Natural Derivatives of Selective HDAC8 Inhibitors with Potent in Vivo Antitumor Efficacy against Breast Cancer.

HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 µM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.

Bipyridine Derivatives as NOP2/Sun RNA Methyltransferase 3 Inhibitors for the Treatment of Colorectal Cancer.

Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3 inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.

Metabolic surgery results in greater metabolic benefits in patients who achieve healthy weight.

BACKGROUND: A percentage of total weight loss (%TWL) >20% as the expected weight loss target after metabolic surgery might be insufficient to produce adequate metabolic benefits. OBJECTIVES: This study identified the optimal weight loss target to achieve substantial benefits from metabolic surgery. SETTING: University-affiliated tertiary care center. METHODS: In this retrospective study, participants were categorized into healthy weight (18.5 kg/m2 ≤ body mass index [BMI] < 24 kg/m2), overweight (24 kg/m2 ≤ BMI < 28 kg/m2), and obesity groups (BMI ≥28 kg/m2) according to their BMI 1 year after metabolic surgery. The weight loss and remission of obesity-related comorbidities were evaluated. Ordinal logistic regression analysis was used to identify predictors for achieving healthy weight 1 year postoperatively. RESULTS: Overall, 125 patients (112 sleeve gastrectomies, 13 Roux-en-Y gastric bypasses) were recruited in this study. Forty-two participants achieved healthy weight, 38 were overweight, and 45 had obesity. Type 2 diabetes mellitus and obstructive sleep apnea were relieved in all groups. Individuals who achieved healthy weight showed more improvements in nonalcoholic fatty liver disease, hypertension, and hyperuricemia than those who did not. Preoperative BMI was an independent predictor for the BMI achieved postoperatively, and the optimal cut-off point for achieving healthy weight was 34.9 kg/m2. CONCLUSIONS: Healthy weight was a more stringent target for patients who underwent metabolic surgery than the %TWL. Populations with a preoperative BMI of <34.9 kg/m2 were prone to realize the goal. Additional weight loss interventions could be considered for those with higher preoperative BMIs and enforced within 1 year postoperatively.

Cytotoxic and Antifungal Staurosporine Derivatives from Marine-Derived Actinomycete Streptomyces sp. ZS-A121.

A novel staurosporine derivate, streptomholyrine A (1), along with 6 known compounds were identified from the rice-based solid fermentation of marine-derived Streptomyces sp. ZS-A121. The planar structure and absolute configuration of streptomholyrine A were elucidated using a combination of 1D, 2D NMR, HRESIMS data analysis, chemical transformation, ECD and NMR calculations. Screening of all these compounds revealed their cytotoxic activity against HCT-116 cell lines, with IC50 values ranging from 0.012 to 11.67 µM, except for the known 1H-indole-3-hydroxyacetyl, which showed no inhibition activity. Furthermore, streptomholyrine A, along with two known staurosporine derivatives, k252d and staurosporine, exhibited activities against Candida albicans, with MICs of 12.5, 25.0 and 50.0 µg/ml, respectively.

Chronic intermittent hypoxia contributes to non-alcoholic steatohepatitis progression in patients with obesity.

