Atorvastatin reduces contrast media-induced pyroptosis of renal tubular epithelial cells by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired renal failure. However, there is no effective treatment of CI-AKI, and its mechanism is unknown. Interestingly, atorvastatin has been reported to be effective in renal injury. Therefore, the aim of this study was to explore the effect and possible molecular mechanism of atorvastatin in CI-AKI. METHODS: On the CI-AKI in vitro model, rat tubular epithelial cells (NRK-52E) were treated with 18 mg I/ml meglumine diatrizoate (MEG) and then pretreated with atorvastatin. pcDNA3.1-TLR4 treatment was performed to overexpress toll-like receptor 4 (TLR4) in NRK-52E cells. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) kits were used to detect NRK-52E cell viability as well as LDH release in each group, respectively; qRT-PCR to determine mRNA expression of TLR4 in cells; western blot to detect protein expression levels of pyroptosis-related proteins (NLRP3, caspase-1, ASC, and GSDMD) and TLR4/MyD88/NF-κB signaling pathway-related proteins (TLR4, MyD88, NF-κBp65, and p-NF-κB p65) in cells. RESULTS: MEG treatment significantly inhibited the viability of NRK-52E cells, increased pro-inflammatory factor levels and promoted pyroptosis, representing successful establishment of a rat tubular epithelial cell (NRK-52E) CI-AKI in vitro model. Notably, atorvastatin increased the activity of MEG-treated NRK-52E cells and alleviated cell injury in a concentration-dependent manner. In addition, atorvastatin significantly down-regulated the expression of TLR4 in MEG-treated NRK-52E cells. However, overexpression of TLR4 inhibited the effects of atorvastatin on increasing cell viability, alleviating cell injury, reducing pro-inflammatory factors (IL-1ß, IL-6, and TNF-α) levels, and inhibiting apoptosis (by down-regulating the expression of NLRP3, caspase-1, ASC, and GSDMD). Furthermore, atorvastatin also inhibited the expression of TLR4/MyD88/NF-κB pathway-related proteins (TLR4, MyD88, and p-NF-κB p65). CONCLUSION: Atorvastatin can attenuate CI-AKI through increasing the activity of MEG-treated renal tubular epithelial cells, relieving cell injury, as well as inhibiting pyroptosis and inflammation. More importantly, the mechanism was achieved by inhibiting the TLR4//MyD88/NF-κB signaling pathway.

Electro-microenvironment modulated inhibition of endogenous biofilms by piezo implants for ultrasound-localized intestinal perforation disinfection.

Endogenous bacterial infections from damaged gastrointestinal (GI) organs have high potential to cause systemic inflammatory responses and life-threatening sepsis. Current treatments, including systemic antibiotic administration and surgical suturing, are difficult in preventing bacterial translocation and further infection. Here, we report a wireless localized stimulator composed of a piezo implant with high piezoelectric output serving as an anti-infective therapy patch, which aims at modulating the electro-microenvironment of biofilm around GI wounds for effective inhibition of bacterial infection if combined with ultrasound (US) treatment from outside the body. The pulsed charges generated by the piezo implant in response to US stimulation transfer into bacterial biofilms, effectively destroying their macromolecular components (e.g., membrane proteins), disrupting the electron transport chain of biofilms, and inhibiting bacterial proliferation, as proven by experimental studies and theoretical calculations. The piezo implant, in combination with US stimulation, also exhibits successful in vivo anti-infection efficacy in a rat cecal ligation and puncture (CLP) model. The proposed strategy, combining piezo implants with controllable US activation, creates a promising pathway for inhibiting endogenous bacterial infection caused by GI perforation.

Redox-Mediated Artificial Non-Enzymatic Antioxidant MXene Nanoplatforms for Acute Kidney Injury Alleviation.

