Podocyte-Specific Silencing of Acid Sphingomyelinase Gene to Abrogate Hyperhomocysteinemia-Induced NLRP3 Inflammasome Activation and Glomerular Inflammation.

Acid Sphingomyelinase has been reported to increase tissue ceramide and thereby mediate hHcy-induced glomerular NLRP3 inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene attenuates hHcy-induced NLRP3 inflammasome activation and associated exosome release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podocre mice compared to control littermates. By nanoparticle tracking analysis, floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary exosome excretion in Podocre mice. In addition, Smpd1 gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podocre mice. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented Hcy-induced elevation of exosome release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared to WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced exosome secretion from podocytes of Smpd1trg/Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of exosome release from podocytes was blocked by ASM inhibitor, but not by NLRP3 inflammasome inhibitors. Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and exosome release.

Design and Synthesis of a Water-Based Nanodelivery Pesticide System for Improved Efficacy and Safety.

Developing an environmentally friendly and safe nanodelivery system is crucial to improve the efficacy of pesticides and minimize environmental and health risks. However, preparing a completely water-based nanopesticide without using harmful solvents is a technical challenge. In this study, a water-based nanodelivery pesticide system was constructed to improve the efficacy and safety of Emamectin Benzoate (EB). A specific surfactant, 29-(4-(5-hydroxynonan-5-yl)phenoxy)-3,6,9,12,15,18,21,24,27-nonaoxanonacosan-1-ol (SurEB) was designed and synthesized to form a water-based nanodelivery system (EBWNS) with EB. Molecular dynamics simulations revealed the self-assembly and interaction forces between SurEB and EB in water, providing insights into the formation mechanism of EBWNS nanoparticles. The nanodelivery system showed the prolonged effectivity of EB with reduced degradation and demonstrated a good control efficacy for multiple target pests, such as red spider mite, beet armyworm larvae (Lepidoptera: Noctuidae), and rice stem borers (Chilo suppressalis). Toxicology tests on various objects demonstrated that the EBWNS has low toxicity for seeds, HaCaT cells, zebrafish, earthworm, and E. coli. This study provides a distinctive perspective for developing environmentally friendly nanopesticide formulations, which clarified a water-based treatment method for specific lipid-soluble pesticides. The water-based nanodelivery pesticide system has the potential to improve the efficacy and safety of pesticides in the process of field applications.

Renal Medullary Overexpression of Sphingosine-1-Phosphate Receptor 1 Transgene Attenuates Deoxycorticosterone Acetate (DOCA)-Salt Hypertension.

BACKGROUND: Our previous studies showed that renal medullary sphingosine-1-phosphate receptor 1 (S1PR1) mediated sodium excretion, high salt intake increased S1PR1 level, deoxycorticosterone acetate (DOCA) blocked high salt-induced S1PR1 in the renal medulla, and that conditional knockout of S1PR1 in the collecting duct aggravated DOCA-salt hypertension. The present study tested the hypothesis that overexpression of S1PR1 transgene in the renal medulla attenuates the sodium retention and hypertension in DOCA-salt mouse model. METHODS: Male C57BL/6J mice received renal medullary transfection of control or S1PR1-expressing plasmids and then DOCA-salt treatment. Renal sodium excretion and arterial pressure were compared between control and S1PR1-overexpressed mice in response to high salt loading or pressure natriuresis. RESULTS: S1PR1-transfected mice showed significantly enhanced urinary sodium excretion in response to acute sodium loading (0.93 ± 0.27 in control vs. 4.72 ± 1.12 µmol/min/gKW in S1PR1-overexpressed mice, P < 0.05) and the pressure natriuresis (3.58 ± 1.77 vs. 9.52 ± 1.38, P < 0.05), less positive sodium balance in response to chronic high-salt intake (3.05 ± 0.39 vs. 1.65 ± 0.39 mmol/72 hr, P < 0.05), and consequently, the attenuation of DOCA-salt hypertension (134.2 ± 6.79 vs. 109.8 ± 3.54 mm Hg, P < 0.05). The αENaC protein amount in the renal medulla was not changed, however, the ßENaC was significantly decreased and the γENaC was significantly increased in S1PR1-overexpressed mice. The immunostaining showed apical membrane translocation of γENaC, while no change of αENaC and ßENaC in control mice, and that the apical membrane translocation of γENaC was blocked in S1PR1-treasffected mice. CONCLUSIONS: These results suggested that activation of S1PR1 in the renal medulla attenuates DOCA-induced sodium retention and salt-sensitive hypertension associated with inhibition of ENaC.

