Renal CD81 interacts with sodium potassium 2 chloride cotransporter and sodium chloride cotransporter in rats with lipopolysaccharide-induced preeclampsia.

The kidney regulates blood pressure through salt/water reabsorption affected by tubular sodium transporters. Expanding our prior research on placental cluster of differentiation 81 (CD81), this study explores the interaction of renal CD81 with sodium transporters in preeclampsia (PE). Effects of renal CD81 with sodium transporters were determined in lipopolysaccharide (LPS)-induced PE rats and immortalized mouse renal distal convoluted tubule cells. Urinary exosomal CD81, sodium potassium 2 chloride cotransporter (NKCC2), and sodium chloride cotransporter (NCC) were measured in PE patients. LPS-PE rats had hypertension from gestational days (GD) 6 to 18 and proteinuria from GD9 to GD18. Urinary CD81 in both groups tented to rise during pregnancy. Renal CD81, not sodium transporters, was higher in LPS-PE than controls on GD14. On GD18, LPS-PE rats exhibited higher CD81 in kidneys and urine exosomes, higher renal total and phosphorylated renal NKCC2 and NCC with elevated mRNAs, and lower ubiquitinated NCC than controls. CD81 was co-immunoprecipitated with NKCC2 or NCC in kidney homogenates and co-immunostained with NKCC2 or NCC in apical membranes of renal tubules. In plasma membrane fractions, LPS-PE rats had greater amounts of CD81, NKCC2, and NCC than controls with enhanced co-immunoprecipitations of CD81 with NKCC2 or NCC. In renal distal convoluted tubule cells, silencing CD81 with siRNA inhibited NCC and prevented LPS-induced NCC elevation. Further, PE patients had higher CD81 in original urines, urine exosomes and higher NKCC2 and NCC in urine exosomes than controls. Thus, the upregulation of renal CD81 on NKCC2 and NCC may contribute to the sustained hypertension observed in LPS-PE model. Urine CD81 with NKCC2 and NCC may be used as biomarkers for PE.

Image Super Resolution-Based Channel Estimation for Orthogonal Chirp Division Multiplexing on Shallow Water Underwater Acoustic Communications.

Orthogonal chirp division multiplexing (OCDM) offers a promising modulation technology for shallow water underwater acoustic (UWA) communication systems due to multipath fading resistance and Doppler resistance. To handle the various channel distortions and interferences, obtaining accurate channel state information is vital for robust and efficient shallow water UWA communication. In recent years, deep learning has attracted widespread attention in the communication field, providing a new way to improve the performance of physical layer communication systems. In this paper, the pilot-based channel estimation is transformed into a matrix completion problem, which is mathematically equivalent to the image super-resolution problem arising in the field of image processing. Simulation results show that the deep learning-based method can improve the channel distortion, outperforming the equalization performed by traditional estimator, the performance of Bit Error Rate is improved by 2.5 dB compared to the MMSE method in OCDM system. At the 7.5 to 20 dB region, it achieves better bit error rate performance than OFDM systems, and the bit error rate is reduced by approximately 53% compared to OFDM when the SNR value is 20, which is very useful in shallow water UWA channels with multipath extension and severe time-varying characteristics.

Interfacial Engineering of Binder-Free Janus Separator with Ultra-Thin Multifunctional Layer for Simultaneous Enhancement of Both Metallic Li Anode and Sulfur Cathode.

Exploring a scalable strategy to fabricate a multifunctional separator is of great significance to overcome the challenges of lithium polysulfides (LiPSs) and dendritic growth in lithium-sulfur batteries (LSBs). Herein, a binder-free Janus separator is constructed by interfacial engineering. At the cathode interface, an ultra-thin covalent triazine piperazine film containing tailorable micropores and adsorption sites is decorated on polyacrylonitrile (PAN) membrane by in situ interfacial polymerization, building a triple barrier for LiPSs. The combination of steric hindrance and chemical adsorption reduces LiPS's migration by 81.85%. Meanwhile, at the anode interface, a fast-ionic conductor Li6.4 La3 Zr1.4 Ta0.6 O12  (LLZTO) is created on the surface of PAN nanofiber by magnetron sputtering to suppress dendrite growth. Even though there is no binder between the ceramic layer and the fibrous separator, sputtering creates an inter-embedded structure that ensures no depowering after cycling. Furthermore, the PAN-based separator displays a high temperature tolerance of 180 °C. Consequently, the cell delivers a high capacity of 1287.9 mAh g-1 at 0.5 C and stable cycling performance with an ultra-low capacity decay rate of 0.059% per cycle over 500 cycles. This work provides a scalable strategy for functionalizing separators to tackle the challenges in LSBs, which is binder-free, stripping-free, and essentially thickening-free.