Acute kidney injury (AKI), as a common oxidative stress-related renal disease, causes high mortality in clinics annually, and many other clinical diseases, including the pandemic COVID-19, have a high potential to cause AKI, yet only rehydration, renal dialysis, and other supportive therapies are available for AKI in the clinics. Nanotechnology-mediated antioxidant therapy represents a promising therapeutic strategy for AKI treatment. However, current enzyme-mimicking nanoantioxidants show poor biocompatibility and biodegradability, as well as non-specific ROS level regulation, further potentially causing deleterious adverse effects. Herein, the authors report a novel non-enzymatic antioxidant strategy based on ultrathin Ti3 C2 -PVP nanosheets (TPNS) with excellent biocompatibility and great chemical reactivity toward multiple ROS for AKI treatment. These TPNS nanosheets exhibit enzyme/ROS-triggered biodegradability and broad-spectrum ROS scavenging ability through the readily occurring redox reaction between Ti3 C2 and various ROS, as verified by theoretical calculations. Furthermore, both in vivo and in vitro experiments demonstrate that TPNS can serve as efficient antioxidant platforms to scavenge the overexpressed ROS and subsequently suppress oxidative stress-induced inflammatory response through inhibition of NF-κB signal pathway for AKI treatment. This study highlights a new type of therapeutic agent, that is, the redox-mediated non-enzymatic antioxidant MXene nanoplatforms in treatment of AKI and other ROS-associated diseases.

Smart Ti3C2Tx MXene Fabric with Fast Humidity Response and Joule Heating for Healthcare and Medical Therapy Applications.

An increasing utilization of flexible healthcare electronics and biomedicine-related therapeutic materials urges the development of multifunctional wearable/flexible smart fabrics for personal therapy and health management. However, it is currently a challenge to fabricate multifunctional and on-body healthcare electronic devices with reliable mechanical flexibility, excellent breathability, and self-controllable joule heating effects. Here, we fabricate a multifunctional MXene-based smart fabric by depositing 2D Ti3C2Tx nanosheets onto cellulose fiber nonwoven fabric via special MXene-cellulose fiber interactions. Such multifunctional fabrics exhibit sensitive and reversible humidity response upon H2O-induced swelling/contraction of channels between the MXene interlayers, enabling wearable respiration monitoring application. Besides, it can also serve as a low-voltage thermotherapy platform due to its fast and stable electro-thermal response. Interestingly, water molecular extraction induces electrical response upon heating, i.e., functioning as a temperature alarm, which allows for real-time temperature monitoring for thermotherapy platform without low-temperature burn risk. Furthermore, metal-like conductivity of MXene renders the fabric an excellent Joule heating effect, which can moderately kill bacteria surrounding the wound in bacteria-infected wound healing therapy. This work introduces a multifunctional smart flexible fabric suitable for next-generation wearable electronic devices for mobile healthcare and personal medical therapy.

[Quantitative Assessment of Skin Thickness using High Frequency Ultrasound in Systemic Sclerosis].

OBJECTIVE: To investigate the performance of high frequency ultrasound in the assessment of skin thickness in patients with systemic sclerosis (SSc). METHODS: The study included 82 SSc (SSc group) and 67 healthy volunteers (control group) from 2014 to 2016. The skin thickness at bilateral middle fingers and forearms,anterior chest and abdominal wall was measured using high frequency ultrasound. All the patients with SSc underwent the modified rodnan skin score (mRSS) over 17 anatomical sites by an experienced dermatologist. The differences in age,sex,height,body mass,body mass index (BMI) and skin thickness between SSc patients and healthy controls were compared. Receiver operating characteristic (ROC) curve analysis was performed to determine the performance of high frequency ultrasound in the differentiation of SSc from healthy skin,and the correlation of mRSS with skin thickness were analyzed. RESULTS: SSc patients and healthy controls shared similar demographic features (age,sex ratio,height,body mass,BMI) (P>0.05). Skin thickness values in SSc patients were increased significantly at fingers and forearms compared with healthy controls (P<0.05). The area under the curve (AUC) was 0.938, 0.905, 0.608, 0.586, 0.398, 0.321 at right and left finger,right and left forearm,chest and abdominal wall. Among them,AUC>0.9 of right and left fingers can be used for diagnosis,The skin thickness cut-off value for determining the diagnosis of SSc were as follows: 1.35 mm at the right finger with 84.1% sensitivity and 95.5% specificity,1.26 mm at the right forearm with 86.6% sensitivity and 89.6% specificity,respectively. Skin thickness increased significantly with mRSS. The correlation of total mRSS scores with total skin thickness was 0.599 (P<0.001),and the correlation of local mRSS score with local skin thickness were 0.400-0.623 (P<0.001),with the highest correlation coefficient at right finger and the lowest at abdomen. CONCLUSION: High frequency ultrasound may reflect extent of skin involvement of SSc,and skin thickness assessed with high frequency ultrasound appeared to be highly specific and sensitive at fingers.

