Search

Study Design: In vitro biomechanical study using human spine specimens. Objective: To find the biomechanical consequences of prophylactic vertebroplasty post fatigue loading. Summary Of Background Data: Percutaneous vertebroplasty man be an effective treatment for osteoporotic vertebral compression fracture. One frequently observed complication post surgery is the adjacent vertebral failure (AVF). The prophylactic vertebroplasty was proposed to prevent the AVF. The vertebroplasty is, nevertheless, an invasive intervention. More scientific proves are needed for the application of this surgery on a still intact vertebra. Methods: Fourteen 5-level fresh human cadaveric thoracic motion segments were divided into standard and prophylactic group. Both ends of the specimen were mounted, leaving the center 3 vertebrae free. The lower level of free vertebrae was artificially injured and cement augmented. The center level vertebra of standard group remained intact and nonaugmented. The center level vertebra of prophylactic group also remained intact, but augmented with bone cement. The specimen was applied with a 2-hour, 5-Hz, 630-N (mean) compressive fatigue loading. Impulse test and CT scanning were conducted both before and after fatigue loading to find the variance of strain compliance of cortical shell and height of vertebral body. Results: The strain compliance of cortical shell is generally not statistically significantly affected by the fatigue loading, cement augmentation and vertebral level (All P > 0.05). The only exception is that the cortical strain compliance of augmented vertebrae tentatively decreased post fatigue loading (P = 0.012 for tensile strain compliance, and P = 0.049 for compressive strain compliance). The height loss of intact vertebra adjacent to a 2-level augmented (or intact-augmented) vertebra is significantly lower than the one adjacent to a 1-level augmented (or injury-augmented) vertebra (P = 0.014). For an osteoporotic vertebra, neither cortical strain compliance nor vertebral height loss is connected with bone mineral density (all P > 0.05). Conclusion: The strain compliance of cortical shell is generally not a sensitive indicator to predict risk of fatigue injury if the fatigue loading is mild. The prophylactic augmentation strengthens the osteoporotic vertebrae, decreases the progression of vertebral height loss, reduces the anterior body shift, and hence protects the adjacent intact vertebra from elevated flexion bending. It can be cautiously suggested that if the vertebra is osteoporotic and adjacent level is located at pivot or lordotic level of spinal column, the prophylactic augmentation may be an option to prevent the AVF. [ABSTRACT FROM AUTHOR]

BACKGROUND: Greater than 50% of dialysis patients experience sleep disturbances. Cognitive-behavioral therapy (CBT) is effective for treating chronic insomnia, but its effectiveness has never been reported in peritoneal dialysis (PD) patients and its association with cytokines is unknown. We investigated the effectiveness of CBT in PD patients by assessing changes in sleep quality and inflammatory cytokines. STUDY DESIGN: Randomized control study with parallel-group design. SETTING & PARTICIPANTS: 24 PD patients with insomnia in a tertiary medical center without active medical and psychiatric illness were enrolled. INTERVENTION: The intervention group (N = 13) received CBT from a psychiatrist for 4 weeks and sleep hygiene education, whereas the control group (N = 11) received only sleep hygiene education. OUTCOMES & MEASUREMENTS: Primary outcomes were changes in the Pittsburgh Sleep Quality Index and Fatigue Severity Scale scores, and secondary outcomes were changes in serum interleukin 6 (IL-6), IL-1beta, IL-18, and tumor necrosis factor alpha levels during the 4-week trial. RESULTS: Median percentages of change in global Pittsburgh Sleep Quality Index scores were -14.3 (interquartile range, -35.7 to - 6.3) and -1.7 (interquartile range, -7.6 to 7.8) in the intervention and control groups, respectively (P = 0.3). Median percentages of change in global Fatigue Severity Scale scores were -12.1 (interquartile range, -59.8 to -1.5) and -10.5 (interquartile range, -14.3 to 30.4) in the intervention and control groups, respectively (P = 0.04). Serum IL-1beta level decreased in the intervention group, but increased in the control group (P = 0.04). There were no significant differences in changes in other cytokines. LIMITATIONS: This study had a small number of participants and short observation period, and some participants concurrently used hypnotics. CONCLUSIONS: CBT may be effective for improving the quality of sleep and decreasing fatigue and inflammatory cytokine levels. CBT can be an effective nonpharmacological therapy for PD patients with sleep disturbances. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Study Design: An in vivo clinical trial, and an in vitro cadaveric biomechanical and micromorphologic analysis. Objective: To find the feasibility of using viscoplastic bone cement for vertebroplasty. Summary Of Background Data: Vertebroplasty involved in bone cement reinforcement of fractured vertebra has shown promising clinical results. The most frequently observed complication of vertebroplasty is the cement leakage during surgery. Many methods were proposed and were successful at reducing the risk of leakage, such as creating a void within vertebra to reduce the injection pressure, increasing the cement viscosity to reduce the cement infiltration, etc. Nevertheless, a more cost-effective and safer surgery method is still the goal for many spine surgeons and researchers. Methods: To deliver the viscoplastic bone cement into the vertebra, a unipedicular tract and a void in the vertebra was created using a curette. The viscoplastic bone cement was then delivered into the void piece by piece and tamped for compactness with a blunt end tool. For the in vitro biomechanical test, 7 thoracic vertebrae were used. The intact specimens were compressed to lose 25% of its intact height, and then augmented with viscoplastic bone cement. Postaugmentation CT scanning was taken to examine the cement distribution, leakage path, and cement filling ratio within the vertebra. Postaugmentation compression test was conducted to examine the vertebral strength and stiffness, and then compared with the intact ones. Finally, the vertebrae were cut into slices for micromorphologic analysis. Results: The 6 in vivo clinical trials were all successfully operated with significant pain relief and showed no leakage during and after the surgery. The in vitro biomechanical test showed the cement augmentation significantly increased the vertebral strength (pre 3164 (229) N vs. post 3905 (484) N, P < 0.003), but tentatively decreased the vertebral stiffness (pre 1074 (74) N/mm vs. post 801 (370) N/mm, P = 0.081). The postaugmentation CT scanning showed the cement was well confined within the vertebra and the cement filling ratio was 21% (ranged from 15% to 29%). The depth that the viscoplastic bone cement infiltrated into the cancellous bone was 3.5 (0.6) mm, which is less than the depth [8.3 (2.2) mm, P < 0.001] of standard viscous bone cement vertebroplasty. Conclusion: Vertebroplasty using viscoplastic bone cement is clinically feasible and can effectively improve the vertebral strength and reduce the cement infiltration depth. The risk of cement leakage can also be decreased by using viscoplastic bone cement. [ABSTRACT FROM AUTHOR]

Excessive intake of free fatty acids (FFAs), especially saturated fatty acids, can lead to atherosclerosis and increase the incidence of cardiovascular diseases. FFAs also contribute to obesity, hyperlipidemia, and nonalcoholic fatty liver disease. Palmitic acid (PA) is human plasma's most abundant saturated fatty acid. It is often used to study the toxicity caused by free fatty acids in different organs, including vascular lipotoxicity. Fatty acid overload induces endothelial dysfunction through various molecular mechanisms. Endothelial dysfunction alters vascular homeostasis by reducing vasodilation and increasing proinflammatory and prothrombotic states. It is also linked to atherosclerosis, which leads to coronary artery disease, peripheral artery disease, and stroke. In this review, we summarize the latest studies, revealing the molecular mechanism of free fatty acid-induced vascular dysfunction, targeting insulin resistance, reactive oxygen species, inflammation, programmed cell death, ER stress, and mitochondrial dysfunction. Meanwhile, this review provides new strategies and perspectives for preventing and reducing the impact of cardiovascular diseases on human health through the relevant targeting molecular mechanism.