Deep-Penetrating Triple-Responsive Prodrug Nanosensitizer Actuates Efficient Chemoradiotherapy in Pancreatic Ductal Adenocarcinoma Models.

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long-term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose-limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple-responsiveness, deep tumor penetration, GSH/hypoxia-responsive drug release/activation, and hypoxia-induced chemoradio-sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.

Glucose-induced decrease of cystathionine ß-synthase mediates renal injuries.

Exogenous hydrogen sulfide (H2 S) protects kidneys from diabetic injuries in animal models. In order to explore the role of endogenous H2 S in diabetic nephropathy, we determined the renal H2S producing enzymes in vivo and in vitro. In diabetic mice, H2 S levels in blood and kidney were decreased while cystathionine ß-synthase (CBS), mainly located in mouse renal proximal convoluted tubules (PCT), was reduced selectively. In cultured mouse PCT cells treated with high glucose, CBS protein and activity was reduced while ubiquitinated CBS was increased, which was abolished by a proteasome inhibitor MG132 at 1 hour; high glucose drove CBS colocalized with proteasome 26S subunit ATPase6, indicating an involvement of ubiquitination proteasome degradation. At 48 hours, high glucose also selectively decreased CBS protein, concentration-dependently, but increased the ubiquitination of CBS; silence of CBS by siRNA increased nitrotyrosine, a marker for protein oxidative injury. Nitrotyrosine was also increased by high glucose treatments. The increases of nitrotyrosine either by cbs-siRNA or by glucose were restored by GYY4137, indicating that the H2 S donor may protect kidney from oxidative injury induced by CBS deficiency. In diabetic kidneys, ubiquitinated CBS and nitrotyrosine were increased but restored by GYY4137. The treatment also ameliorated albuminuria and renal morphologic changes in diabetic mice. Our findings suggest that high glucose induces reduction of renal CBS protein and activity in vivo and in vitro that is critical to the pathogenesis of diabetic kidney disease.

Exploring the Origin of Maximum Entropy States Relevant to Resonant Modes in Modern Chladni Plates.

The resonant modes generated from the modern Chladni experiment are systematically confirmed to intimately correspond to the maximum entropy states obtained from the inhomogeneous Helmholtz equation for the square and equilateral triangle plates. To investigate the origin of maximum entropy states, the inhomogeneous Helmholtz equation is modified to consider the point interaction coming from the driving oscillator. The coupling strength associated with the point interaction is characterized by a dimensionless factor α. The δ potential of the point interaction is numerically modelled by a truncated basis with an upper index N. The asymptotic behavior for the upper index N is thoroughly explored to verify that the coupling strength of α = 1.0 can make the theoretical resonant modes agree excellently with the maximum entropy states as N→∞. It is further authenticated that nearly the same resonant modes can be obtained by using a larger coupling strength α when a smaller upper index N is exploited in the calculation.

A preliminary study on pollution characteristics of surfactant substances in fine particles in the Beibu Gulf Region of China.