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice.

Cisplatin is a potent first-line therapy for many solid malignancies, such as breast, ovarian, lung, testicular, and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects; however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatin-induced AKI. Male wild-type C57BL6 (WT) and Faah-/- mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later. Faah-/- mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers, and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (palmitoylethanolamide and oleoylethanolamide), attenuated nuclear factor-κB/p65 activity, DNA damage markers p53 and p21, and decreased expression of the inflammatory cytokine interleukin-1ß, as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity. SIGNIFICANCE STATEMENT: Mice lacking the Faah gene are protected from cisplatin-induced inflammation, DNA damage response, tubular damage, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity.

Impaired autophagic flux and dedifferentiation in podocytes lacking Asah1 gene: Role of lysosomal TRPML1 channel.

Podocytopathy and associated nephrotic syndrome have been reported in a mouse strain (Asah1fl/fl/Podocre) with a podocyte-specific deletion of α subunit (the main catalytic subunit) of acid ceramidase (Ac). However, the pathogenesis of podocytopathy in these mice remains unclear. The present study tested whether Ac deficiency impairs autophagic flux in podocytes through blockade of transient receptor potential mucolipin 1 (TRPML1) channel as a potential pathogenic mechanism of podocytopathy in Asah1fl/fl/Podocre mice. We first demonstrated that impairment of autophagic flux occurred in podocytes lacking Asah1 gene, which was evidenced by autophagosome accumulation and reduced lysosome-autophagosome interaction. TRPML1 channel agonists recovered lysosome-autophagosome interaction and attenuated autophagosome accumulation in podocytes from Asah1fl/fl/Podocre mice, while TRPML1 channel inhibitors impaired autophagic flux in WT/WT podocytes and worsened autophagic deficiency in podocytes lacking Asah1 gene. The effects of TRPML1 channel agonist were blocked by dynein inhibitors, indicating a critical role of dynein activity in the control of lysosome movement due to TRPML1 channel-mediated Ca2+ release. It was also found that there is an enhanced phenotypic transition to dedifferentiation status in podocytes lacking Asah1 gene in vitro and in vivo. Such podocyte phenotypic transition was inhibited by TRPML1 channel agonists but enhanced by TRPML1 channel inhibitors. Moreover, we found that TRPML1 gene silencing induced autophagosome accumulation and dedifferentiation in podocytes. Based on these results, we conclude that Ac activity is essential for autophagic flux and maintenance of differentiated status of podocytes. Dysfunction or deficiency of Ac may impair autophagic flux and induce podocyte dedifferentiation, which may be an important pathogenic mechanism of podocytopathy and associated nephrotic syndrome.

Temperature-Dependent Nanogel for Pesticide Smart Delivery with Improved Foliar Dispersion and Bioactivity for Efficient Control of Multiple Pests.

The use of nanomaterials and nanotechnology to construct a smart pesticide delivery system with target-oriented and controlled-release functions is important to increase the effective utilization rate and minimize environmental residue pollution. A temperature-dependent delivery system can modulate the release of pesticide with temperature to improve the efficacy and precision targeting. A series of poly(N-isopropylacrylamide) (PNIPAM)-based nanogels with high deformability and tunable structure were successfully constructed for smart pesticide delivery and effective pest control. A lambda-cyhalothrin (LC)-loaded Pickering emulsion (LC@TNPE) with a stable gel-like network structure was further formed by the temperature-dependent nanogel to encapsule the pesticide. The foliar wettability, photostability, and controlled-release property of LC@TNPE were effectively enhanced compared to the commercial formulation because of the encapsulation and stabilization of nanogel. The release rate of LC positively correlated with temperature changes and thereby adapted to the trend of pest population increase at higher temperature. The LC@TNPE displayed improved control efficacy on multiple target pests including Plutella xylostella, Aphis gossypii, and Pieris rapae compared with the commercial suspension concentrate and microcapsule suspension, and it showed marked efficacy to control Pieris rapae for an extended duration even at a 40% reduced dosage. Furthermore, the safety was evaluated systematically on cells in vitro and with a nontarget organism. Studies confirmed that the system was relatively safe for HepG2 cells and aquatic organism zebrafish. This research provides an insight into creating an efficient and environmentally friendly pesticide nanoformulation for sustainable agriculture production.