The development of durable photosensitizers is pivotal for advancing phototherapeutic applications in biomedicine. Here, we introduce a core-shell azobenzene-spiropyran structure on gold nanoparticles, engineered to enhance singlet oxygen generation. These nano-photosensitizers exhibit increased structural stability and thermal resistance, as demonstrated by slowed O-N-C bond recombination dynamics via in-situ Raman spectroscopy. Notably, the in-situ formation of merocyanine and a light-induced compact shell arrangement extend its half-life from 47 minutes to over 154 hours, significantly boosting singlet oxygen output. The nano-photosensitizer also shows high biocompatibility and notably inhibits tau protein aggregation in neural cells, even with phosphatase inhibitors. Further, it promotes dendritic growth in neuro cells, doubling typical lengths. This work not only advances chemical nanotechnology but also sets a foundation for developing long-lasting phototherapy agents for treating neurodegenerative diseases., (© 2024 Wiley-VCH GmbH.)

Aims: Advanced glycation end-products (AGEs) are implicated in the age-related decline of renal function, exacerbated by conditions, such as hyperglycemia and oxidative stress. The accumulation of AGEs in the kidneys contributes to the progressive decline in renal function observed with aging. However, the precise role and mechanisms of AGEs in the age-related decline of renal function remain unclear. In this study, we investigated the impact and potential mechanisms of AGEs on aging kidneys in naturally aging mice., Materials and Methods: Male C57BL/6 mice were divided into three groups: 6-, 57-, and 107-week-old. First, the 6- and 107-week-old mice were euthanized. The remaining mice were divided into young (6 weeks) and old (57 weeks) groups. The 57-week-old mice were orally administered aminoguanidine (100 mg/kg/day), an AGEs inhibitor, or vehicle for 13 weeks, resulting in a final age of 70 weeks. The serum and kidney tissues were collected for biochemical measurement, histological examination, immunohistochemistry staining, and immunoblotting analysis., Key Findings: Our findings revealed a notable accumulation of AGEs in both serum and kidney tissue specimens and renal dysfunction in naturally aging mice. Aminoguanidine not only reversed AGEs accumulation but also ameliorated renal dysfunction. Additionally, aminoguanidine attenuated the upregulation of fibrosis markers (phosphorylated p38/α-SMA and C/EBP homologous protein, CHOP), senescence markers (p53 and p21), and oxidative stress marker (4-HNE) in the aging kidneys., Significance: These findings underscore the critical role of AGEs in age-related renal dysfunction and highlight the therapeutic potential of aminoguanidine in mitigating fibrosis and senescence, offering prospective avenues for combating age-associated renal ailments., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Frailty describes the cumulative subtle health deficits leading to an increased vulnerability to insults among older individuals or disease-laden ones. The prevalence of frailty increases substantially and relentlessly over declining renal function. Frailty in patients with chronic kidney disease (CKD) carries kidney-specific risk factors, clinical correlates and outcomes associations, hence alternatively termed frail kidney phenotype by researchers. Pathogenetically, miRNAs participate extensively in the development and aggravation of frailty, including the occurrence of frail kidney phenotype in CKD patients. These understandings spark profound interest in discovering biomarkers for identifying this detrimental phenotype, and extracellular miRNAs emerge as potentially useful ones. Pilot studies identify promising miRNA candidates for evaluating intermediates and surrogates of frail kidney phenotype, and more are underway. Several potential miRNA species in biologic fluids, such as circulating miR-29b and miR-223 (as inflammatory markers), exosomal miR-16-5p, miR-17/92 cluster members, and miR-106-5p (for uremic vasculopathy), serum exosomal miR-203a-3p (for uremic sarcopenia) have been examined and can be promising choices. Nonetheless, there remains research gap in affirming the direct connections between specific miRNAs and frail kidney phenotype. This stems partially from multiple limitations less well acknowledged before. From this perspective, we further outline the limitations and precautions prior to validating specific extracellular miRNA(s) for this purpose, from the definition of frailty definition, the functional and tissue specificity of miRNAs, the severity of CKD, and various technical considerations. It is expected that more affirmative studies can be produced for extending the utility of extracellular miRNAs in predicting frail kidney phenotype.

The unambiguous identification of protein species requires high sequence coverage. In this study, we successfully improved the sequence coverage of early secretory 10 kDa cell filtrate protein (CFP-10) and 6 kDa early secretory antigenic target (ESAT-6) proteins from the Mycobacterium tuberculosis complex (MTC) in broth culture media with the use of the 4-chloro-α-cyanocinnamic acid (Cl-CCA) matrix. Conventional matrices, α-cyano-hydroxy-cinnamic acid (CHCA) and 2,5-dihydroxybenzoic acid (DHB), were also used for comparison. After nanodiamond (ND) extraction, the sequence coverage of the CFP-10 protein was 87% when CHCA and DHB matrices were used, and the ESAT-6 protein was not detected. On the other hand, the sequence coverage for ND-extracted CFP-10 and ESAT-6 could reach 94% and 100%, respectively, when the Cl-CCA matrix was used and with the removal of interference from bovine serum albumin (BSA) protein and α-crystallin (ACR) protein. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was also adopted to analyze the protein mass spectra. A total of 6 prominent ion signals were observed, including ESAT-6 protein peaks at mass-to-charge ratios ( m / z ) of ∼7931, ∼7974, ∼9768, and ∼9813 and CFP-10 protein peaks at m / z of ∼10 100 and ∼10 660. The ESAT-6 ion signals were always detected concurrently with CFP-10 ion signals, but CFP-10 ion signals could be detected alone without the ESAT-6 ion signals. Furthermore, the newly found ESAT-6 peaks were also confirmed using a Mag-Beads-Protein G kit with an ESAT-6 antibody to capture the ESAT-6 protein, which was also consistent with the sequence coverage analysis.

Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI., (© 2024. The Author(s).)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients., (© 2024 Asian Pacific Society of Nephrology.)

Background: Older adults have a higher risk of developing vascular calcification (VC). Circulating miRNAs can be potential risk indicators. However, prior studies used single miRNA mostly, whereas miRNA panels were rarely evaluated. We aimed to examine whether a miRNA panel outperformed each miRNA alone, and analyzed whether advanced age affected VC risk predictive performance offered by the miRNA panel., Methods: We prospectively enrolled older adults (age ≥65 years) during their annual health checkup in 2017, and examined their VC severity followed by analyzing sera for VC regulatory miRNAs (miR-125b-5p, miR-125b-3p, and miR-378a-3p). We used multiple regression analyses to determine associations between each miRNA or a 3-combind panel and VC risk, followed by area under the receiver-operating-characteristics curve (AUROC) analysis. Participants were further divided to those of 65-75 and ≥75 years for comparison., Results: From 199 older adults screened, 169 (median age, 73.3 years) with available calcification assessment were analyzed, among whom 74.6 % having VC. Those with VC had significantly lower circulating miR-125b-5p, miR-125b-3p, and miR-378a-3p levels than those without. Regression analyses showed that the 3-combined miRNA panel exhibited significant associations with VC risk, with significantly higher AUROC than those of models based on individual miRNA. Importantly, in those ≥75 years, the miRNA-predicted risk of VC was more prominent than that in the 65-75 years group., Conclusion: A miRNA panel for VC risk prediction might outperform individual miRNA alone in older adults, and advanced age modified the association between circulating miRNAs and the risk of VC., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial competing interests to declare in relation to this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This review offers a synthesis of the current understanding of the impact of low-dose thallium (Tl) on public health, specifically emphasizing its diverse effects on various populations and organs. The article integrates insights into the cytotoxic effects, genotoxic potential, and molecular mechanisms of thallium in mammalian cells. Thallium, a non-essential heavy metal present in up to 89 different minerals, has garnered attention due to its adverse effects on human health. As technology and metallurgical industries advance, various forms of thallium, including dust, vapor, and wastewater, can contaminate the environment, extending to the surrounding air, water sources, and soil. Moreover, the metal has been identified in beverages, tobacco, and vegetables, highlighting its pervasive presence in a wide array of food sources. Epidemiological findings underscore associations between thallium exposure and critical health aspects such as kidney function, pregnancy outcomes, smoking-related implications, and potential links to autism spectrum disorder. Thallium primarily exerts cellular toxicity on various tissues through mitochondria-mediated oxidative stress and endoplasmic reticulum stress. This synthesis aims to shed light on the intricate web of thallium exposure and its potential implications for public health, emphasizing the need for vigilant consideration of its risks., Competing Interests: The authors declare no conflicts of interest.

