Hypertensive nephropathy is a chronic kidney disease caused by hypertension. Eicosapentaenoic acid (EPA) has been reported to possess an antihypertensive effect, and our previous study suggested that ...EPA-enriched phospholipid (EPA-PL) had more significant bioactivities compared with traditional EPA. However, the effect of dietary EPA-PL on hypertensive nephropathy has not been studied. The current study was designed to examine the protection of EPA-PL against kidney damage in spontaneously hypertensive rats (SHRs). Treatment with EPA-PL for three weeks significantly reduced blood pressure through regulating the renin-angiotensin system in SHRs. Moreover, dietary EPA-PL distinctly alleviated kidney dysfunction in SHRs, evidenced by reduced plasma creatinine, blood urea nitrogen, and 24 h proteinuria. Histology results revealed that treatment of SHRs with EPA-PL alleviated renal injury and reduced tubulointerstitial fibrosis. Further mechanistic studies indicated that dietary EPA-PL remarkably inhibited the activation of TGF-β and Smad 3, elevated the phosphorylation level of PI3K/AKT, suppressed the activation of NF-κB, reduced the expression of pro-inflammatory cytokines, including IL-1β and IL-6, and repressed the oxidative stress and the mitochondria-mediated apoptotic signaling pathway in the kidney. These results indicate that EPA-PL has potential value in the prevention and alleviation of hypertensive nephropathy.
Eicosapentaenoic acid (EPA)-enriched phosphoethanolamine plasmalogens (EPA-PlsEtns) might be retained in the intestine rich in gut microbiota for a long time after treatment. It reminded us that ...EPA-PlsEtns might affect intestinal microbiota composition and its metabolites, which have been identified as a contributing factor in the development of cardiovascular diseases. In the present study, EPA-PlsEtn administration for 8 weeks significantly reduced the atherosclerotic lesion area in low-density lipoprotein receptor deficient (LDLR–/–) mice. Notably, the serum total cholesterol and low-density lipoprotein cholesterol levels were significantly reduced by 33.6 and 38.2%, respectively, by EPA-PlsEtns instead of EPA in the form of ethyl ester (EPA-EE) treatment compared with the model group. EPA-PlsEtn administration also increased total neutral sterol and bile acids in feces by 92 and 39%, respectively, rather than EPA-EE. Mechanistically, EPA-PlsEtns might affect the abundance of gut microbiota contributing to the alteration of bile acid profiles, which might further accelerate bile acid synthesis via increasing cholesterol 7 α-hydroxylase expression induced by the inhibition of farnesoid X receptor activation.
A novel photoredox catalysis for multiple functionalization of two different types of unactivated alkenes in a single operation was reported through a conceptually new mode of annulation–alkynyl ...migration. A wide array of cyclopentane carboxylates were synthesized in a highly selective and functional-group-compatible manner via C-centered radical induced cascade 5-exo-trig/5-exo-dig bicyclization and C–C bond cleavage process. This methodology might open a new entry for designing annulation–functional group migration to create structurally applicable cyclic ring systems.
Artesunate (ART) is an anti-malaria drug that has been shown to exhibit anti-tumor activity, and functional lysosomes are reported to be required for ART-induced cancer cell death, whereas the ...underlying molecular mechanisms remain largely elusive. In this study, we aimed to elucidate the molecular mechanisms underlying ART-induced cell death. We first confirmed that ART induces apoptotic cell death in cancer cells. Interestingly, we found that ART preferably accumulates in the lysosomes and is able to activate lysosomal function via promotion of lysosomal V-ATPase assembly. Furthermore, we found that lysosomes function upstream of mitochondria in reactive oxygen species production. Importantly, we provided evidence showing that lysosomal iron is required for the lysosomal activation and mitochondrial reactive oxygen species production induced by ART. Finally, we showed that ART-induced cell death is mediated by the release of iron in the lysosomes, which results from the lysosomal degradation of ferritin, an iron storage protein. Meanwhile, overexpression of ferritin heavy chain significantly protected cells from ART-induced cell death. In addition, knockdown of nuclear receptor coactivator 4, the adaptor protein for ferritin degradation, was able to block ART-mediated ferritin degradation and rescue the ART-induced cell death. In summary, our study demonstrates that ART treatment activates lysosomal function and then promotes ferritin degradation, subsequently leading to the increase of lysosomal iron that is utilized by ART for its cytotoxic effect on cancer cells. Thus, our data reveal a new mechanistic action underlying ART-induced cell death in cancer cells.
Background: Artesunate is capable of inducing cell death in cancer cells.
Results: Artesunate accumulates in lysosomes and promotes lysosomal function and ferritin degradation, leading to mitochondrial reactive oxygen species production and eventually cell death.
Conclusion: Intracellular iron and ferritin degradation is essential for artesunate-induced lysosomal activation and cell death.
Significance: This work reveals a novel mechanism underlying artesunate-induced cell death.
Pillarnarenes can be constructed using a Friedel–Crafts alkylation process. However, due to the reversible nature of the alkylation, mixture of large pillarnarenes (n≥7) are obtained as minor ...products, and thus laborious purification are necessary to isolate the larger pillarnarenes. Moreover, inert methylene bridges are introduced during the alkylation process, and the multi‐functionalization of the bridges has never been investigated. Herein, an irreversible Friedel–Crafts acylation is used to prepare pillarnarenes. Due to the irreversible nature of the acylation, the reaction of precursors bearing carboxylic acids and electron‐rich arene rings results in a size‐exclusive formation of pillarnarenes, in which the ring‐size is determined by the precursor length. Because of this size‐selective formation, laborious separation of undesired macrocycles is not necessary. Moreover, the bridges of pillarnarenes are selectively installed with reactive carbonyl groups using the acylation method, whose positions are determined by the precursor used. The carbonyl bridges can be easily converted into versatile functional groups, leading to various laterally modified pillarnarenes, which cannot be accessed by the alkylation strategy.