Simple and fast colorimetric detection of lipopolysaccharide based on aptamer and SYBR Green I mediated aggregation of gold nanoparticles.

Lipopolysaccharide (LPS) poses a considerable threat to food safety and human health. A colorimetric assay for LPS detection based on LPS binding aptamer (LBA) and SYBR Green I (SG) mediated aggregation of gold nanoparticles (AuNPs) was established. In the absence of LPS, the LBA was absorbed onto the AuNPs surface which prevented SG-induced aggregation of AuNPs, and the sensing system exhibited red color. When LPS was added, it interacted with the LBA, forming a complex. At higher LPS concentration, many LBAs were exhausted resulting in SG-induced aggregation of AuNPs, and color change from red to blue. The range of colorimetric detection of LPS was linear in 0-12 EU/mL, with a limit of detection of 0.1698 EU/mL. Spiked LPS in real samples and interfering substances were also identified. This assay ingeniously using the fluorescent dye SG as an effective trigger of AuNPs aggregation, is rapid and facile than most of those earlier reported LBA-based LPS assays, and there is potential to be modified to construct assays for other targets.

Construction and characterization of ethyl cellulose-based nano-delivery system for phenamacril.

Fungicide-resistant Fusarium has become a threaten to wheat production. Novel fungicide formulations can improve the efficacy of active ingredient and minimize the emergence of resistance. Encapsulation of fungicides in biodegradable carriers, especially, in polysaccharide, is a feasible approach to develop environment-friendly and efficient formulation. This study focused on the synthesis of ethyl cellulose-based phenamacril nano-delivery system by combining emulsion-solvent evaporation and high-pressure homogenization technology to improve the control of fusarium head blight in wheat. Emulsifier 125 and Tersperse 2500 were screened from eleven commonly used surfactants. Emulsifier 125 and Tersperse 2500 in a ratio of 2:1 and phenamacril nanocapsules with the mean particle size of 152.5 ± 1.3 nm were prepared. These showed excellent storage stability and wettability on crop leaves. A bioassay comparing the nanocapsules with a commercial preparation against Fusarium graminearum showed significantly improved biological activity. This formulation could be used to effectively not only to control fusarium head blight but also delay the occurrence of resistance.

Renomedullary exosomes produce antihypertensive effects in reversible two-kidney one-clip renovascular hypertensive mice.

The rapid fall in blood pressure following unclipping of the stenotic renal artery in the Goldblatt two-kidney one-clip (2K1C) model of renovascular hypertension is proposed to be due to release of renomedullary vasodepressor lipids, but the mechanism has remained unclear. In this study, we hypothesized that the hypotensive response to unclipping is mediated by exosomes released from the renal medulla. In male C57BL6/J mice made hypertensive by the 2K1C surgery, unclipping of the renal artery after 10 days decreased mean arterial pressure (MAP) by 23 mmHg one hr after unclipping. This effect was accompanied by a 556% increase in the concentration of exosomes in plasma as observed by nanoparticle tracking analysis. Immunohistochemical analysis of exosome markers, CD63 and AnnexinII, showed increased staining in interstitial cells of the inner medulla of stenotic but not contralateral control kidney of clipped 2K1C mice. Treatment with rapamycin, an inducer of exosome release, blunted the hypertensive response to clipping, whereas GW-4869, an exosome biosynthesis inhibitor, prevented both the clipping-induced increase in inner medullary exosome marker staining and the unclipping-induced fall in MAP. Plasma exosomes isolated from unclipped 2K1C mice showed elevated neutral lipid content compared to sham mouse exosomes by flow cytometric analysis after Nile red staining. Exosomes from 2K1C but not sham control mice exerted potent MAP-lowering and diuretic-natriuretic effects in both 2K1C and angiotensin II-infused hypertensive mice. These results are consistent with increased renomedullary synthesis and release of exosomes with elevated antihypertensive neutral lipids in response to increased renal perfusion pressure.