From the traditional Chinese medicine point of view, although Houttuynia cordata extract (HCE) possesses an incredible amount of phytonutrients and exhibits antioxidant activities, excessive doses of HCE can cause danger to organisms and lead to death. In this study, we first examine HCE's overall phenolic and flavonoid content, antioxidant efficacy, and antibacterial activity. Results show that HCE is suitable as a bio-reducing agent for the microwave-assisted synthesis of silver nanoparticles (HCE-AgNPs) with enhanced antioxidant and antimicrobial performance. Under an optimized microwave condition (i.e., 100 °C for 10 min), the HCE-stabilized AgNPs were confirmed with a UV-visible peak at 430 nm and 19.7 ± 4.2 nm in size. Physicochemical properties of HCE-AgNPs were extensively characterized by zeta-potential, FT-IR, XRD, and XPS measurements. Compared to the HC extract counterpart, HCE-AgNPs display superior antioxidant activity, higher DPPH scavenging efficiency, and enhanced broad-spectrum bactericidal activity to inhibit the growth of all tested bacterial strains at doses of 2 μg/mL. Biosafety evaluation indicated that HCE-AgNPs are noncytotoxic on human red blood cells. These data show that the microwave synthesis of AgNPs exhibits a great antioxidant ability, superior antibacterial activity, and a trivial hemolytic effect, providing another bactericidal therapy strategy to address the increasing healthcare-associated infections.

Purpose: Coronavirus disease pandemic makes high requirements in delivering remote and efficient communication, and patient education. Because of the increases of digital and social media applications in Taiwan, we aim to apply Artificial Intelligence of LINE Chatbot to improve the self-care ability of patients undergoing peritoneal dialysis., Materials and Methods: We conducted the project since 1 May 2021 to 30 April 2022. We designed an automatically replied Chatbot system, and divided into six scopes of interaction interfaces, including peritoneal dialysis technique operation video, clinical reminder, home caring, hospital registration service, dietary guideline, and Automatic Peritoneal dialysis guidance. We surveyed patients' satisfaction with the LINE Chatbot 3 months later by the Likert 1-5 score-based questionnaire and the higher score indicated higher satisfaction., Results: There were 440 patients who joined the PD AI Chatbot study and use the Chatbot, but the satisfaction questionnaire recovery rate was only 297 patients. We found that 91.7% of participants agreed 'Overall satisfaction with patient intelligent Chatbot application'. More than 4 points accounted for 86.6%. We traced every click in each section of the Chatbot and explored the potential scenario patients face. The Chatbot statistically significant reduced infection rate of exit site and tunnel infection before using (p = .049 and .024). Furthermore, peritonitis rate decreased from 0.93 to 0.8/100 patient month after using Artificial Intelligence technique. Peritoneal dialysis Artificial Intelligence Chatbot had similar effect with face-to-face education., Conclusion: The innovative Chatbot allowed delivering remote and digital information's to improve patients' self-care ability. Peritoneal dialysis patients were highly recognized and satisfied with the tools. It deserves to further explore the long-term impact of Artificial Intelligence Chatbot in peritoneal dialysis care., (© 2023 Asian Pacific Society of Nephrology.)

Low-intensity pulsed ultrasound (LIPUS) is a kind of therapeutic ultrasound. It can help improve bone fracture repair and soft tissue healing. Our previous study found that LIPUS treatment could halt the chronic kidney disease (CKD) progression in mice; unexpectedly, we observed the improvement of CKD-reduced muscle weights by LIPUS treatment. Here, we further tested the protective potential of LIPUS on CKD-associated muscle wasting/sarcopenia using the CKD mouse models. Mouse models of both unilateral renal ischemia/reperfusion injury (IRI) with nephrectomy and adenine administration were used to induce CKD. LIPUS with condition of 3 MHz, 100 mW/cm 2 , 20 min/day was applied to the kidney of CKD mice. LIPUS treatment significantly reversed the increased serum BUN/creatinine levels in CKD mice. LIPUS effectively prevented the decrease in grip strength, muscle weight (soleus, tibialis anterior, and gastrocnemius muscles), cross-section areas of muscle fibres, and muscular phosphorylated Akt protein expression by immunohistochemistry, and the increase in muscular atrogenes Atrogin1 and MuRF1 protein expression by immunohistochemistry in CKD mice. These results indicated that LIPUS could help improve weak muscle strength, muscle mass loss, muscle atrophy-related protein expression, and Akt inactivation. LIPUS application may be an alternative non-invasive therapeutic intervention on the management of CKD-associated muscle wasting.

The accumulation of the uremic toxin indoxyl sulfate (IS) is a key pathological feature of chronic kidney disease (CKD). The effect of IS on ferroptosis and the role of IS-related ferroptosis in CKD are not well understood. We used a renal tubular cell model and an adenine-induced CKD mouse model to explore whether IS induces ferroptosis and injury and affects iron metabolism in the renal cells and the kidneys. Our results showed that exposure to IS induced several characteristics for ferroptosis, including iron accumulation, an impaired antioxidant system, elevated reactive oxygen species (ROS) levels, and lipid peroxidation. Exposure to IS triggered intracellular iron accumulation by upregulating transferrin and transferrin receptors, which are involved in cellular iron uptake. We also observed increased levels of the iron storage protein ferritin. The effects of IS-induced ROS generation, lipid peroxidation, ferroptosis, senescence, ER stress, and injury/fibrosis were effectively alleviated by treatments with an iron chelator deferoxamine (DFO) in vitro and the adsorbent charcoal AST-120 (scavenging the IS precursor) in vivo. Our findings suggest that IS triggers intracellular iron accumulation and ROS generation, leading to the induction of ferroptosis, senescence, ER stress, and injury/fibrosis in CKD kidneys. AST-120 administration may serve as a potential therapeutic strategy.

Owing to the widespread emergence and proliferation of antibiotic-resistant bacteria, the therapeutic benefits of antibiotics have been reduced. In addition, the ongoing evolution of multidrug-resistant pathogens poses a challenge for the scientific community to develop sensitive analytical methods and innovative antimicrobial agents for the detection and treatment of drug-resistant bacterial infections. In this review, we have described the antibiotic resistance mechanisms that occur in bacteria and summarized the recent developments in detection strategies for monitoring drug resistance using different diagnostic methods in three aspects, including electrostatic attraction, chemical reaction, and probe-free analysis. Additionally, to understand the effective inhibition of drug-resistant bacterial growth by recent nano-antibiotics, the underlying antimicrobial mechanisms and efficacy of biogenic silver nanoparticles and antimicrobial peptides, which have shown promise, and the rationale, design, and potential improvements to these methods are also highlighted in this review. Finally, the primary challenges and future trends in the rational design of facile sensing platforms and novel antibacterial agents against superbugs are discussed.