The pollution characteristics of surfactant substances in fine particles (PM2.5) in spring were studied in the Beibu Gulf Region of China, 68 samples of PM2.5 were collected at Weizhou Island in Beihai City from March 12 to April 17, 2015. The Anionic Surfactant Substances (ASS) and Cationic Surfactant Substances (CSS) in the samples were analyzed using Byethyl Violet Spectrophotometry and Disulfide Blue Spectrophotometry, respectively. Combined with the data from backward trajectory simulation, the effects of air pollutants from remote transport on the pollution characteristics of surfactant substances in PM2.5 in the Beibu Gulf Region were analyzed and discussed. The results showed that the daily mean concentrations of ASS and CSS in spring in the Beibu Gulf Region were 165.20 pmol/m3 and 8.05pmol/m3, and the variation ranges were 23.21-452.55 pmol/m3 and 0.65-31.31 pmol/m3, accounting for 1.82‰ ± 1.65‰ and 0.12‰ ± 0.11‰ of the mass concentration of PM2.5, respectively. These concentrations were lower than those in comparable regions around the world. There was no clear correlation between the concentrations of ASS and CSS in PM2.5 and the mass concentrations of PM2.5. Tourism and air transport had a positive contribution on the concentrations of ASS. The concentration of surfactant substances in PM2.5 was significantly impacted by wind speed and wind direction. Atmospheric temperature, air pressure and precipitation had little effect on the concentrations of surfactant substances. Surfactant substances in PM2.5 significantly impacted visibility. Results also showed that the main sources of surfactant substances were from the southern China and Southeast Asia.

Effect of Vitamin D Supplementation on Some Inflammatory Biomarkers in Type 2 Diabetes Mellitus Subjects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIMS: The mechanism, by which vitamin D influences inflammatory biomarkers in type 2 diabetes mellitus (T2DM), is not very well known. Thus, a meta-analysis of randomized controlled trials was conducted to assess the effect of vitamin D supplementation on some inflammatory biomarkers in T2DM subjects. METHODS: We searched randomized controlled trials from PubMed and the Cochrane Library in October 2017 and conducted a meta-analysis to evaluate the effectiveness of vitamin D supplementation on high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Either a fixed-effects or a random-effects model was used to calculate pooled effects. RESULTS: We identified 13 studies that met our inclusion criteria. The results indicated that the vitamin D supplementation significant decreased the hs-CRP level by 0.45 µg/mL, whereas the vitamin D supplementation did not  influence the TNF-α and IL-6. Subgroup analysis showed that vitamin D significantly lowered hs-CRP by 0.34 µg/mL among trials with a daily vitamin D dose ≤4,000 IU and by 0.31 µg/mL among trials with time of vitamin D supplementation > 12 weeks. CONCLUSIONS: Vitamin D supplementation is beneficial for the reduction of hs-CRP inT2DM subjects but does not have a significant influence on TNF-α and IL-6 in T2DM subjects.

Increased circulating bioactive C-type natriuretic peptide is associated with reduced heart rate variability in patients with chronic kidney disease.

BACKGROUND: C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family and have been implicated to be involved in maintaining vascular homeostasis and acting as a cardiac chronotropic agent in experimental studies. However, clinical evidence of its participation in cardiovascular regulation is lacking, especially in patients with chronic kidney disease (CKD). We aimed to explore the association of circulating CNP with cardiovascular alterations in CKD. METHODS: Seventy-six subjects with CKD were recruited. Plasma CNP-22, the bioactive form of CNP in the circulation, was measured by an enzyme immunoassay. The patients also underwent several cardiovascular evaluations including measurement of blood pressure, endothelial function, heart rate variability (HRV) and pulse wave velocity. RESULTS: Mean (±standard deviation) age of the patients were 59.9 (±14.9) years and 56.6% were male. Average plasma CNP level was 790.8 ± 309.1 pg/ml. Plasma CNP level was not increased as estimated glomerular filtration rate declined. There was no significant difference of CNP between patients with or without endothelial dysfunction (with vs. without endothelial dysfunction: 844.6 ± 365.5 pg/ml vs. 738.3 ± 231.8 pg/ml, p = 0.14). Plasma CNP showed no association with blood pressure or pulse wave velocity, but was negatively associated with time-domain HRV parameters (SDNN, RMSSD, Triangular Index). The association of CNP with HRV persisted after adjustment for potential covariates. CONCLUSIONS: Our data highlights a possible link between circulating CNP and autonomic dysfunction in CKD patients. Further studies are warranted to explore the mechanisms underlying this association, as well as evaluate the ability of circulating CNP in predicting adverse cardiovascular event in CKD patients.

Erythropoietin protects the tubular basement membrane by promoting the bone marrow to release extracellular vesicles containing tPA-targeting miR-144.