Nephrotoxicity in cancer treatment: An update.

It has been estimated that nearly 80% of anticancer drug-treated patients receive potentially nephrotoxic drugs, while the kidneys play a central role in the excretion of anticancer drugs. Nephrotoxicity has long been a serious complication that hampers the effectiveness of cancer treatment and continues to influence both mortality and length of hospitalization among cancer patients exposed to either conventional cytotoxic agents or targeted therapies. Kidney injury arising from anticancer drugs tends to be associated with preexisting comorbidities, advanced cancer stage, and the use of concomitant non-chemotherapeutic nephrotoxic drugs. Despite the prevalence and impact of kidney injury on therapeutic outcomes, the field is sorely lacking in an understanding of the mechanisms driving cancer drug-induced renal pathophysiology, resulting in quite limited and largely ineffective management of anticancer drug-induced nephrotoxicity. Consequently, there is a clear imperative for understanding the basis for nephrotoxic manifestations of anticancer agents for the successful management of kidney injury by these drugs. This article provides an overview of current preclinical research on the nephrotoxicity of cancer treatments and highlights prospective approaches to mitigate cancer therapy-related renal toxicity.

Loss of sphingosine kinase 2 protects against cisplatin-induced kidney injury.

Cisplatin is an established chemotherapeutic drug for treatment of solid-organ cancers and is the primary drug used in the treatment of head and neck cancer; however, cisplatin-induced nephrotoxicity largely limits its clinical use. Inhibition of sphingosine kinase 2 (SphK2) has been demonstrated to alleviate various kidney diseases. Therefore, we hypothesized that inhibition of SphK2 could also protect against cisplatin-induced nephrotoxicity. Results from the present study showed that the SphK2 inhibitor ABC294640 or knockdown of SphK2 by siRNA blocked the cisplatin-induced increase of cellular injury markers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and cleaved caspase-3) by Western blot analysis in HK-2 cells, a human renal tubular cell line. In addition, SphK2 inhibition blocked cisplatin-induced activation of NF-κB by Western blot analysis and immunostaining analysis. Furthermore, SphK2 inhibition suppressed cisplatin-induced increases of proinflammatory markers (NLR family pyrin domain containing 3, interleukin-1ß, and interleukin-6). Genetic deletion of the SphK2 gene in mice further confirmed that inhibition of SphK2 protected against cisplatin-induced kidney damage in vivo. Compared with wild-type mice, SphK2 knockout mice exhibited less renal dysfunction and reduced promotion of kidney injury markers, inflammatory factors, tubular morphology damage, and fibrotic staining. At the same time, the SphK2 inhibitor ABC294640 failed to interfere with the activity of cisplatin or radiation in two cell culture models of head and neck cancer. It is concluded that inhibition of Sphk2 protects against cisplatin-induced kidney injury. SphK2 may be used as a potential therapeutic target for the prevention or treatment of cisplatin-induced kidney injury.NEW & NOTEWORTHY The present study provides new findings that sphingosine kinase 2 (SphK2) is highly expressed in renal tubules, cisplatin treatment increases the expression of SphK2 in proximal tubular cells and kidneys, and inhibition of SphK2 alleviates cisplatin-induced kidney injury by suppressing the activation of NF-κB, production of inflammatory factors, and apoptosis. SphK2 may serve as a potential therapeutic target for the prevention or treatment of cisplatin-induced nephrotoxicity.

Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis.