Background: Vascular calcification (VC) constitutes an important vascular pathology with prognostic importance. The pathogenic role of transforming growth factor-β (TGF-β) in VC remains unclear, with heterogeneous findings that we aimed to evaluate using experimental models and clinical specimens., Methods: Two approaches, exogenous administration and endogenous expression upon osteogenic media (OM) exposure, were adopted. Aortic smooth muscle cells (ASMCs) were subjected to TGF-β1 alone, OM alone, or both, with calcification severity determined. We evaluated miR-378a-3p and TGF-β1 effectors (connective tissue growth factor; CTGF) at different periods of calcification. Results were validated in an ex vivo model and further in sera from older adults without or with severe aortic arch calcification., Results: TGF-β1 treatment induced a significant dose-responsive increase in ASMC calcification without or with OM at the mature but not early or mid-term VC period. On the other hand, OM alone induced VC accompanied by suppressed TGF-β1 expressions over time; this phenomenon paralleled the declining miR-378a-3p and CTGF expressions since early VC. TGF-β1 treatment led to an upregulation of CTGF since early VC but not miR-378a-3p until mid-term VC, while miR-378a-3p overexpression suppressed CTGF expressions without altering TGF-β1 levels. The OM-induced down-regulation of TGF-β1 and CTGF was also observed in the ex vivo models, with compatible results identified from human sera., Conclusions: We showed that TGF-β1 played a context-dependent role in VC, involving a time-dependent self-regulatory loop of TGF-β1/miR-378a-3p/CTGF signaling. Our findings may assist subsequent studies in devising potential therapeutics against VC.

Low-intensity pulsed ultrasound (LIPUS), a therapeutic type of ultrasound, is known to enhance bone fracture repair processes and help some tissues to heal. Here, we investigated the therapeutic potential of LIPUS for the treatment of chronic kidney disease (CKD) in two CKD mouse models. CKD mice were induced using both unilateral renal ischemia/reperfusion injury (IRI) with nephrectomy and adenine administration. The left kidneys of the CKD mice were treated using LIPUS with the parameters of 3 MHz, 100 mW/cm 2 , and 20 min/day, based on the preliminary experiments. The mice were euthanized 14 days after IRI or 28 days after the end of adenine administration. LIPUS treatment effectively alleviated the decreases in the body weight and albumin/globulin ratio and the increases in the serum renal functional markers, fibroblast growth factor-23, renal pathological changes, and renal fibrosis in the CKD mice. The parameters for epithelial-mesenchymal transition (EMT), senescence-related signal induction, and the inhibition of α-Klotho and endogenous antioxidant enzyme protein expression in the kidneys of the CKD mice were also significantly alleviated by LIPUS. These results suggest that LIPUS treatment reduces CKD progression through the inhibition of EMT and senescence-related signals. The application of LIPUS may be an alternative non-invasive therapeutic intervention for CKD therapy.

A dimeric dithiolate-bridged species, [Fe(NO)(PS2)] 2 ( 1 ) containing two {FeNO} 7 units, can be isolated by treating [Fe(CO) 2 (NO) 2 ] with PS2H 2 (PS2H 2 = bis(2-dimercaptophenyl)phenylphosphine). Crystallographic studies reveal the syn-configuration of NO units and the bridging thiolates in the butterfly shape of the 2Fe2S core. Addition of PPh 3 to the solution of dinuclear 1 leads to the formation of mononuclear {FeNO} 7 [Fe(NO)(PS2)(PPh 3 )] ( 2 ) that shows electrochemical responses similar to those of 1 . One-electron reduction of 1 with Cp* 2 Co or KC 8 results in the isolation of thiolate-bridged bimetallic DNIC, [(PS2)Fe(μ-PS2)Fe(NO) 2 ] - ([ 3 ] - ), confirmed by several spectroscopies including single-crystal X-ray diffraction studies. The bimetallic DNIC [ 3 ] - is a rare example obtained from the one-electron reduction of a dinuclear Fe-NO {FeNO} 7 model complex. With the assistance of redox behaviors of 2 , electrochemical studies imply that the reduction of 1 leads to the formation of a mononuclear {FeNO} 8 [Fe(NO)(PS2)(THF)] - intermediate, which involves disproportionation or NO - transfer to yield [ 3 ] - . Based on IR data and magnetic properties, the electronic structure of [ 3 ] - can be described as a Fe II /{Fe(NO) 2 } 9 state. Isolation of the {Fe(NO) 2 } 9 moiety coordinated by the Fe ancillary complex lends strong support to the NO scrambling behavior in the effectiveness of the activity of flavodiiron nitric oxide reductases (FNORs).

Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD)., Methods: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia-reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1 cKO ) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism., Results: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1 cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-β1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest., Conclusion: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway., (© 2022. The Author(s).)

Acute kidney injury (AKI) is known as a sudden episode of kidney injury, which happens suddenly within a few hours or a few days. Quercetin (3,3',4',5,7-pentahydroxyflavone) is a flavonoid found in plants. Quercetin is known to have several biological activities, such as anti-oxidant, anti-inflammatory, and anti-carcinogenic effects. However, low water solubility and bioavailability are the limitations of quercetin for its clinical applications. Moreover, ischemia/reperfusion (I/R) injury is a common cause of AKI. There are no satisfactory strategies for I/R-induced AKI. Developing suitable preventive or therapeutic intervention for AKI is an important and urgent issue. We investigated the benefit effect of synthesized polyethylene glycol (PEG) conjugated polyethyleneimine (PEI) nanoparticles for targeted delivery of quercetin on AKI in a mouse model. An I/R-induced AKI mouse model was used to evaluate the therapeutic effect of quercetin polymeric nanoparticles by intravenous injection. Biochemical changes for renal function in blood samples were analyzed. Histological and immunohistochemical changes were also analyzed. The biochemical changes of blood urea nitrogen (BUN), creatinine, and cystatin C were significantly increased in I/R-induced AKI mice, which could be significantly reversed by quercetin polymeric nanoparticles. Quercetin polymeric nanoparticles could also significantly decrease the histological lesions, positive staining for 3-nitrotyrosine and cyclooxygenase-2, and lipid peroxidation in the kidneys of I/R-induced AKI mice. These results demonstrate for the first time that quercetin polymeric nanoparticles possess therapeutic potential for the treatment of I/R-induced AKI in vivo., Competing Interests: Declaration of competing interest We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A green method for synthesizing Pd nanoparticles/graphene composites from a choline chloride-oxalic acid deep eutectic solvent (DES) without a reducing agent or a surfactant is reported. Deep eutectic solvents are usually composed of halide salts and hydrogen-bond donors, and many are biocompatible and biodegradable. The merits of deep eutectic solvents include that they serve as reducing agents and dispersants, and Pd nanoparticles are tightly anchored to graphene. The size and dispersion of Pd particles are improved when supercritical carbon dioxide (scCO 2 ) is used because it has gaslike diffusivity and near-zero surface tension, which results in excellent wettability between the scCO 2 and the carbon surface. The prepared sc-Pd NPs/GR/SPCE shows excellent activity toward glycerol oxidation compared to composites not fabricated by scCO 2 processes. This study demonstrates the potential of using this scCO 2 -assisted protocol combined with deep eutectic solvents to further construct nanoparticles/graphene composites., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Saturated free fatty acids (FFAs) strongly correlate with metabolic syndromes and are well-known risk factors for cardiovascular diseases (CVDs). The mechanism of palmitic acid (PA)-induced vascular lipotoxicity under endoplasmic reticulum (ER) stress is unknown. In the present paper, we investigate the roles of spliced form of X-box-binding protein 1 (XBP1s) target gene oxidative stress-induced growth inhibitor 1 (OSGIN1) in PA-induced vascular dysfunction. PA inhibited the tube formation assay of primary human umbilical vein endothelial cells (HUVECs). Simultaneously, PA treatment induced the XBP1s expression in HUVECs. Attenuate the induction of XBP1s by silencing the XBP1s retarded cell migration and diminished endothelial nitric oxide synthase (eNOS) expression. OSGIN1 is a target gene of XBP1s under PA treatment. The silencing of OSGIN1 inhibits cell migration by decreasing phospho-eNOS expression. PA activated autophagy in endothelial cells, inhibiting autophagy by 3-methyladenine (3-MA) decreased endothelial cell migration. Silencing XBP1s and OSGIN1 would reduce the induction of LC3 II; therefore, OSGIN1 could maintain autophagy to preserve endothelial cell migration. In conclusion, PA treatment induced ER stress and activated the inositol-requiring enzyme 1 alpha-spliced XBP1 (IRE1α-XBP1s) pathway. OSGIN1, a target gene of XBP1s, could protect endothelial cells from vascular lipotoxicity by regulating autophagy.