Renal fibrosis is an inevitable outcome of chronic kidney disease (CKD). Erythropoietin (EPO) has been recently reported to be able to mitigate renal fibrosis. The mechanism underlying the protective effect of EPO, however, remains elusive. In the present study, employing a mouse model of renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO), we demonstrated that EPO markedly reduced the disruption of the tubular basement membrane (TBM) through attenuating the activation of tissue plasminogen activator (tPA) and matrix metalloproteinase 9 (MMP9), the major matrix proteolytic network in the obstructed kidney. Instead of acting directly on tPA in the kidney, EPO strongly increased the level of circulating microRNA (miR)-144, which was delivered to the injured renal fibroblasts via extracellular vesicles (EVs) to target the tPA 3'-untranslated region and suppress tPA expression. The protective effect of EPO on mouse TBM was inhibited by miR-144 antagomir. Furthermore, in vitro results confirmed that EPO could stimulate bone marrow-derived Sca-1(+)CD44(+)CD11b(-)CD19(-) cells to secrete miR-144-containing EVs, which markedly suppressed tPA expression, as well as metalloproteinase 9 (MMP9) level and activity, in cultured renal fibroblasts. In conclusion, our study provides the first evidence that EPO protects mouse renal TBM through promoting bone marrow cells to generate and secrete miR-144, which, in turn, is efficiently delivered into the mouse kidney via EVs to inhibit the activation of the tPA/MMP9-mediated proteolytic network. This finding thus suggests that EPO, a hormone widely used to treat anemia in CKD, is a potential therapeutic strategy for renal fibrosis.

[Protective Effect of Hydrogen Sulfide in the Secondary Renal Disease and Renal Transplantation].

The prevalence of kidney disease was increasing,which has become an important threaten to the health of the population.Hydrogen sulfide is the third gas signaling molecules after CO and NO.It has toxic effect at high concentration,but plays an important role in relaxing blood vessel ,antioxidation anti -inflammation and anti-apoptosis at physiological concentration.Kidney disease,especially seconda-ry kidney disease such as obstructive nephropathy,renal transplantation,diabetic nephropathy and hyper-tensive kidney lesion are closely related to vascular leision,oxidative stress and inflammation.Then what's the relationship between hydrogen sulfide and kidney disease?This article will review the relationship between hydrogen sulfide and kidney disease.

Pollution characteristics and health risk assessment of benzene homologues in ambient air in the northeastern urban area of Beijing, China.

Ambient benzene homologues were measured at a site in the northeastern urban area of Beijing, China, from August 24 to September 4, 2012 by SUMMA canister sampling followed by laboratory determination using cryogenic cold trap pre-concentration-GC-MS/FID, and their health risks were also assessed. Daily total benzene homologues ranged from 0.99 to 49.71 microg/m3 with an average of 11.98 microg/m3. Benzene homologues showed higher concentrations in the morning and evening than that at noontime. Comparison with previous studies revealed a trend of decrease for ambient benzene homologues probably due to the effective emission control in Beijing in recent years. Vehicular exhaust was the main source while volatilization of paints and solvents also made substantial contributions. Health risk assessment showed that BTEX (benzene, toluene, ethylbenzene, o-xylene, m-xylene and p-xylene) and styrene had no appreciable adverse non-cancer health risks for the exposed population, while benzene has potential cancer risk of 1.34E-05. Available data from cities in China all implied that benzene imposes relatively higher cancer risk on the exposed populations and therefore strict control measures should be taken to further lower ambient benzene levels in China.

Cationic cellulose nanofiber solid electrolytes: A pathway to high lithium-ion migration and polysulfide adsorption for lithium-sulfur batteries.

