Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects.

Cardiovascular diseases (CVDs) persist as the predominant cause of mortality, urging the exploration of innovative pharmaceuticals. Mitochondrial dysfunction stands as a pivotal contributor to CVDs development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase known for its crucial role in protecting mitochondria against damage and dysfunction, has emerged as a promising therapeutic target for CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated in vivo using a zebrafish model, establishing a deduced structure-activity relationship. Among these, derivative 5v exhibited significant efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine models. Subsequent investigations revealed that 5v selectively elevated SIRT3 expression, leading to the upregulation of SOD2 and OPA1 expression, effectively preventing mitochondrial dysfunction, mitigating oxidative stress, and preserving cardiomyocyte viability. As a novel structural class of SIRT3 activators with robust therapeutic effects, 5v emerges as a promising candidate for further drug development.

Synthesis and neuroprotective effects of new genipin derivatives against glutamate-induced oxidative damage.

Glutamate-induced oxidative stress is well-known to play a crucial role in the development of neurodegenerative diseases, such as stroke. Genipin, a natural iridoid compound, has demonstrated potential neuroprotective properties but is unstable in physiological conditions. The present study aimed to develop new derivatives of genipin that exhibit improved stability and activity for the treatment of stroke. Nineteen new derivatives were thus designed and synthesized. Their neuroprotective effect against glutamate-induced injury was evaluated in HT22 cells. Among the newly synthesized derivatives, 3e demonstrated significantly greater neuroprotection and improved stability compared to genipin. Specifically, 0.01 µM of 3e was found to effectively attenuate glutamate-induced oxidative damage by inhibiting ROS over-accumulation, reducing MDA content, and restoring the endogenous antioxidative system. Further investigation revealed that 3e inhibited oxidative stress by downregulating the phosphorylation levels of p38 MAPK and activating Nrf2 and HO-1 proteins. These results suggested that 3e has the potential to serve as a promising candidate for the treatment of stroke by protecting against glutamate-induced oxidative stress.

M@C78 (M = U, Th): Inherent Topological Connectivity Existed in Thermodynamically Stable Isomers and the Possibility of an Endohedral Fullerene Containing One Heptagon Ring.

The density functional theory combined with statistical thermodynamic analyses of M@C78 (M = U and Th) demonstrated that four isomers, M@D3h(24109)-C78, M@C2v(24107)-C78, M@C1(22595)-C78, and M@C1(23349)-C78, and a nonclassical isomer, M@C1(id7)-C78, containing one heptagon ring possess outstanding thermodynamic stabilities in the two M@C78 series. Especially, the M@C1(id7)-C78 isomer is the first nonclassical C78 fullerene that can exist stably. Importantly, these five fullerene cages are found to be related in the form of Stone-Wales (SW) transformations. Geometric analyses disclosed that, unlike lanthanide metals, actinide metals are more likely to bond with sumanene-type hexagonal rings when they are encapsulated in IPR C78 cages. Frontier molecular orbital analysis showed that both U and Th atoms donate four electrons to the C78 carbon cages.

Discovery of New D-Ring Modified Isosteviol Derivatives as Potent Cardioprotective Agents against Oxidative Stress-Trigged Damage.

Cardiovascular diseases (CVDs) are a major global health concern, and oxidative stress is known to play a central role in their pathogenesis. The identification of new agents capable of inhibiting oxidative stress presents a promising strategy for preventing and treating CVDs. Natural products and their derivatives offer a valuable source for drug discovery, and isosteviol, a readily available natural product, is known to exhibit cardioprotective effects. In this study, 22 new D-ring modified isosteviol derivatives were synthesized and evaluated for their cardioprotective effect in vivo using the zebrafish cardiomyopathy model. The findings revealed that derivative 4e exhibited the most potent cardioprotective effect, surpassing its parent compound isosteviol and the positive drug levosimendan. At 1 µM, derivative 4e significantly protected the cardiomyocytes from injury, while at 10 µM it effectively maintained normal heart phenotypes, preventing cardiac dysfunction in zebrafish. Further investigation demonstrated that 4e protected cardiomyocytes from oxidative stress-induced damage by inhibiting reactive oxygen species overaccumulation, activating superoxide dismutase 2 expression, and enhancing the endogenous antioxidant defense system. These results suggest that isosteviol derivatives, particularly 4e, have the potential to serve as a novel class of cardioprotective agents for the prevention and treatment of CVDs.

The Clinical Diagnostic Value of Lumbar Intervertebral Disc Herniation Based on MRI Images.