BACKGROUND AND PURPOSE: The association between the severity of obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in patients with obesity remains unclear. We conducted this study to determine the effects of OSA on the severity of NAFLD in individuals with obesity and its link to the development of non-alcoholic steatohepatitis (NASH). METHODS: Patients were subjected to standard polysomnography up to 1 week before undergoing bariatric surgery, during which liver biopsy specimens were obtained. The apnea-hypopnea index (AHI) obtained by polysomnography was used to determine the severity of OSA. RESULTS: In total, 183 patients with obesity and biopsy-confirmed NAFLD were included; 49 (27%) had NASH. Patients with NASH had higher AHIs (p = 0.014) and oxygen desaturation indices (p = 0.031), more frequent OSA (p = 0.001), and lower minimum oxygen saturation (p = 0.035). The severity of OSA was directly correlated with the NAFLD activity score (p < 0.001), NASH activity grade (p < 0.001), semi-quantitative indices of lobular inflammation (p = 0.001), and hepatocyte ballooning (p = 0.006). The odds ratios (95% confidence intervals) for NASH and severe NASH (activity grade ≥ 3) associated with moderate-to-severe OSA were 3.85 (1.35-10.94; p < 0.05) and 5.02 (1.66-15.18; p < 0.01), respectively, after adjusting for sex, age, body mass index, waist circumference, insulin resistance values, and metabolic syndrome. CONCLUSIONS: Chronic intermittent hypoxia caused by OSA may aggravate NAFLD and lead to a higher risk of NASH in patients with obesity.

PMMA Bone Cement Composite Functions as an Adjuvant Chemotherapeutic Platform for Localized and Multi-Window Release during Bone Reconstruction.

Primary bone tumor resections often result in critical size defects, which then necessitate challenging clinical management approaches to reconstruct. One such intervention is the Masquelet technique, in which poly(methyl methacrylate) (PMMA) bone cement is placed as a spacer temporarily while adjuvant chemotherapeutics are administered systemically. The spacer is later removed and replaced with bone autograft. Local recurrence remains an important and devastating problem, therefore, a system capable of locally delivering chemotherapeutics will present unique advantages. In this work, a refillable chemotherapeutic (doxorubicin, DOX) delivery platform comprised of PMMA bone cement and insoluble γ-cyclodextrin (γ-CD) polymeric microparticles is developed and explored towards application as a temporary adjuvant chemotherapeutic spacer. The system is characterized for porosity, mechanical strength, DOX filling and refilling capacity, elution kinetics, and cytotoxicity. Since residual chemotherapeutics can adversely impact bone healing, it is important that virtually all DOX be released from material. Composites containing 15 wt% γ-CD microparticles demonstrate 100% DOX release within 100 days, whereas only 6% DOX is liberated from PMMA with free DOX over same period. Refillable properties of PMMA composite system may find utility for customizing dosing regimens. Findings suggest that PMMA composites can have potential as chemotherapeutic delivery platforms to assist in bone reconstruction.

Are Chinese Patients with Type 2 Diabetes and a Body Mass Index of 27.5-32.5 kg/m2 Suitable for Metabolic Surgery? A One-Year Post-Surgery Study.

INTRODUCTION: The aim of this study was to clarify the efficacy and safety of metabolic surgery in Chinese patients with type 2 diabetes mellitus (T2DM) and a body mass index (BMI) of 27.5-32.5 kg/m2. METHODS: A total of 99 patients with T2DM were enrolled in this retrospective cohort study. Of these patients, 53 had a BMI of 27.5-32.5 kg/m2 and had undergone metabolic surgery (n = 21) or were on conventional antidiabetic therapy (n = 32)]; 46 had a BMI ≥ 32.5 kg/m2 and all had undergone metabolic surgery. Primary endpoints included the triple endpoint [hemoglobin A1c < 6.5%, low-density lipoprotein cholesterol (LDL-C) < 2.6 mmol/L, and systolic blood pressure (SBP) < 130 mmHg] and successful weight loss 1 year later. Remission of diabetes, glucose and lipid metabolism, medication usage, and adverse events were evaluated. RESULTS: Of patients with BMI 27.5-32.5 kg/m2 undergoing metabolic surgery, 33.33% achieved the composite endpoints, and 100% achieved successful weight loss. This result was similar to that in patients with BMI ≥ 32.5 and better than those with BMI 27.5-32.5 kg/m2 receiving conventional antidiabetic therapy. A significant and similar reduction in BMI, waist circumference, SBP, serum LDL-C, hemoglobin A1c, and uric acid, as well as similar frequency postoperative adverse events, were confirmed in both metabolic surgery groups. Patients with BMI 27.5-32.5 kg/m2 who had undergonemetabolic surgery showed more metabolic improvement than those only receiving medications but they experienced more adverse events. CONCLUSION: A BMI cutoff of 27.5 kg/m2 for metabolic surgery may be suitable for Chinese patients with T2DM.