Although cannabinoid receptors (CB) are recognized as targets for renal fibrosis, the roles of endogenous cannabinoid anandamide (AEA) and its primary hydrolytic enzyme, fatty acid amide hydrolase (FAAH), in renal fibrogenesis remain unclear. The present study used a mouse model of post-ischemia-reperfusion renal injury (PIR) to test the hypothesis that FAAH participates in the renal fibrogenesis. Our results demonstrated that PIR showed upregulated expression of FAAH in renal proximal tubules, accompanied with decreased AEA levels in kidneys. Faah knockout mice recovered the reduced AEA levels and ameliorated PIR-triggered increases in blood urea nitrogen, plasma creatinine as well as renal profibrogenic markers and injuries. Correspondingly, a selective FAAH inhibitor, PF-04457845, inhibited the transforming growth factor-beta 1 (TGF-ß1)-induced profibrogenic markers in human proximal tubular cell line (HK-2 cells) and mouse primary cultured tubular cells. Knockdown of FAAH by siRNA in HK-2 cells had similar effects as PF-04457845. Tubular cells isolated from Faah-/- mice further validated the protection against TGF-ß1-induced damages. The CB 1 or CB2 receptor antagonist and exogenous FAAH metabolite arachidonic acid failed to reverse the protective effects of FAAH inactivation in HK-2 cells. However, a substrate-selective inhibitor of AEA-cyclooxygenase-2 (COX-2) pathway significantly suppressed the anti-profibrogenic actions of FAAH inhibition. Further, the AEA-COX-2 metabolite, prostamide E2 exerted anti-fibrogenesis effect. These findings suggest that FAAH activation and the consequent reduction of AEA contribute to the renal fibrogenesis, and that FAAH inhibition protects against fibrogenesis in renal cells independently of CB receptors via the AEA-COX-2 pathway by the recovery of reduced AEA.

Polylactic acid nanoparticles for co-delivery of dinotefuran and avermectin against pear tree pests with improved effective period and enhanced bioactivity.

Pesticide compounding technology for disease and pest control emerges as an effective way to increase the effectiveness of pesticides while reducing pesticides resistance. Nanomaterials and encapsulation technology have offered a new insight into preparing efficient pesticide formulations, especially constructing a co-delivery nanoparticle for synergistic pesticides. In this study, a dinotefuran/avermectin co-delivery nanoparticles (DACNPs) against pear tree pests with polylactic acid (PLA) as the wall material were constructed by double-emulsion method combined with high-pressure homogenization technique. The drug content of the DACNPs was 39.1% with an average size of 245.7 ± 4.2 nm and the mean polymer dispersity index (PDI) value was 0.123. The DACNPs showed high foliar retention and good spread performance on target leaves due to the nanoscale effect. The obtained DACNPs showed a better control effect on Grapholitha molesta Busck and Psylla chinensis Yang et Li compared with the commercial formulations, which could significantly prolong the effective duration and enhance the bioactivity with lower amounts and application frequency of pesticides. This study may provide new insights into developing novel pesticide formulations to improve the utilization rate of pesticides, reduce environmental pollution and minimize the cost of farming.

Preparation, Characterization, and Evaluation of Pyraclostrobin Nanocapsules by In Situ Polymerization.

In this study, pyraclostrobin nanocapsules were prepared by in situ polymerization with urea-formaldehyde resin as a wall material. The effects of different emulsifiers, emulsifier concentrations, and solvents on the physicochemical properties of pyraclostrobin nanocapsules were investigated. Solvesso™ 100 was selected as the solvent, and Emulsifier 600# was used as the emulsifier, which accounted for 5% of the aqueous phase system, to prepare pyraclostrobin nanocapsules with excellent physical and chemical properties. The particle size, ζ potential, and morphology of the nanocapsules were characterized by a particle size analyzer and transmission electron microscope. The nanocapsules were analyzed by Fourier-transform infrared spectroscopy, and the loading content and sustained release properties of the nanocapsules were measured. The results show that the size of the prepared nanocapsules was 261.87 nm, and the polydispersity index (PDI) was 0.12, presenting a uniform spherical appearance. The loading content of the pyraclostrobin nanocapsules was 14.3%, and their cumulative release rate was 70.99% at 250 h, providing better efficacy and sustainability compared with the pyraclostrobin commercial formulation.

Nanomaterials and nanotechnology for the delivery of agrochemicals: strategies towards sustainable agriculture.