Blood compatibility comparison for polysulfone membranes modified by grafting block and random zwitterionic copolymers via surface-initiated ATRP.

For blood-contacting materials, good blood compatibility, especially good anticoagulant property is of great importance. Zwitterionic polymers have been proved to be resistant to nonspecific protein adsorption and platelet adhesion; however, their anticoagulant property is always inadequate. In this study, two kinds of zwitterionic copolymers (sulfobetaine methacrylate and sodium p-styrene sulfonate random copolymer and block copolymer) with sulfonic groups were covalently grafted from polysulfone (PSf) membranes via surface-initiated atom transfer radical polymerization (SI-ATRP) to improve blood compatibility. Field emission scanning electron microscopy (FE-SEM), attenuated total reflectance-Fourier transform infrared spectra (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), and static water contact angle (WCA) were applied to characterize the morphologies, chemical compositions and hydrophilicity of the modified membranes. All the zwitterionic copolymer modified membranes showed improved blood compatibility, especially the anticoagulant property was obviously enhanced compared to the pristine PSf and simple zwitterionic polymer modified membranes. We also found that the random copolymer modified membranes showed better resistance to platelet adhesion than the block copolymer modified membranes. The zwitterionic copolymer modified membranes with integrated antifouling property and blood compatibility provided wide choice for specific applications such as hemodialysis, hemofiltration, and plasma separation.

[Diagnostic value of ultrasound imaging in chronic gouty arthritis].

OBJECTIVE: To determine the diagnostic value of ultrasound imaging in chronic gouty arthritis. METHODS: Ultrasound imaging of 32 patients with chronic gouty arthritis were compared with those of 36 patients with non-gouty joint diseases. A logistic model was obtained to establish the associations between ultrasound appereances and gouty arthritis. Receiver operator characteristic (ROC) curve was constructed to evaluate the performance of the logistic model. RESULTS: A double contour sign of articular cartilage, a snowstorm appearance of the joint fluid, and a hyperecho around the periarticular tendon had diagnostic value for chronic gouty arthritis. According to the logistic regression analysis, the accuracy of predicting chronic gouty arthritis was 95.59% (65/ 68), and the area under curve of ROC was 3.987 +/- 0.011 (P < 0.05). CONCLUSION: A double contour sign of articular cartilage, a snowstorm appearance of the joint fluid, and a hyperecho around the periarticular tendon have diagnostic value. The combination of these appearances can improve diagnosis of chronic gouty arthritis.

[Contrast-enhanced ultrasound parameters for early chronic kidney diseases and their associations with laboratory results].