The combined effects of elevated atmospheric CO2 and cadmium exposure on flavonoids in the leaves of Robinia pseudoacacia L. seedlings.

Flavonoids participate in several plant processes such as growth and physiological protection in adverse environments. In this study, we investigated the combined effects of eCO2 and cadmium (Cd)-contaminated soils on the total flavonoid and monomer contents in the leaves of Robinia pseudoacacia L. seedlings. Elevated CO2, Cd, and eCO2+ Cd increased the total flavonoids in the leaves relative to the control, and eCO2 mostly increased (p < 0.05) the total flavonoid content under Cd exposure. Elevated CO2 increased (p < 0.05) robinin, rutin, and acacetin contents in the leaves of 45-day seedlings and decreased (p < 0.05) the content of robinin and acacetin at 90 and 135 d under Cd exposure except for robinin at day 45 under Cd1 and acacetin on day 135 under Cd1. Quercetin content decreased (p < 0.05) under the combined conditions relative to Cd alone. Kaempferol in the leaves was only detected under eCO2 on day 135. The responses of total chlorophyll, total soluble sugars, starch, C, N, S, and the C/N ratio in the leaves to eCO2 significantly affected the synthesis of total flavonoids and monomers under Cd exposure. Overall, rutin was more sensitive to eCO2+ Cd than the other flavonoids. Cadmium, CO2, and time had significant interactive effects on the synthesis of flavonoids in the leaves of R. pseudoacacia L. seedlings. Elevated CO2 may improve the protection and defense system of seedlings grown in Cd-contaminated soils by promoting the synthesis of total flavonoids, although robinin, rutin, quercetin, and acacetin yields may reduce with time. Additionally, increased Cd in the leaves suggested that eCO2 could improve the phytoremediation of Cd-contaminated soils.

Effects of elevated CO2 on arbuscular mycorrhizal fungi associated with Robinia pseudoacacia L. grown in cadmium-contaminated soils.

As symbionts capable of reciprocal rewards, arbuscular mycorrhizal fungi (AMF) can alleviate heavy metal toxicity to host plants and are easily influenced by elevated CO2 (ECO2). Although the individual effects of ECO2 and cadmium (Cd) on AMF have been widely reported, the response of AMF to ECO2 + Cd receives little attention. We evaluated the combined effects of ECO2 and Cd on AMF in the rhizosphere soil and roots of Robinia pseudoacacia L. seedlings. Under ECO2 + Cd relative to Cd, AMF gene copies and richness in rhizosphere soils increased (p < 0.05) and the diversity reduced (p < 0.05) at 4.5 mg Cd kg-1 dry soil; whereas root AMF abundance at 4.5 mg Cd kg-1 dry soil and the diversity and richness reduced (p < 0.05). Elevated CO2 caused obvious differences in the dominant genera abundance between rhizosphere soils and roots upon Cd exposure. Responses of C, water-soluble organic nitrogen (WSON), pH, and diethylene triamine penta-acetic acid (DTPA)-Cd in rhizosphere soils and root N to ECO2 shaped dominant genera in Cd-polluted rhizosphere soils. Levels of DTPA-Cd, WSON, C and pH in rhizosphere soils and C/N ratio, N, and Cd in roots to ECO2 affected (p < 0.05) dominant genera in roots under Cd exposure. AMF richness and diversity were lower in roots than in rhizosphere soils. Elevated CO2 altered AMF communities in rhizosphere soils and roots of R. pseudoacacia seedlings exposed to Cd. AMF associated with R. pseudoacacia may be useful/interesting to be used for improving the phytoremediation of Cd under ECO2.