Polyethylene oxide (PEO) solid electrolytes, acknowledged for their safety advantages over liquid counterparts, confront inherent challenges, including low ionic conductivity, restricted lithium ion migration, and mechanical fragility, notably pronounced in lithium­sulfur batteries due to the polysulfide shuttling phenomenon. To address these limitations, we integrate a quaternary ammonium cation-modified cellulose (QACC) nanofiber, electrospun with cellulose acetate (CA) from recycled cigarette filters, into the PEO electrolyte matrix. The nitrogen atom within the quaternary ammonium group exhibits a pronounced affinity for polysulfide compounds, effectively curtailing polysulfide migration. Concurrently, Lewis acid-base interactions between quaternary ammonium groups and lithium salt anions facilitate the release of additional Li+, achieving a lithium-ion transference number 1.5 times higher than its pure PEO counterpart. Furthermore, the introduction of a larger trifluoromethanesulfonimide (TFSI) group on the QACC macromolecule (TFSI-QACC) disrupts the ordered arrangement of PEO macromolecules, resulting in a noteworthy enhancement in ionic conductivity, reaching 2.07 × 10-4 S cm-1 at 60 °C, thus addressing the challenge of low PEO electrolyte conductivity. Moreover, the nanofiber enhances the mechanical strength of the PEO electrolyte from 0.49 to 7.50 MPa, mitigating safety concerns related to lithium dendrites puncturing the electrolyte. Consequently, the composite PEO demonstrates exemplary performance in lithium symmetrical batteries, enduring 500 h of continuous operation and completing 100 cycles at both room and elevated temperatures. This integrated approach, transitioning from waste to wealth, adeptly addresses a spectrum of challenges in the efficiency of solid-state electrolytes, holding considerable promise for advancing lithium­sulfur battery technology.

The shape parameters of coal and gangue particles derived from 3D scanning.

The irregular shape of mineral particles directly affects the angle of repose, bulk density and flow-properties, and the interaction behaviour between the particles and a contact surface. This paper presents a dataset of spatial data and shape parameters collected from 37 gangue particles and 135 anthracite coal particles, which come from the Shangzhuang Coal Mine. The particle surface models were obtained by a Wiiboox white light raster 3D scanner and Reeyee software. To obtain the scanning surface, each particle was scanned 8 times in different axial rotation directions. The final scanning model was obtained by stacking two scanning surfaces, and the shape parameters, such as length ratio, flatness ratio, and Zingg index, were obtained. This dataset is particularly useful for researchers and engineers who want to investigate the shape of coal and gangue particles or who want to test or benchmark measurement methods concerning the three-dimensional morphology of particles.

A low-salt diet with candesartan administration is associated with acute kidney injury in nephritis by increasing nitric oxide.

A low-salt diet may activate the renin-angiotensin-aldosterone system (RAAS) and is often applied simultaneously with RAAS inhibitors, especially for treatment of proteinuric nephritis. To explore the effect of a low-salt diet combined with angiotensin receptor blockers (ARB) on kidney function, the proteinuric nephritis model was induced by single intravenous injection of doxorubicin, and then the SD rats were administrated with candesartan intraperitoneal injection and fed with different salt diets. Rats with low-salt plus candesartan, not either alone, experienced acute kidney injury (AKI) at day 7 and could not self-restore when extending the experiment time from 7 days to 21 days, unless switching low-salt to normal-salt. Among three nitric oxide synthetases (NOS), endothelial NOS (eNOS) was obviously elevated and PI3K-Akt-eNOS signal pathway was activated. NG-Nitro-L-Arginine Methyl Ester (L-NAME), an eNOS inhibitor, reversed the decreased blood pressure and recovered the kidney dysfunction induced by low-salt with candesartan. The increased TUNEL-positive cells, Bax/Bcl-2 and cleaved-caspase3 protein abundance was ameliorated by L-NAME in vivo. In vitro, sodium nitroprusside, a nitric oxide donor, can also increase Bax/Bcl-2 and cleaved-caspase3 protein level in HK-2 cell. Thus, low-salt diet combined with candesartan in nephritis rats led to AKI, and the mechanism involved the increase of eNOS/NO, which linked to the decrease of blood pressure and the increase of apoptosis. This study provides practical guidance for salt intake in cases of RAS inhibitor usage clinically.

GYY4137, a H2S donor, ameliorates kidney injuries in diabetic mice by modifying renal ROS-associated enzymes.