Background: Vascular calcification (VC) constitutes subclinical vascular burden and increases cardiovascular mortality. Effective therapeutics for VC remains to be procured. We aimed to use a deep learning-based strategy to screen and uncover plant compounds that potentially can be repurposed for managing VC., Methods: We integrated drugome, interactome, and diseasome information from Comparative Toxicogenomic Database (CTD), DrugBank, PubChem, Gene Ontology (GO), and BioGrid to analyze drug-disease associations. A deep representation learning was done using a high-level description of the local network architecture and features of the entities, followed by learning the global embeddings of nodes derived from a heterogeneous network using the graph neural network architecture and a random forest classifier established for prediction. Predicted results were tested in an in vitro VC model for validity based on the probability scores., Results: We collected 6,790 compounds with available Simplified Molecular-Input Line-Entry System (SMILES) data, 11,958 GO terms, 7,238 diseases, and 25,482 proteins, followed by local embedding vectors using an end-to-end transformer network and a node2vec algorithm and global embedding vectors learned from heterogeneous network via the graph neural network. Our algorithm conferred a good distinction between potential compounds, presenting as higher prediction scores for the compound categories with a higher potential but lower scores for other categories. Probability score-dependent selection revealed that antioxidants such as sulforaphane and daidzein were potentially effective compounds against VC, while catechin had low probability. All three compounds were validated in vitro ., Conclusions: Our findings exemplify the utility of deep learning in identifying promising VC-treating plant compounds. Our model can be a quick and comprehensive computational screening tool to assist in the early drug discovery process., Competing Interests: The authors have no relevant financial or nonfinancial competing interests to declare in relation to this manuscript., (Copyright © 2022 Chia-Ter Chao et al.)

Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic toxins in CKD has become the conventional treatment in the clinic. However, studies rarely pay attention to uremic toxin clearance in the early stage of acute kidney injury (AKI) to prevent progression to CKD despite increasing reports demonstrating that uremic toxins are correlated with the severity of injury or mortality. This review highlights the current evidence of uremic toxin accumulation in AKI and the therapeutic value to prevent CKD progression specific to protein-bound uremic toxins (PBUTs).

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Backgrounds: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated., Methods: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used., Results: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3-41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042)., Conclusion: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Ochratoxin A (OTA) is a mycotoxin widely found in various foods and feeds that have a deleterious effect on humans and animals. It has been shown that OTA causes multiorgan toxicity, and the kidney is the main target of OTA among them. This present article aims to review recent and latest intracellular molecular interactions and signaling pathways of OTA-induced nephrotoxicity. Pyroptosis, lipotoxicity, organic anionic membrane transporter, autophagy, the ubiquitin-proteasome system, and histone acetyltransferase have been involved in the renal toxicity caused by OTA. Meanwhile, the literature reviewed the alternative or method against OTA toxicity by reducing ROS production, oxidative stress, activating the Nrf2 pathway, through using nanoparticles, a natural flavonoid, and metal supplement. The present review discloses the molecular mechanism of OTA-induced nephrotoxicity, providing opinions and strategies against OTA toxicity.

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

In this study, we accentuate the facile and green synthesis of ecologically viable silver nanoparticles (AgNPs) using aqueous (A-BGE) and ethanolic (E-BGE) dried bitter gourd (Momordica charantia) fruit extract as reducing and capping agents. Although AgNPs synthesized using BGEs have been reported earlier in fundamental antimicrobial studies, the possible antioxidant activity, antibacterial efficacy against superbugs, and a potential antimicrobial mechanism are still lacking. The characterization of as-prepared AgNPs was studied through UV-vis, TEM, Zeta-potential, FT-IR, XRD, and XPS analysis. The antioxidant ability of BG-AgNPs was extensively evaluated through DPPH and FRAP assays, which showed that A-BG-AgNPs possessed higher scavenging ability and superior reducing power due to the high phenolic content present in the BG extract. Furthermore, A-BG-AgNPs were highly stable in various physiological media and displayed excellent antibacterial activity against drug-resistant bacterial strains (i.e., MIC value of 4 µg/mL). The generation of reactive oxygen species evidenced that the possible antimicrobial mechanism was induced by BG-AgNPs, resulting in bacterial cell damage. Within the minimal hemolysis, the BG-mediated AgNPs possessed synergistic antioxidant and antibacterial agents and open another avenue for the inhibition of the growth of pathogens.

Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called "ER stress". Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.

Aims: Vascular calcification (VC) increases the future risk of cardiovascular events in uraemic patients, but effective therapies are still unavailable. Accurate identification of those at risk of developing VC using pathogenesis-based biomarkers is of particular interest and may facilitate individualized risk stratification. We aimed to uncover microRNA (miRNA)-target protein-based biomarker panels for evaluating uraemic VC probability and severity., Methods and Results: We created a three-tiered in vitro VC model and an in vivo uraemic rat model receiving high phosphate diet to mimic uraemic VC. RNAs from the three-tiered in vitro and in vivo uraemic VC models underwent miRNA and mRNA microarray, with results screened for differentially expressed miRNAs and their target genes as biomarkers. Findings were validated in original models and additionally in an ex vivo VC model and human cells, followed by functional assays of identified miRNAs and target proteins, and tests of sera from end-stage renal disease (ESRD) and non-dialysis-dependent chronic kidney disease (CKD) patients without and with VC. Totally 122 down-regulated and 119 up-regulated miRNAs during calcification progression were identified initially; further list narrowing based on miRNA-mRNA pairing, anti-correlation, and functional enrichment left 16 and 14 differentially expressed miRNAs and mRNAs. Levels of four miRNAs (miR-10b-5p, miR-195, miR-125b-2-3p, and miR-378a-3p) were shown to decrease throughout all models tested, while one mRNA (SULF1, a potential target of miR-378a-3p) exhibited the opposite trend concurrently. Among 96 ESRD (70.8% with VC) and 59 CKD patients (61% with VC), serum miR-125b2-3p and miR-378a-3p decreased with greater VC severity, while serum SULF1 levels increased. Adding serum miR-125b-2-3p, miR-378a-3p, and SULF1 into regression models for VC substantially improved performance compared to using clinical variables alone., Conclusion: Using a translational approach, we discovered a novel panel of biomarkers for gauging the probability/severity of uraemic VC based on miRNAs/target proteins, which improved the diagnostic accuracy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

A nucleic acid aptamer that specifically recognizes methicillin-resistant Staphylococcus aureus (MRSA) has been immobilized on magnetic nanoparticles to capture the target bacteria prior to mass spectrometry analysis. After the MRSA species were captured, they were further eluted from the nanoparticles and identified using matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). The combination of aptamer-based capture/enrichment and MS analysis of microorganisms took advantage of the selectivity of both techniques and should enhance the accuracy of MRSA identification. The capture and elution efficiencies for MRSA were optimized by examining factors such as incubation time, temperature, and elution solvents. The aptamer-modified magnetic nanoparticles showed a capture rate of more than 90% under the optimized condition, whereas the capture rates were less than 11% for non-target bacteria. The as-prepared nanoparticles exhibited only a 5% decrease in the capture rate and a 9% decrease in the elution rate after 10 successive cycles of utilization. Most importantly, the aptamer-modified nanoparticles revealed an excellent selectivity towards MRSA in bacterial mixtures. The capture of MRSA at a concentration of 10 2 CFU/mL remained at a good percentage of 82% even when the other two species were at 10 4 times higher concentration (10 6 CFU/mL). Further, the eluted MRSA bacteria were successfully identified using MALDI mass spectrometry.