MRI was used to measure the changes in the angle of the facet joints of the lumbar spine and analyze the relationship between it and the herniated lumbar intervertebral disc. Analysis of the causes of lumbar disc herniation from the anatomy and morphology of the spine provides a basis for the early diagnosis and prevention of lumbar disc herniation. There is a certain correlation between the changes shown in MRI imaging of lumbar disc herniation and the TCM syndromes of lumbar intervertebral disc herniation. There is a correlation between the syndromes of lumbar disc herniation and the direct signs of MRI: pathological type, herniated position, and degree of herniation. Indirect signs with MR, nerve root compression and dural sac compression, are related. The MRI examination results can help syndrome differentiation to improve its accuracy to a certain extent. MRI has high sensitivity for the measurement of the angle of the facet joints of the lumbar spine and can be used to study the correlation between the changes of the facet joint angles and the herniated disc. Facet joint asymmetry is closely related to lateral lumbar disc herniation, which may be one of its pathogenesis factors. The herniated intervertebral disc is mostly on the sagittal side of the facet joint, and the facet joint angle on the side of the herniated disc is more sagittal. The asymmetry of the facet joints is not related to the central lumbar disc herniation, and the angle of the facet joints on both sides of the central lumbar disc herniation is partial sagittal.

Physicochemical, functional and structural properties of the major protein fractions extracted from Cordyceps militaris fruit body.

The physicochemical and functional as well as structural properties of major protein fractions (albumin, globulin, glutelin) sequentially extracted in water, salt, alkaline solution respectively from Cordyceps militaris Minfu20 fruit body were investigated. The glutelin (43.11%, w/w) was the predominant protein component of C. militaris fruit body followed by albumin (36.47%) and globulin (17.94%). The three proteins extracted from different solvents showed different characteristics, which were related to the alternation of amino acid composition, surface hydrophobicity, and structural feature. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that the albumin and globulin mainly consisted of polypeptides with size < 20 kDa. The glutelin showed serious staining on the lane which may have a relatively bigger molecular weight. Intrinsic fluorescence intensity (FI) suggested glutelin contained more unfolding conformations (highest FI) which were probably resulted in a better foaming capacity of 151% and emulsion formation with the smallest size oil droplets (10.410 µm). The protein fractions showed great nutritional quality since they satisfied all recommended essential amino acid allowances for adults of Food & Agriculture Organization (FAO)/World Health Organization (WHO). Therefore, Cordyceps militaris Minfu20 fruit body proteins have potential alternative renewable edible fungi (mushroom) protein and could be used effectively as a food ingredient to improve food nutrition and product diversification compared with plant proteins.

Rapid fabrication of TiO2@carboxymethyl cellulose coatings capable of shielding UV, antifog and delaying support aging.

Agricultural plastic films capable of shielding UV, filtering visible light and antifog are important to prolong their life and protect safeties of agriculturists and crops. In this work, high stable and small size TiO2@polymer nanoparticles (NPs) were prepared by an efficient one-pot microwave synthesis using titanic sulfate as Ti resource, carboxymethyl cellulose sodium (CMC) as complexing agent and stabilizer. The TiO2@CMC NPs obtained were then utilized to fabricate poly(ethylene imine) (PEI)/TiO2@CMC coatings on the surface of polypropylene films by a layer-by-layer assembly technique. The TiO2@CMC NPs show rapid deposition rate because small, spherical and anion-rich TiO2@CMC NPs possess large specific surface area and fast diffusion rate. More importantly, property experiments confirm that (PEI/TiO2@CMC)*15 coatings can not only effectively shield UV rays, filter visible light and prevent fogging but also delay the aging of their supports.

[Effect of diubiquitin gene silencing by small interfering RNA on proliferation and invasion of tongue carcinoma Tca8113 cells].

OBJECTIVE: To study the effect of diubiquitin (FAT10) down-regulation by small interfering RNA-mediated RNA interference (RNAi) on the biological features of tongue carcinoma cell line Tca8113. METHODS: Tca8113 cells were transfected with synthetic small interfering RNA (siRNA) targeting FAT10. Expression of FAT10 mRNA and protein were respectively measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, transfection efficiencies were monitored. The distribution of cell cycle phases was determined using flow cytometry. The proliferative and invasive ability of Tca8113 cells in vitro was evaluated by the colony-forming unit assay and Transwell migration assay respectively. RESULTS: Both FAT10 mRNA and protein expression were significantly decreased in the experimental group (pU-FAT10-siRNA: mRAN 0.36 ± 0.03, Protein 0.39 ± 0.04) compared with controls ( CONTROL: mRNA 0.95 ± 0.05, Protein 0.69 ± 0.05; pU-siRNA: mRNA 0.92 ± 0.07, Protein 0.64 ± 0.05) (P < 0.05). The cell cycle was arrested in the G(1) phase [pU-FAT10-siRNA: (72.45 ± 5.81)%, CONTROL: (45.95 ± 3.80)%, pU-siRNA: (45.95 ± 3.80)%]. The proliferation and invasiveness of treated Tca8113 cells were inhibited in vitro (pU-FAT10-siRNA: 41.83 ± 8.19, CONTROL: 317.21 ± 69.48, pU-siRNA: 339.36 ± 73.84). CONCLUSIONS: Delivery of siRNA targeting FAT10 seems efficient in down-regulating FAT10 expression and diminishing the growth, proliferation and invasiveness of Tca8113 cells, suggesting that siRNA-based strategy targeting FAT10 may lay a foundation for the clinical management of tongue carcinoma.