Diabetic nephropathy (DN) is a common microvascular complication of both type 1 and type 2 diabetes mellitus and often advances to end-stage renal disease. Oxidative stress plays an important role in the pathogenesis and progress of DN. Hydrogen sulfide (H2S) is considered as a promising candidate for the management of DN. But the antioxidant effects of H2S in DN have not been fully studied. In mouse model induced by high-fat diet and streptozotocin, GYY4137, a H2S donor, ameliorated albuminuria at weeks 6 & 8 and decreased serum creatinine at week 8, but not hyperglycemia. Renal nitrotyrosine and urinary 8-isoprostane were reduced along with the suppressed levels of renal laminin and kidney-injury-molecule 1. Renal NADPH oxidase (NOX) 2 was lower but heme oxygenase (HO) 2, paraoxonase (PON) 1, PON2 were higher in DN+GYY than DN group. NOX1, NOX4, HO1, superoxide dismutases 1-3 were similar between groups. Except for a rise at HO2, all the affected enzymes were unchanged in mRNA levels. The affected reactive-oxygen-species (ROS) enzymes were mainly located in the renal sodium-hydrogen-exchanger positive proximal tubules with similar distribution but changed immunofluorence in GYY4137 treated DN mice. Kidney morphological alterations in DN mice under light and electrical-microscopes were also improved by GYY4137. Thus, exogenous H2S administration may improve the renal oxidative damage in DN by reducing ROS production and enhancing ROS cleavage in kidney via the affected enzymes. This study may shed a light on therapeutic applications in diabetic nephropathy with H2S donors in the future.

Assessment of Urinary Exosomal NHE3 as a Biomarker of Acute Kidney Injury.

The diagnosis of acute kidney injury (AKI) traditionally depends on the serum creatinine (Scr) and urine output, which lack sufficient sensitivity and specificity. Using urinary exosomes as a biomarker has unique advantages. To assess whether urinary exosomal Na+/H+ exchanger isoform 3 (NHE3) protein could serve as a biomarker of AKI, we constructed four AKI rat models: cisplatin (7.5 mg/kg) injected intraperitoneally (IP), furosemide (20 mg/kg, IP) with a low-NaCl (0.03%) diet, a low-NaCl (0.03%) diet with candesartan (1 mg/kg, IP) and bilateral ischemia and reperfusion (I/R) injury for 40 min. Additionally, we assessed six sepsis-associated AKI patients and six healthy volunteers. Urinary exosomes were extracted by ultracentrifugation, and the NHE3 protein abundance was tested by immunoblotting for all the AKI rats and human subjects. The isolated cup-shaped particles with an average diameter of 70 nm and enrichment in CD63 were identified as exosomes. NHE3 abundance was six times higher in exosomes than in the whole urine. In cisplatin-induced AKI rats, urinary exosomal NHE3 was increased on day 2, one day earlier than the increases in Scr and blood urea nitrogen (BUN). In additional rats, urinary exosomal NHE3 decreased along with the decline in Scr after EPO pretreatment. In volume-depletion AKI induced by furosemide injection with a low-NaCl diet, the urinary exosomal NHE3 expression was higher than that in the control. Under a low-NaCl diet with candesartan-related AKI, the urinary exosomal NHE3 was elevated on day 5, earlier than Scr. In I/R-injury AKI, the urinary exosomal NHE3 was also raised compared with that in the control. In humans, the urinary exosomal NHE3 level was also elevated in sepsis-associated AKI patients in comparison with that in the healthy volunteers. The urinary exosomal NHE3 was increased in multiple AKI; it may be used as a diagnostic biomarker of AKI.

Hydroxychloroquine Inhibits Cardiac Conduction in Aged Patients with Nonmalaria Diseases.

BACKGROUND: The COVID-19 pandemic has brought increased focus on hydroxychloroquine (HCQ), as doctors, the medical community, and policymakers around the world attempt to understand how the risks of HCQ weigh against unknown benefits. We aim to evaluate the effects of HCQ on cardiac conduction, thus contributing to the global understanding of implications of HCQ use. METHODS: We reviewed 717 cases of nonmalaria patients treated with HCQ (302) or without HCQ (415) in our hospital from 2008 to 2019, analyzed the cardiac conduction recorded by electrocardiogram (122 vs. 180) including heart rate (HR), PR, and corrected-QT (QTc) intervals, and explored the relationship of cardiac conduction with age, HCQ dosage, HCQ duration, sex, and primary diseases in HCQ users. RESULTS: The all-cause mortality is similar between HCQ and non-HCQ groups (4.0 vs. 4.3%, p = 0.85). Patients aged 45 years or older, not younger ones, have lower HR (80.1 ± 1.7 vs. 85.7 ± 1.8 bpm, p = 0.03) but longer PR (163 ± 3.4 vs. 146.6 ± 4.2 ms, p = 0.003) and QTc (417.8 ± 3.8 vs. 407.7 ± 2.7 ms, p = 0.03) in HCQ than those in non-HCQ. The age in the HCQ group is positively correlated with PR (R = 0.31, p < 0.01) and QTc (R = 0.34, p < 0.01) but not HR. HR, PR, and QTc are not related to HCQ dosage (0.1-0.6 g/day), HCQ duration (0.2-126 months), sex, primary diseases, and repeated exams. CONCLUSION: Age is the most important risk factor of HCQ on cardiac conduction in nonmalaria patients. Electrocardiogram monitoring is suggested in aged patients due to the effects of HCQ on HR, PR, and QTc.