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder which has been considered as the second common cause of infant death, with an estimated prevalence of 1 in 10,000 live births. The disorder is caused by survival motor neuron 1 gene ( SMN1 ) deficiency leading to limb weakness, difficult swallowing and abnormal breathing. Here, a fast and accurate method for SMA detection has been developed. Genomic DNA sample collected from whole blood, amniotic fluid, or dried blood spots can be analysed by using the Clarity™ Digital PCR (dPCR) System for determining the copy numbers of SMN1 and SMN2 genes. Two hundred and fourteen clinical samples determined by qPCR-based method were enrolled and used to establish the cut-off ranges for unaffected individual, SMA carrier and SMA patient categories. After setting the cut-off range for each group, 12 samples were analyzed by both dPCR-based method and MLPA (multiplex ligation-dependent probe amplification), the current testing golden standard for SMA, and 100% concordant results between the two testing methods were performed. CSB SMA Detection Kit combined with dPCR platform provides a robust and precise approach to distinguish unaffected individuals, SMA carrier and SMA patients. This rapid molecular diagnostic method can be adapted to pre-pregnancy eugenics inspection, prenatal testing as well as newborns screening and help physicians or genetic counselors to improve population SMA incidence.

Vascular calcification (VC) describes the pathophysiological phenotype of calcium apatite deposition within the vascular wall, leading to vascular stiffening and the loss of compliance. VC is never benign; the presence and severity of VC correlate closely with the risk of myocardial events and cardiovascular mortality in multiple at-risk populations such as patients with diabetes and chronic kidney disease. Mitochondrial dysfunction involving each of vascular wall constituents (endothelia and vascular smooth muscle cells (VSMCs)) aggravates various vascular pathologies, including atherosclerosis and VC. However, few studies address the pathogenic role of mitochondrial dysfunction during the course of VC, and mitochondrial reactive oxygen species (ROS) seem to lie in the pathophysiologic epicenter. Superoxide dismutase 2 (SOD2), through its preferential localization to the mitochondria, stands at the forefront against mitochondrial ROS in VSMCs and thus potentially modifies the probability of VC initiation or progression. In this review, we will provide a literature-based summary regarding the relationship between SOD2 and VC in the context of VSMCs. Apart from the conventional wisdom of attenuating mitochondrial ROS, SOD2 has been found to affect mitophagy and the formation of the autophagosome, suppress JAK/STAT as well as PI 3 K/Akt signaling, and retard vascular senescence, all of which underlie the beneficial influences on VC exerted by SOD2. More importantly, we outline the therapeutic potential of a novel SOD2-targeted strategy for the treatment of VC, including an ever-expanding list of pharmaceuticals and natural compounds. It is expected that VSMC SOD2 will become an important druggable target for treating VC in the future., Competing Interests: The authors have no relevant financial or nonfinancial conflicts of interests to declare in relation to this manuscript., (Copyright © 2021 You-Tien Tsai et al.)

Objective: Gustatory function is frequently impaired in patients with chronic kidney disease (CKD), and the associated taste dysfunction contributes to compromised nutrition. Whether gustatory dysfunction is an underappreciated risk factor for frailty in patients with CKD remains unclear. The objective of this work was to examine the role of gustatory dysfunction as a risk factor for frailty in patients with CKD., Methods: We prospectively enrolled patients with stage 3 or higher CKD from a single institute, with their gustatory function assessed using both objective (taste strip method) and subjective approaches, and frailty identified using the Edmonton frail scale, FRAIL scale, and Study of Osteoporotic Fracture (SOF) scale. Multiple regression analyses were performed to investigate whether results from gustatory function tests independently correlated with frailty., Results: Among the enrolled patients with CKD, 14 (17.9%) were found to be frail. We discovered that higher taste strip scores, or better taste function, were significantly associated with a lower frail probability (odds ratio [OR] 0.74 per score, 95% confidence interval [CI] 0.57-0.97), independent of clinical features, while better subjective taste function (OR 0.84 per score, 95% CI 0.74-0.96) and better oral cavity intactness (OR, 0.94; 95% CI, 0.9-0.98) were similarly associated with a lower frail probability among patients with CKD., Conclusion: Gustatory dysfunction may be an important risk factor for frailty in patients with CKD. It is tempting to presume that interventions aiming to ameliorate such deficits may bear the potential of reducing frailty severity in this population with a high frailty burden., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Withaferin A is a functional ingredient of a traditional medicinal plant, Withania somnifera, which has been broadly used in India for protecting against chronic diseases. This bioactive steroidal lactone possesses multiple functions such as anti-oxidation, anti-inflammation, and immunomodulation. Chronic kidney disease (CKD) is one of the major health problems worldwide with the high complication, morbidity, and mortality rates. The detailed effects and underlying mechanisms of withaferin A on CKD progression still remain to be clarified., Purpose: We aimed to investigate whether withaferin A treatment ameliorates the development of renal fibrosis and its related mechanisms in a CKD mouse model., Methods: A mouse model of unilateral ureteral obstruction (UUO) was used to mimic the progression of CKD. Male adult C57BL/6J mice were orally administered with 3 mg/kg/day withaferin A for 14 consecutive days after UUO surgery. Candesartan (5 mg/kg/day) was used as a positive control., Results: Both Withaferin A and candesartan treatments significantly ameliorated the histopathological changes and collagen deposition in the UUO kidneys. Withaferin A could significantly reverse the increases in the protein levels of pro-fibrotic factors (fibronectin, transforming growth factor-β, and α-smooth muscle actin), inflammatory signaling molecules (phosphorylated nuclear factor-κB-p65, interleukin-1β, and cyclooxygenase-2), and cleaved caspase-3, apoptosis, and infiltration of neutrophils in the UUO kidneys. The protein levels of endoplasmic reticulum (ER) stress-associated molecules (GRP78, GRP94, ATF4, CHOP, phosphorylated eIF2α, and cleaved caspase 12) were increased in the kidneys of UUO mice, which could be significantly reversed by withaferin A treatment., Conclusion: Withaferin A protects against the CKD progression that is, at least in part, associated with the moderation of ER stress-related apoptosis, inflammation, and fibrosis in the kidneys of CKD. Withaferin A may serve as a potential therapeutic agent for the development of CKD., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

The therapeutic effects of low intensity pulsed ultrasound (LIPUS) on renal ischemia/reperfusion injury (IRI) with acute kidney injury (AKI) are still unclear. A renal tubule cell model under H 2 O 2 or hypoxia/reoxygenation (H/R) conditions with or without LIPUS pre-treatment (1 MHz, 30 and 100 mW/cm 2 , 15 min) was used to test the in vitro effects of LIPUS. An AKI mouse model of unilateral IRI with nephrectomy of the contralateral kidney for 48 h with or without LIPUS treatment (3 MHz, 100 mW/cm 2 , 20 min/day) 5 day before IRI were used to investigate the in vivo effects of LIPUS. LIPUS significantly protected the renal tubule cell viability and prevented inflammatory signals against H 2 O 2 challenge. LIPUS could inhibit the apoptosis-related molecular signals and increase the protein levels of endogenous antioxidant enzymes, α-Klotho, and Sirt1 in renal tubule cells after H/R challenge. LIPUS alleviated the increases in the serum levels of blood urea nitrogen, creatinine, and cystatin C, renal pathological changes and apoptosis-related molecular signals, and impaired antioxidant enzymes in AKI mice. The IRI-induced inflammatory responses in the kidneys and spleens could be reversed by LIPUS. These findings suggest that LIPUS treatment displays the benefits for renal protection in IRI-induced AKI mice.