Nanomaterials (NMs) have received considerable attention in the field of agrochemicals due to their special properties, such as small particle size, surface structure, solubility and chemical composition. The application of NMs and nanotechnology in agrochemicals dramatically overcomes the defects of conventional agrochemicals, including low bioavailability, easy photolysis, and organic solvent pollution, etc. In this review, we describe advances in the application of NMs in chemical pesticides and fertilizers, which are the two earliest and most researched areas of NMs in agrochemicals. Besides, this article concerns with the new applications of NMs in other agrochemicals, such as bio-pesticides, nucleic acid pesticides, plant growth regulators (PGRs), and pheromone. We also discuss challenges and the industrialization trend of NMs in the field of agrochemicals. Constructing nano-agrochemical delivery system via NMs and nanotechnology facilitates the improvement of the stability and dispersion of active ingredients, promotes the precise delivery of agrochemicals, reduces residual pollution and decreases labor cost in different application scenarios, which is potential to maintain the sustainability of agricultural systems and improve food security by increasing the efficacy of agricultural inputs.

NRF2 Inhibits Cardiomyocyte Pyroptosis Via Regulating CTRP1 in Sepsis-Induced Myocardial Injury.

ABSTRACT: C1q/tumor necrosis factor-related protein 1 (CTRP1) has been demonstrated as a crucial regulator in myocardial injury (MI). The present study aims to evaluate the mechanism of CTRP1 in sepsis-induced MI. The septic mouse model was established via cecal ligation and puncture and the in vitro cell model was established via lipopolysaccharide treatment. The mouse survival rate within 96 h was recorded. Morphologic changes of cardiomyocytes were observed and cell viability and cardiac functions were detected. CTRP1 and nuclear factor erythroid 2-related factor (Nrf2) expressions, creatine troponin-T, and creatine phosphokinase isoenzyme levels, and expressions of pyroptotic markers were determined. The binding relationship between Nrf2 and the CTRP1 promotor was predicted and verified. Rescue experiments were designed to confirm the role of CTRP1. CTRP1 was poorly expressed in septic mice. CTRP1 overexpression inhibited cardiomyocyte pyroptosis and improved cardiac functions, MI, and survival rate in septic mice. Nrf2was decreased in cecal ligation and puncture -treated mice. Nrf2 overexpression promoted CTRP1 expression via binding to the CTRP1 promotor and suppressed cardiomyocyte pyroptosis. CTRP1 downregulation abolished the inhibitory effect of Nrf2 overexpression on cardiomyocyte pyroptosis. Overall, Nrf2 promoted CTRP1 expression via binding to the CTRP1 promotor to inhibit cardiomyocyte pyroptosis, thereby alleviating MI in septic mice.

Exosome Biogenesis and Lysosome Function Determine Podocyte Exosome Release and Glomerular Inflammatory Response during Hyperhomocysteinemia.

Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation in podocytes is reportedly associated with enhanced release of exosomes containing NLRP3 inflammasome products from these cells during hyperhomocysteinemia (hHcy). This study examined the possible role of increased exosome secretion during podocyte NLRP3 inflammasome activation in the glomerular inflammatory response. Whether exosome biogenesis and lysosome function are involved in the regulation of exosome release from podocytes during hHcy in mice and upon stimulation of homocysteine (Hcy) in podocytes was tested. By nanoparticle tracking analysis, treatments of mice with amitriptyline (acid sphingomyelinase inhibitor), GW4869 (exosome biogenesis inhibitor), and rapamycin (lysosome function enhancer) were found to inhibit elevated urinary exosomes during hHcy. By examining NLRP3 inflammasome activation in glomeruli during hHcy, amitriptyline (but not GW4869 and rapamycin) was shown to have an inhibitory effect. However, all treatments attenuated glomerular inflammation and injury during hHcy. In cell studies, Hcy treatment stimulated exosome release from podocytes, which was prevented by amitriptyline, GW4869, and rapamycin. Structured illumination microscopy revealed that Hcy inhibited lysosome-multivesicular body interactions in podocytes, which was prevented by amitriptyline or rapamycin but not GW4869. Thus, the data from this study shows that activation of exosome biogenesis and dysregulated lysosome function are critically implicated in the enhancement of exosome release from podocytes leading to glomerular inflammation and injury during hHcy.

Advances in Controlled-Release Pesticide Formulations with Improved Efficacy and Targetability.