OBJECTIVE: To determine the value of contrast-enhanced ultrasound (CEUS) for assessing renal blood perfusion changes and severity of early chronic kidney diseases (CKD). METHODS: The study included 20 patients with clinical diagnosed CKD (grade 1-3) (case group) and fifteen normal adults (control group). They were given real time CEUS, assessing left renal cortex blood perfusion. We identified the time-intensity curve (TIC) parameters that could differentiate participants between the two groups, and tested their correlations with glomerular filtration rate (eGFR), quantity of urinary protein and cystatin C. RESULTS: Significant differences were found in rise time (RT), area under the curve (AUC), time from peak to one half, and time to peak (TTP) between the two groups (P< 0.05). eGFR was negatively correlated with all of the four TIC parameters (P<0. 05). The quantity of urinary protein was positively correlated with three of the four TIC parameters (except RT). Cystatin C was positively correlated with all of the four TIC parameters (P<0. 05). CONCLUSION: CEUS can detect changes of blood flow perfusion in patients with early chronic kidney disease. The perfusion parameters are associated with laboratory results reflecting renal damages.

Ultrasonic appearance of rhabdomyolysis in patients with crush injury in the Wenchuan earthquake.

BACKGROUND: On May 12, 2008, a major earthquake hit Wenchuan County in Sichuan Province of China. The number of cases of crush injury following this event was high. Ultrasonic appearance of rhabdomyolysis (RM) caused by crush injury in the Wenchuan earthquake was observed to evaluate the diagnostic value of ultrasound for detection of rhabdomyolysis. METHODS: We analyzed clinical and ultrasonic manifestations of 50 cases of RM and 18 cases of RM with osteofascial compartment syndrome (OCS). All cases were caused by crush injury in the Wenchuan earthquake. For these RM patients, we also evaluated the correlations between creatine kinase (CK) and the scope of the muscle lesions as observed by ultrasound. RESULTS: There were differences in clinical symptoms, physical signs and ultrasonic appearance between the two groups of patients. The ultrasonic characteristics of the RM were as follows: the striated muscle in the lesions thickened with good overall continuity, and the muscle texture was vague; the strength of the echo was uneven and the echo was cloudy or ground glass-like. Liquid dark zones appeared between muscles and were spindle-like or irregular in shape. There were no blood flow signals in the liquid dark areas. The volume of the striated muscle increased in patients with OCS; the fascia wrapping the muscle showed arched protrusions and significant displacement. The flow velocity of the distal arteries decreased and the spectrum was abnormal. The muscle lesion scope of RM group and RM and OCS group was (7.8 +/- 2.0) cm and (13.6 +/- 3.1) cm, respectively. The correlation coefficient (r) between the muscle lesion scope and the CK was 0.681 for the RM group (P < 0.05) and 0.516 for the RM and OCS group (P < 0.05). CONCLUSIONS: The ultrasonogram of RM has characteristic manifestations and can provide important information for clinical diagnosis and treatment of rhabdomyolysis.

Preparation of Cu2+-loaded porous chitosan particles for immunoglobulin G adsorption.

Chitosan porous particles were prepared using a precipitation technique. The porous particles could bind Cu(2+), from which Cu(2+)-loaded porous particles were prepared. The Cu(2+)-loaded porous chitosan particles could remove immunoglobulin (Ig) G more selectively than albumin, IgA and IgM from aqueous solutions and human plasma. The effect of the volume ratio of plasma to particles on protein adsorption was studied, with the results indicating that a volume ratio of 3:1 might be a good choice for clinical use. The particles could be easily incorporated into a column. When human plasma was applied to the particle column, higher removal efficiency was obtained. These results suggested that Cu(2+)-loaded porous particles may be a potentially good sorbent for IgG removal from plasma.

Evaluation of polyethersulfone highflux hemodialysis membrane in vitro and in vivo.

A new hemodialysis membrane manufactured by a blend of polyethersulfone (PES) and polyvinylpyrrolidone (PVP) was evaluated in vitro and in vivo. Goat was selected as the experimental animal. The clearance and the reduction ratio after the hemodialysis of small molecules (urea, creatinine, phosphate) for the PES membrane were higher in vitro than that in vivo. The reduction ratio of beta(2)-microglobulin was about 50% after the treatment for 4 h. The biocompatibility profiles of the membranes indicated slight neutropenia and platelet adhesion at the initial stage of the hemodialysis. Electrolyte, blood gas, and blood biochemistry were also analyzed before and after the treatment. The results indicated that PES hollow fiber membrane had a potential widely use for hemodialysis.