Patients with chronic kidney disease (CKD) have an increased risk of vascular calcification (VC), including aortic arch calcification (AAC). Few investigated the influence of gustatory function on the probability of having VC. We examined whether gustatory function results modulated the probability of having VC in patients with CKD. We prospectively enrolled adults with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ), with their AAC rated semi-quantitatively and gustatory function assessed by objective and subjective approaches. Multiple logistic regression was used to analyze the relationship between gustatory function results and AAC. Those with AAC had significantly better objective gustatory function in aggregate scores ( p = 0.039) and categories ( p = 0.022) and less defective bitter taste ( p = 0.045) and scores ( p = 0.037) than those without. Multiple regression analyses showed that higher aggregate scores (odds ratio (OR) 1.288, p = 0.032), or better gustatory function, and higher bitter taste scores (OR 2.558, p = 0.019) were each associated with a higher probability of having AAC among CKD patients; such an association was modulated by serum phosphate levels. In conclusion, better gustatory function was independently correlated with having AAC among CKD patients. A follow-up of VC severity may be an underrecognized component of care for CKD patients with a preserved gustatory function.

Light triggers the formation of HNO from a metal-nitrosyl species, facilitated by an intramolecular pendant thiol proton. Two {FeNO} 6 complexes (the Enemark-Felthan notation), [Fe(NO)( TMS PS2)( TMS PS2H)] ( 1 , TMS PS2H 2 = 2,2'-dimercapto-3,3'-bis(trimethylsilyl)diphenyl)phenylphosphine; H is a dissociable proton) with a pendant thiol and [Fe(NO)( TMS PS2)( TMS PS2CH 3 )] ( 2 ) bearing a pendant thioether, are spectroscopically and structurally characterized. Both complexes are highly sensitive to visible light. Upon photolysis, complex 2 undergoes NO dissociation to yield a mononuclear Fe(III) complex, [Fe( TMS PS2)( TMS PS2CH 3 )] ( 3 ). In contrast, the pendant SH of 1 can act as a trap for the departing NO radical upon irradiation, resulting in the formation of an intermediate A with an intramolecular [SH···ON-Fe] interaction. As suggested by computational results (density functional theory), the NO stretching frequency (ν NO ) is sensitive to the intramolecular interaction between the pendant ligand and the iron-bound NO, and a shift of ν NO from 1833 ( 1 ) to 1823 cm -1 ( A ) is observed experimentally. Subsequent photolysis of the intermediate A results in HNO production and a thiyl group that then coordinates to the Fe center for the formation of [Fe( TMS PS2) 2 ] ( 4 ). In contrast with the common acid-base coupling pathway, the HNO is not voluntarily yielded from 1 but rather is generated by the photopromoted pathway. The photogenerated HNO can further react with [Mn III ( TMS PS3)(DABCO)] ( TMS PS3H 3 = (2,2'2''-trimercapto-3,3',3''-tris(trimethylsilyl)triphenylphosphine; DABCO = 1,4-diazabicyclo[2.2.2]octane) in organic media to yield anionic [Mn(NO)( TMS PS3)] - ( 5 - ) with a {MnNO} 6 electronic configuration, whereas [Mn III ( TMS PS3)(DABCO)] reacts with NO gas for the formation of a {MnNO} 5 species, [Mn(NO)( TMS PS3)] ( 6 ). Effective differentiation of the formation of HNO from complex 1 with the pendant SH versus NO from 2 with the pendant SMe is achieved by the employment of [Mn III ( TMS PS3)(DABCO)].

Background: The association between incident chronic kidney disease (CKD) or end-stage renal disease (ESRD) and exposure to outdoor air pollution is under debate. We aimed to examine this relationship based on a systematic review with random-effects meta-analysis., Methods: We screened the literature on long-term air pollution exposure assessment in the general population using an electronic search of PubMed, Medline, Embase, and Cochrane Library from inception to 20 October 2019. Observational studies investigating the association between long-term exposure to gaseous (CO, SO 2 , NO 2 , O 3 ) or particulate (PM 2.5 or PM 10 ) outdoor air pollutants and CKD, ESRD, or renal dysfunction were included, and summary risks were estimated., Results: Of 4419 identified articles, 23 met our inclusion criteria after screening and 14 were included in the meta-analysis. Pooled effect estimates had the following summary risk ratios (RRs) for CKD: 1.10 (95% confidence intervals [CI] 1.00, 1.21; derived from four studies) per 10 μg/m 3 increase in PM 2.5 and 1.16 (95% CI 1.05, 1.29; derived from four studies) for PM 10 ; 1.31 (95% CI 0.86, 2.00; derived from two studies) per 10 ppm increase in CO; and 1.11 (95% CI 1.09, 1.14; derived from three studies) per 10 ppb increase in NO 2 . For the pooled effect on eGFR, increases in PM 10 and PM 2.5 (of 10 μg/m 3 ) were associated with eGFR decline by -0.83 (95% CI -1.54, -0.12; derived from two studies) and -4.11 (95% CI -12.64, 4.42; derived from two studies) mL/min/1.73 m 2 , respectively., Conclusions: Air pollution was observed to be associated with CKD and renal function decline. Although more longitudinal studies are required, we argue that air pollution is pernicious to kidney health., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aging is associated with cognitive decline and dysregulation of the circadian system, which modulates hippocampal-dependent memory as well as biological processes underlying hippocampal function. While circadian dysfunction and memory impairment are common features of aging and several neurodegenerative brain disorders, how aging impacts the circadian expression patterns of proteins involved in processes that underlie hippocampal-dependent memory is not well understood. In this study, we profiled the hippocampal proteomes of young and middle-aged mice across two circadian cycles using quantitative mass spectrometry in order to explore aging-associated changes in the temporal orchestration of biological pathways. Of the ∼1,420 proteins that were accurately quantified, 15% (214 proteins) displayed circadian rhythms in abundance in the hippocampus of young mice, while only 1.6% (23 proteins) were rhythmic in middle-aged mice. Remarkably, aging disrupted the circadian regulation of proteins involved in cellular functions critical for hippocampal function and memory, including dozens of proteins participating in pathways of energy metabolism, neurotransmission, and synaptic plasticity. These included processes such as glycolysis, the tricarboxylic acid cycle, synaptic vesicle cycling, long-term potentiation, and cytoskeletal organization. Moreover, aging altered the daily expression rhythms of proteins implicated in hallmarks of aging and the pathogenesis of several age-related neurodegenerative brain disorders affecting the hippocampus. Notably, we identified age-related alterations in the rhythmicity of proteins involved in mitochondrial dysfunction and loss of proteostasis, as well as proteins involved in the pathogenesis of disorders such as Alzheimer's disease and Parkinson's disease. These insights into aging-induced changes in the hippocampal proteome provide a framework for understanding how the age-dependent circadian decline may contribute to cognitive impairment and the development of neurodegenerative diseases during aging., (Copyright © 2020 Adler, Chiang, Mayne, Ning, Zhang, Xu, Cheng and Figeys.)