Different lateral functionalized pillarnarenes can be obtained using Friedel–Crafts acylation. The irreversible nature of acylation results in the macrocycles being obtained selectively in terms of ring sizes and functional positions. Further derivatization of the ketones is also possible to afford various laterally modified pillarnarenes that cannot be accessed by general Friedel–Crafts alkylation reactions.
Clayey silt reservoirs bearing natural gas hydrates (NGH) are considered to be the hydrate-bearing reservoirs that boast the highest reserves but tend to be the most difficult to exploit. They are ...proved to be exploitable by the first NGH production test conducted in the South China Sea in 2017. Based on the understanding of the first production test, the China Geological Survey determined the optimal target NGH reservoirs for production test and conducted a detailed assessment, numerical and experimental simulation, and onshore testing of the reservoirs. After that, it conducted the second offshore NGH production test in 1225 m deep Shenhu Area, South China Sea (also referred to as the second production test) from October 2019 to April 2020. During the second production test, a series of technical challenges of drilling horizontal wells in shallow soft strata in deep sea were met, including wellhead stability, directional drilling of a horizontal well, reservoir stimulation and sand control, and accurate depressurization. As a result, 30 days of continuous gas production was achieved, with a cumulative gas production of 86.14 ×104 m3. Thus, the average daily gas production is 2.87 ×104 m3, which is 5.57 times as much as that obtained in the first production test. Therefore, both the cumulative gas production and the daily gas production were highly improved compared to the first production test. As indicated by the monitoring results of the second production test, there was no anomaly in methane content in the seafloor, seawater, and atmosphere throughout the whole production test. This successful production test further indicates that safe and effective NGH exploitation is feasible in clayey silt NGH reservoirs. The industrialization of hydrates consists of five stages in general, namely theoretical research and simulation experiments, exploratory production test, experimental production test, productive production test, and commercial production. The second production test serves as an important step from the exploratory production test to experimental production test.
To investigate the effects of hydrogen (H) on the mechanical properties of 316L austenitic stainless steel (316L) additively manufactured using laser-powder bed fusion (L-PBF), tensile, ...nanoindentation, and micropillar compression tests were performed on samples in both the as-built (AB) and H-charged (HC) conditions. Microstructural characterization revealed that the electrochemical H charging exerted marginal effects on grains, phases, and overall dislocation densities of L-PBF 316L. However, the dislocation networks inherent to L-PBF 316L appear to disentangle upon H charging and are distributed more homogeneously through the matrix. Mechanical test results showed that H charging results in a marginal reduction in hardness and strength, indicating H-induced softening, possibly due to the elastic shielding effects of H that weaken the interactions between dislocations. The elastic shielding effect and the enhanced slip planarity, facilitate the H accumulation along slip bands and twins, promote H-enhanced localized plasticity, resulting cracking when a critical H concentration is reached. This, in turn, aids in H embrittlement mechanism that results in a significant loss in ductility upon H charging. A detailed discussion of all these micromechanisms is presented.
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Activating transcription factor 4 (ATF4) is critical for chondrocyte proliferation and bone formation. Exosomes are considered as promising gene‐delivery vehicles for the treatment of osteoarthritis ...(OA). This study utilized the serum‐derived exosomes from OA mice as the gene‐delivery vehicles for ATF4 gene therapy and explored their therapeutic effects on OA. Meniscus injury‐induced OA model was established by the excision of anterior part of medial meniscus in the right knee of C57BL/6J mice. Exosomes were isolated from serum samples of sham and OA mice, and were referred to as sham‐Exo and OA‐Exo, respectively. ATF4‐overexpressing OA‐Exo (ATF4‐OA‐Exo) was developed by introducing ATF4 mRNA into OA‐Exo via electroporation. Four weeks after surgery, OA mice received intra‐articular injections of sham‐Exo, OA‐Exo, and ATF4‐OA‐Exo, respectively. The results showed that intra‐articular injection of ATF4‐OA‐Exo alleviated articular cartilage degeneration or damage and inflammatory response of OA mice. Autophagy was weakened in knee joint cartilage of OA mice, which was partially restored by intra‐articular injection of ATF4‐OA‐Exo. Further in vitro assays revealed that ATF4‐OA‐Exo promoted chondrocyte autophagy and inhibited chondrocyte apoptosis in the TNF‐α‐ or tunicamycin‐treated chondrocytes. Together, ATF4‐modified serum exosomes derived from OA mice protect cartilage and alleviate OA progression by inducing autophagy.
A novel radical‐induced annulation/1,8‐halosulfonylation of β‐alkynyl ketones with haloaryl diazonium tetrafluoroborates and DABCO.bis(sulfur dioxide) was first achieved via the ...cleavage/recombination of C(sp3)−C(sp3) and C(sp2)‐halogen bonds, from which 47 examples of sulfone‐containing 1,3‐dimethylene‐substituted (Z,Z)‐isobenzofurans as single stereoisomers were synthesized in generally good yields. This multicomponent pathway is proposed to proceed through the in‐situ generation of arylsulfonyl radicals, followed by selective radical addition‐cyclization and ring‐opening of the cyclopropyl unit as well as C(sp2)‐halogen bond cleavage, resulting in the consecutive construction of three new chemical bonds, including C−S, C−O and C‐halogen bonds.
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