Pesticides are commonly used in modern agriculture and are important for global food security. However, postapplication losses due to degradation, photolysis, evaporation, leaching, surface runoff, and other processes may substantially reduce their efficacy. Controlled-release formulations can achieve the permeation-regulated transfer of an active ingredient from a reservoir to a target surface. Thus, they can maintain an active ingredient at a predetermined concentration for a specified period. This can reduce degradation and dissipation and other losses and has the potential to improve efficacy. Recent developments in controlled-release technology have adapted the concepts of intelligence and precision from the pharmaceutical industry. In this review, we present recent advances in the development of controlled-release formulations and discuss details of the preparation methods, material improvements, and application technologies.

Overexpression of MicroRNA-429 Transgene Into the Renal Medulla Attenuated Salt-Sensitive Hypertension in Dahl S Rats.

BACKGROUND: We have previously shown that high salt stimulates the expression of miR-429 in the renal medulla, which induces mRNA decay of HIF prolyl-hydroxylase 2 (PHD2), an enzyme to promote the degradation of hypoxia-inducible factor (HIF)-1α, and increases the HIF-1α-mediated activation of antihypertensive genes in the renal medulla, consequently promoting extra sodium excretion. Our preliminary results showed that high salt-induced increase of miR-429 was not observed in Dahl S rats. This present study determined whether correction of this impairment in miR-429 would reduce PHD2 levels, increase antihypertensive gene expression in the renal medulla and attenuate salt-sensitive hypertension in Dahl S rats. METHODS: Lentiviruses encoding rat miR-429 were transfected into the renal medulla in uninephrectomized Dahl S rats. Sodium excretion and blood pressure were then measured. RESULTS: Transduction of lentiviruses expressing miR-429 into the renal medulla increased miR-429 levels, decreased PHD2 levels, and upregulated HIF-1α target gene NOS-2, which restored the adaptive mechanism to increase the antihypertensive gene after high-salt intake in Dahl S rats. Functionally, overexpression of miR-429 transgene in the renal medulla significantly improved pressure natriuretic response, enhanced urinary sodium excretion, and reduced sodium retention upon extra sodium loading, and consequently, attenuated the salt-sensitive hypertension in Dahl S rats. CONCLUSIONS: Our results suggest that the impaired miR-429-mediated PHD2 inhibition in response to high salt in the renal medulla may represent a novel mechanism for salt-sensitive hypertension in Dahl S rats and that correction of this impairment in miR-429 pathway could be a therapeutic approach for salt-sensitive hypertension.

Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury.

Inhibition of hypoxia-inducible factor-prolyl hydroxylase (PHD) has been shown to protect against various kidney diseases. However, there are controversial reports on the effect of PHD inhibition in renoprotection. The present study determined whether delivery of PHD2 small interfering RNA (siRNA) using an siRNA carrier, folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA), would mainly target kidneys and protect against renal ischemia/reperfusion injury (I/R). The renal I/R was generated by clipping the renal pedicle for 30 minutes in uninephrectomized mice. Mice were sacrificed 48 hours after I/R. Normal saline or G5-FA complexed with control or PHD2 siRNA was injected via tail vein 24 hours before ischemia. After the injection of near-infrared fluorescent dye-labeled G5-FA, the fluorescence was mainly detected in kidneys but not in other organs. The reduction of PHD2 mRNA and protein was only observed in kidneys but not in other organs after injection of PHD2-siRNA-G5-FA complex. The injection of PHD2-siRNA-G5-FA significantly alleviated renal I/R injury, as shown by the inhibition of increases in serum creatinine and blood urea nitrogen, the blockade of increases in kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and the improvement of histologic damage compared with mice treated with control siRNA. PHD2 siRNA can be delivered specifically into kidneys using G5-FA, and that local knockdown of PHD2 gene expression within the kidney alleviates renal I/R injury. Therefore, G5-FA is an efficient siRNA carrier to deliver siRNA into the kidney, and that local inhibition of PHD2 within the kidney may be a potential strategy for the management of acute I/R injury. SIGNIFICANCE STATEMENT: Folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA) was demonstrated to be an effective carrier to deliver small interfering RNA (siRNA) into kidneys. Delivery of prolyl hydroxylase domain protein 2 siRNA with G5-FA effectively protected the kidneys against the acute renal ischemia/reperfusion injury.