Aim: Laboratory deficit-based frailty index (LFI) exhibited outcome-prediction ability in the elderly, but not in those with end-stage renal disease (ESRD). We hypothesized that LFI results might have outcome correlation and correlate closely with other instruments in ESRD patients., Methods: We prospectively enroled ESRD patients between 2014 and 2015 and administered self-report frailty instruments (Strawbridge questionnaire, Edmonton frail scale (EFS), Groningen frailty indicator (GFI), Tilburg frailty indicator, G8 questionnaire and FRAIL scale), and Cardiovascular Health Study (CHS) scale, with two types of LFI calculated. They were followed up until June 30, 2017. Correlations between the results of six instruments, CHS scale, and those of LFI were identified, followed by Kaplan-Meier survival analyses and logistic regression analyses to compare those with high and low LFI., Results: The frailty prevalence was 33.3% (CHS), 78.8% Strawbridge questionnaire, 45.5% (EFS), 57.6% (GFI), 27.3% (Tilburg frailty indicator), 84.8% (G8) and 18.2% (FRAIL) among ESRD participants. LFI-1 results were significantly correlated with those of LFI-2 (P < 0.01), EFS (P = 0.04) and GFI (P < 0.01), while LFI-2 results were not. Those with CHS or GFI-identified frailty had significantly lower 1,25-(OH) 2 -D levels than those without. After 32.3 ± 5.4 months, patients with high LFI-1 scores, but not LFI-2, had a significantly higher mortality than those with lower scores. GFI and EFS scores were also independently associated with LFI-1, while CHS scores exhibited borderline association only., Conclusion: Among a group of predominantly older ESRD patients, LFI differentiates patients with good and poor outcomes, supporting its applicability in these patients., (© 2019 Asian Pacific Society of Nephrology.)

Epigenetic changes, particularly non-coding RNAs, have been implicated extensively in the pathogenesis of vascular diseases. Specific miRNAs are involved in the differentiation, phenotypic switch, proliferation, apoptosis, cytokine production and matrix deposition of endothelial cells and/or vascular smooth muscle cells. MicroRNA-125b has been studied in depth for its role in carcinogenesis with a double-edged role; that is, it can act as an oncogene in some cancer types and as a tumour suppressor gene in others. However, cumulative evidence from the use of advanced miRNA profiling techniques and bioinformatics analysis suggests that miR-125b can be a potential mediator and useful marker of vascular diseases. Currently, the exact role of miR-125b in vascular diseases is not known. In this systematic review, we intend to provide an updated compilation of all the recent findings of miR-125b in vascular diseases, using a systematic approach of retrieving data from all available reports followed by data summarization. MiR-125b serves as a pathogenic player in multiple vascular pathologies involving endothelia and vascular smooth muscle cells and also serves as a diagnostic marker for vascular diseases. We further provide a computational biologic presentation of the complex network of miR-125b and its target genes within the scope of vascular diseases., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Diabetes-associated advanced glycation end-products (AGEs) can increase extracellular matrix (ECM) expression and induce renal fibrosis. Calbindin-D28k, which plays a role in calcium reabsorption in renal distal convoluted tubules, is increased in a diabetic kidney. The role of calbindin-D28k in diabetic nephropathy still remains unclear. Here, calbindin-D28k protein expression was unexpectedly induced in the renal tubules of db / db diabetic mice. AGEs induced the calbindin-D28k expression in human renal proximal tubule cells (HK2), but not in mesangial cells. AGEs induced the expression of fibrotic molecules, ECM proteins, epithelial-mesenchymal transition (EMT) markers, and endoplasmic reticulum (ER) stress-related molecules in HK2 cells, which could be inhibited by a receptor for AGE (RAGE) neutralizing antibody. Calbindin-D28k knockdown by siRNA transfection reduced the cell viability and obviously enhanced the protein expressions of fibrotic factors, EMT markers, and ER stress-related molecules in AGEs-treated HK2 cells. Chemical chaperone 4-Phenylbutyric acid counteracted the AGEs-induced ER stress and ECM and EMT markers expressions. Calbindin-D28k siRNA in vivo delivery could enhance renal fibrosis in db / db diabetic mice. These findings suggest that inducible calbindin-D28k protects against AGEs/RAGE axis-induced ER stress-activated ECM induction and cell injury in renal proximal tubule cells.

Background: The pathology change of renal tubulointerstitial fibrosis is a critical feature of chronic kidney disease (CKD), regardless of the primary insults. The infiltration of inflammatory cells and the consecutive secretion of profibrotic factors are frequently and conspicuously observed during the development of renal fibrosis. Icariin, an active polyphenol of the Epimedium genus, has been found to alleviate the symptoms of chronic diseases like diabetes, neurodegeneration, and heart and renal diseases. The effect and mechanism of icariin on the prevention of CKD-associated renal fibrosis still needed clarification., Purpose: The aims of this study were to investigate whether icariin treatment improves the development of CKD-associated renal fibrosis and its possible mechanism., Methods: An experimental unilateral ureteral obstruction (UUO)-induced chronic renal fibrosis mouse model was used. Mice were orally administered with icariin (20 mg/kg/day) for 3 consecutive days before and 14 consecutive days after UUO surgery., Results: The pathological changes, collagen deposition, and protein expressions of profibrotic factors (transforming growth factor-β and connective tissue growth factor) and fibrotic markers (α-smooth muscle actin and fibronectin), which were significantly elevated in the kidneys of UUO mice, could be significantly reversed by icariin treatment. Icariin treatment also significantly inhibited the increased Smad2/3 and decreased E-cadherin protein expressions in the kidneys of UUO mice. Icariin treatment prominently mitigated the protein expression of proinflammatory factors like nuclear factor-κB, cyclooxygenase-2, interleukin 1-β and prooxidative enzyme (NADPH oxidase-4), and it increased the protein expression of antioxidative enzymes (superoxide dismutase and catalase)., Conclusion: Icariin treatment protects against CKD-associated renal fibrosis via its antifibrotic and anti-inflammatory properties. Icariin may serve as a therapeutic agent in the prevention of CKD-associated renal fibrosis., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Cardiovascular events associated with oral hypoglycemic agents (OHAs) have raised significant safety concerns. This study assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4i) and the risk of cardiovascular events in patients with type 2 diabetes mellitus with or without chronic kidney disease (CKD)., Study Design: A retrospective cohort study using Taiwan's National Health Insurance Research Database., Settings and Participants: Our study included patients with type 2 diabetes who received OHAs between March 1, 2009, and December 31, 2012. All eligible subjects were classified into CKD and non-CKD cohorts and further categorized as the DPP-4i and non-DPP-4i users in each cohort., Methods: The DPP-4i and non-DPP-4i groups were matched 1:1 by propensity score to attenuate potential selection bias. Propensity score was estimated by logistic regression, using demographics, co-medications, comorbidities. and adapted diabetic complication severity index at baseline., Outcomes: Outcomes of interest included a composite endpoint of ischemic stroke, myocardial infarction, cardiovascular death (major adverse cardiac events [MACE]), and hospitalization for heart failure (hHF). COX proportional hazard models were applied to examine the association between DPP-4i and outcomes of interest., Results: We identified 37,641 and 87,604 patients with type 2 diabetes with and without CKD, respectively. After propensity score matching, 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients were included for analysis. In the CKD cohort, DPP-4i were associated with a 25% increased risk of hHF (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 15.0 vs. 9.9, HR = 1.25; 95% CI 1.01-1.54, p = 0.037) but not with the risk of MACE (HR = 0.89, p = 0.144). In the non-CKD cohort, DPP-4i were associated with a lower risk of MACE (DPP-4i vs. non-DPP-4i incidence/1,000 person-years: 9.8 vs. 12.6 HR = 0.73; 95% CI 0.61-0.87, p = 0.0007), but not the risk of hHF (HR = 1.09, p = 0.631)., Conclusions: DPP-4i were found to be associated with decreased risk of MACE in the non-CKD cohort in our study. However, DPP-4i were associated with increased risk of hHF in the CKD cohort. DPP-4i in the CKD cohort should be used cautiously., Competing Interests: The authors have declared that no competing interests exist.