction monitoring mode with precursor-to-product transitions at m/z 225.1 → 161.1 for senkyunolide I and at m/z 349.1 → 305.1 for an internal standard. The assay was linear over the tested concentration range, from 0.5 ng mL-1 to 1000 ng mL-1 , with a correlation coefficient >0.9992. The mean extraction recovery from dog plasma was within the range of 85.78-93.25%, while the matrix effect of the analyte was within the range of 98.23-108.89%. The intra- and inter-day precisions (RSD) were <12.12% and the accuracy (RR) ranged from 98.89% to 104.24%. The validated assay was successfully applied to pharmacokinetic and bioavailability studies of senkyunolide I in dogs. The results demonstrated that (a) senkyunolide I showed short elimination half-life (<1 h) in dog, (b) its oral bioavailability was >40% and (c) senkyunolide I showed dose-independent pharmacokinetic profiles in dog plasma over the dose range of 1-50 mg kg-1 .

Simultaneous determination of 20(S)-protopanaxadiol and its three metabolites in rat plasma by LC-MS/MS: application to their pharmacokinetic studies.

The aim of this study was to develop an LC-MS/MS method for simultaneous determination of 20(S) protopanaxadiol (PPD) and its three metabolites, PPD-glucuronide (M1), (20S,24S)-epoxy-dammarane-3,12,25-triol (M2) and (20S,24R)-epoxydammarane-3,12,25-triol (M3), in rat plasma. Precipitation with acetonitrile was employed for sample preparation and chromatographic separations were achieved on a C18 column. The sample was detected using triple quadrupole tandem mass spectrometer with selected reaction monitoring mode. The monitored precursor-to-product ion transitions were m/z 459.4 → 375.3 for PPD, m/z 635.4 → 113.0 for M1, m/z 477.4 → 441.4 for M2 and M3 and m/z 475.4 → 391.3 for IS. The developed assay was validated according to the guidelines of the US Food and Drug Administration. The calibration curves showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 1 ng/mL for all analytes. The intra- and inter-day precisions (RSD) were < 9.51% while the accuracy (RE) ranged from -8.91 to 12.84%. The extraction recovery was >80% and no obvious matrix effect was detected. The analytes were stable in rat plasma with the RE ranging from -12.34 to 9.77%. The validated assay has been successfully applied to the pharmacokinetic study of PPD as well as its metabolites in rat plasma. According to the pharmacokinetic parameters, the in vivo exposures of M1, M2 and M3 were 11.91, 47.95 and 22.62% of that of PPD, respectively.

Controlled Photoredox Ring-Opening Polymerization of O-Carboxyanhydrides.

Poly(α-hydroxy acids) are important biodegradable polymers with wide applications. Attempts to synthesize them from O-carboxyanhydrides with pendant functional groups by various methods, including methods involving organocatalysts or organometallics, have been plagued by uncontrolled polymerization, including epimerization for some monomers, which hampers the preparation of stereoregular high-molecular-weight polymers. Herein we describe an effective protocol that combines photoredox Ni/Ir catalysis with the use of a Zn-alkoxide for efficient ring-opening polymerization, allowing for the synthesis of isotactic polyesters with expected molecular weights (>140 kDa) and narrow molecular weight distributions (Mw/Mn < 1.1). Mechanistic studies indicate that the use of a low temperature (-20 °C) and photoredox Ni/Ir catalysis synergistically accelerates ring-opening and decarboxylation of the monomer for chain propagation while avoiding the formation of the undesired Ni-carbonyl complex.

Aptamer photoregulation in vivo.

The in vivo application of aptamers as therapeutics could be improved by enhancing target-specific accumulation while minimizing off-target uptake. We designed a light-triggered system that permits spatiotemporal regulation of aptamer activity in vitro and in vivo. Cell binding by the aptamer was prevented by hybridizing the aptamer to a photo-labile complementary oligonucleotide. Upon irradiation at the tumor site, the aptamer was liberated, leading to prolonged intratumoral retention. The relative distribution of the aptamer to the liver and kidney was also significantly decreased, compared to that of the free aptamer.