[Effects of interferon-gamma on tubular epithelial-myofibroblast transdifferentiation in vitro].

OBJECTIVE: To investigate the effects of interferon-gamma (IFN-gamma) on tubular epithelial-myofibroblast transdifferentiation (TEMT) induced by transforming growth factor (TGF-beta1). METHODS: The normal rat kidney tubular epithelial cells (NRK52E) were cultured and divided into blank (NRK52E cells only) control group, TGF-beta1 (3 ng/mL) treated group, IFN-gamma (1000 IU/mL) treated group, and IFN-gamma inhibition group (TGF-beta1 3 ng/mL + IFN-gamma 200, 400, 600, 1000, 2000, 3000 IU/mL). After 72 hours of treatment, the morphology of cells was observed under phase-contrast microscopy and scanning electron microscopy. The expressions of a-smooth muscle actin (alpha-SMA) and connective tissue growth factor (CTGF) were detected by immunocytochemistry. Flowcytometry was employed to measure the percentage of alpha-SMA+ cells and the mean channel fluorescence (MCF). The expressions of alpha-SMA mRNA and CTGF mRNA were examined by reverse transcription-polymerase chain reaction analyses (RT-PCR). The level of collagen in the culture supernatant was measured by Enzyme-linked immunoadsordent assay (ELISA). RESULTS: NRK52E cells cultured in the control group showed a classic cobblestone morphology. TGF-beta1 induced NRK52E cells to transdifferentiate into myofibroblast-like cells, which showed strong alpha-SMA immunostaining. The TGF-beta1 treated cells had higher percentage of a-SMA+ cells, MCF and alpha-SMA mRNA, increased CTGF mRNA expression, and ascended collagen III than the blank controls (P<0.05). IFN-gamma treated alone did not make any changes to the cell morphology, the expressions of alpha-SMA mRNA and CTGF mRNA and the level of collagen III (P>0.05). IFN-gamma exerted a strong inhibitory effect on the TEMT induced by TGF-beta1. With the increase of IFN-gamma, the percentage of alpha-SMA+ cells, the level of collagen III, and the expressions of alpha-SMA mRNA and CTGF mRNA decreased (P<0.05). CONCLUSION: IFN-gamma inhibits the TEMT induced by TGF-beta1 and reduces the level of collagen III.

[Inflammatoin, oxidative stress and carbonyl stress in uremic patients].

OBJECTIVE: To evaluate the states of inflammation, oxidative stress and carbonyl stress in uremic patients and analyze their relationships. METHODS: One hundred and twenty-eight cases were divided into 6 groups: non-dialysis uremia group (n=25), peritoneal dialysis group (n=19), hemophan(Hem) membrane dialysis group (n=25), polyamide (PS) membrane dialysis group (n=25), diabetes with normal renal function group (n= 23) and normal control group (n=11). Spectrophotometry and immune turbidimetry were used to measure the serum SOD, VitC, VitE, MDA and total carbonyl compounds (TCC) levels. RESULTS: Compared with non-uremia groups, the uremia groups had lower serum SOD, VitE and VitC levels, but higher CRP, MDA and TCC levels (P < 0.01). The peritoneal dialysis group had higher SOD, VitC, VitE levels in comparison with the Hem group, but did not differ from PS group in those levels (P > 0.05). The MDA and TCC levels in the peritoneal dialysis group were lower than those in the two hemodialysis groups, but there were no significant differences in CRP level between the groups. Compared with Hem group, the PS group had higher VitC, VitE levels, higher TCC clearance, and the same SOD, MDA, CRP and pre-dialysis TCC levels. When the variables were analyzed with TCC, the results of multi-variate regression showed that the standardized coefficients were MDA (0.727, P < 0.01), CRP (0.370, P < 0.01), SOD (0.192, P < 0.05), VitC (-0.153, P < 0.01), VitE (0.054, P = 0.30) respectively. CONCLUSION: Uremic patients are in inflammatory, oxidative-stress and carbonyl-stress states. Inflammation and oxidative stress are probably the important mechanism of carbonyl stress. It is not yet clear whether dialysis methods can influence uremic inflammatory, oxidative-stress or carbonyl-stress state.