Early 1,25-Dihydroxyvitamin D3 Supplementation Effectively Lowers the Incidence of Type 2 Diabetes Mellitus via Ameliorating Inflammation In KK-Ay Mice.

Few studies have been performed to investigate the effect of vitamin D supplementation and T2DM in type 2 diabetic animal models. The present study aimed to explore the relationship between early 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the incidence of T2DM and determine whether early 1,25(OH)2D3 supplementation was associated with inflammation in KK-Ay mice. The KK-Ay mice were divided into 4 vitamin D treatment groups, the low-dose vitamin D supplementation group (VDS-L, 1.5 µg/kg 1,25(OH)2D3), moderate-dose vitamin D supplementation group (VDS-M, 3.0 µg/kg 1,25(OH)2D3), high-dose vitamin D supplementation group (VDS-H, 6.0 µg/kg 1,25(OH)2D3) and the model control group (MC). C57BL/6J mice were used as the controls. The treatment period lasted for 9 wk. During this treatment period, fasting blood glucose (FBG) level of the mice was measured on a weekly basis. The levels of lipid profile, insulin and inflammation biomarkers were determined after 9 wk of 1,25(OH)2D3 intragastric gavage. After 9 wk of 1,25(OH)2D3 intragastric gavage, FBG level was significantly decreased in the vitamin D treatment groups compared with the MC group. The number of T2DM incidence in the VDS-L group (n=7), VDS-M group (n=5) and VDS-H group (n=3) was lower than those in the MC group (n=10) on week 9. Moreover, serum C-reactive protein (CRP) and interleukin-6 (IL-6) in the vitamin D treatment groups were significantly suppressed by 1,25(OH)2D3 administration compared with the MC group. Early 1,25(OH)2D3 supplementation could effectively lower the incidence of T2DM via ameliorating inflammation in KK-Ay mice.

Prodrug Nanomedicine Inhibits Chemotherapy-Induced Proliferative Burst by Altering the Deleterious Intercellular Communication.

Chemotherapy is one of the most commonly used clinical antitumor strategies. However, the therapy-induced proliferative burst, which always accompanies drug resistance and metastasis, has become a major obstacle during treatment. Except for some endogenous cellular or genetic mechanisms and some microenvironmental selection pressures, the intercellular connections in the tumor microenvironment (TME) are also thought to be the driving force for the acquired drug resistance and proliferative burst. Even though some pathway inhibitors or cell exempting strategies could be applied to partially avoid these unwanted communications, the complexity of the TME and the limited knowledge about those unknown detrimental connections might greatly compromise the efforts. Therefore, a more broad-spectrum strategy is urgently needed to relieve the drug-induced burst proliferation during various treatments. In this article, based on the possible discrepancies in metabolic activity between cells with different growth rates, several ester-bond-based prodrugs were synthesized. After screening, 7-ethyl-10-hyodroxycamptothecin-based prodrug nanoparticles were found to efficiently overcome the paclitaxel resistance, to selectively act on the malignantly proliferated drug-resistant cells and, furthermore, to greatly diminish the proliferative effect of common cytotoxic agents by blocking the detrimental intercellular connections. With the discriminating ability against malignant proliferating cells, the as-prepared prodrug nanomedicine exhibited significant anticancer efficacy against both drug-sensitive and drug-resistant tumor models, either by itself or by combining with highly potent nonselective chemotherapeutics. This work provides a different perspective and a possible solution for the treatment of therapy-induced burst proliferation.