[Effects of panax notoginseng saponins on the process of renal interstitial fibrosis after unilateral ureteral obstruction in rats].

OBJECTIVE: To evaluate the effects of panax notoginseng saponins (PNS) on the process of renal interstitial fibrosis after unilateral ureteral obstruction in rats. METHODS: In this study, female sprague-Dawley rats were randomly divided into 3 groups: Sham operation group (S group), Operation group (O group), and Operation plus PNS group (P group). The unilateral ureters of the rats were ligated as the operation to create renal interstitium fibrosis. The rats were sacrificed at postoperative days 3, 7, 14 and 21. After sacrifice, the obstructed kidneys of the rats were sliced to make pathological sections. The sections observed under light microscope to evaluate the results of hematoxylin and eosin (HE) staining, Masson staining or proliferative cell nuclear antigen(PCNA) and alpha-smooth muscle actin (alpha-SMA) detected by immunohistochemistry. RESULTS: After operation, the operated rats showed progressive renal interstitium fibrosis. The expression of alpha-smooth muscle actin in renal tubular epithelial cell and interstitium increased significantly. In comparison with the rats of operation group, the PNS-treated rats had less alpha-smooth muscle actin in interstitium. In addition, PNS could significantly increase the number of cell expressed proliferative cell nuclear antigen in tubules. CONCLUSION: The lesions of tubules-interstitium got worse and the renal interstitium showed progressive fibrosis gradually in rats with unilateral ureteral obstruction. PNS was noted to have ameliorative effects on the fibrotic process of renal interstitium; it can block tubular epithelial-myofibroblast transdifferentiation.

[Effects of hepatocyte growth factor on IL-1alpha triggered tubular epithelial-myofibroblast transdifferentiation and fibronectin secretion in vitro].

OBJECTIVE: To observe the effects of hepatocyte growth factor (HGF) on tubular epithelial-myofibroblast transdifferentiation (TEMT) triggered by IL-1alpha and the fibronectin secretion of TEMT. METHODS: The normal rat kidney tubular epithelial cell line (NRK52E) was cultured for six days on plastic or collagen type I-coated plates in the presence or absence of HGF or IL-1alpha. The morphology of transdifferentiation tubular cells was observed by scanning electron microscopy (SEM) and phase-contrast microscopy. The number of alpha-SMA+ cells, the percentage of alpha-SMA+ cells and the mean channel fluorescence (MCF) were assessed by immunohistochemistry and flowcytometry. The level of fibronectin in supernatant was measured by ELISA. RESULTS: The NRK52E cells triggered by IL-1alpha became fibroblast-like morphologically, and strong alpha-SMA immunostaining of those cells was seen. The level of FN in the culture supernatant, the percentage of alpha-SMA+ cells and the MCF of cells triggered by IL-1alpha were obviously higher than those of blank control group (P<0.05). In the groups with IL-1alpha and different doses of HGF, the transdifferentiation of NRK52E cells was inhibited. With the increase of HGF dose, the percentage of alpha-SMA+ cells and the level of FN showed a tendency to decrease. There was no significant difference between the groups treated with only HGF at different dose levels and the blank control group (P>0.05). CONCLUSION: IL-1alpha can induce tubular epithelial cell to transdifferentiate to myofibroblast and increase the secretion of FN. These results suggest that TEMT may play an important role in the pathogenesis of renal fibrosis. HGF could block the transdifferentiation of tubular epithelial cell and inhibit the secretion of FN. These would provide a novel therapeutic strategy for the treatment of renal interstitial fibrosis and end stage renal disease.