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Highlight: • It was proven that renal injury in Corona Virus Disease 2019 (COVID-19) patients has been a real concern. • There are three possible mechanisms of renal injury in COVID-19 infection: direct viral mediated, prolonged cytokine storm mediated, and drug-induced renal injury. • There is no targeted drug therapy in the treatment of renal injury, while Chinese Herbal Medicine can be a potential solution. • Huang Qi, Fu Ling, Di Huang, Shan Yao and Bai Zhu are the core herbs in Chinese Herbal Medicine to treat renal injury. • Chinese Herbal Medicine may act on PTGS2, PTGS1, IL6 and CASP3, etc., to prevent the pharmacological and non-pharmacological COVID-19 related renal injury., Clinical studies have shown that renal injury in Corona Virus Disease 2019 (COVID-19) patients has been a real concern, which is associated with high mortality and an inflammation/apoptosis-related causality. Effective target therapy for renal injury has yet been developed. Besides, potential anti-COVID-19 medicines have also been reported to cause adverse side effects to kidney. Chinese Herbal Medicine (CHM), however, has rich experience in treating renal injury and has successfully applied in China in the battle of COVID-19. Nevertheless, the molecular mechanisms of CHM treatment are still unclear. In this study, we searched prescriptions in the treatment of renal injury extensively and the potential mechanisms to treat COVID-19 related renal injury were investigated. The association rules analysis showed that the core herbs includes Huang Qi, Fu Ling, Bai Zhu, Di Huang, Shan Yao. TCM herbs regulate core pathways, such as AGE-RAGE, PI3K-AKT, TNF and apoptosis pathway, etc. The ingredients (quercetin, formononetin, kaempferol, etc.,) from core herbs could modulate targets (PTGS2 (COX2), PTGS1 (COX1), IL6, CASP3, NOS2, and TNF, etc.), and thereby prevent the pharmacological and non-pharmacological renal injury comparable to that from COVID-19 infection. This study provides therapeutic potentials of CHM to combat COVID-19 related renal injury to reduce complications and mortality.

After a major surgery, a central nervous system complication often occurs, which is called as POCD, the Postoperative Cognitive Dysfunction. Clinical manifestations normally include the loss of learning ability, memory, thinking ability and executive and expression ability (Feinkohl et al., 2017a, Needham et al., 2017). POCD may last from a few hours, to a few days or weeks after surgery. In some cases, the disorder may exist for a few months, or even be permanent. Thus, it will result in reducing medication compliance, prolonging hospital stay, and increasing patients’ costs, etc. (Carr et al., 2018). With the rising number of surgery patients; the quantity of patients suffered from POCD is increasing year by year. Therefore, finding effective methods to treat POCD has become a thorny problem. The specific pathogenesis and mechanism of POCD remains unclear. Most scholars believe that POCD is caused by the degeneration of central nervous system in elder patients and induced by surgery and anesthesia. The brain energy metabolism disorder is caused by a combination of various risk factors and leads to neurological dysfunction (Cascella and Bimonte, 2017, Cropsey et al., 2015, Steinmetz and Rasmussen, 2016). Perioperative patients often have fluctuations in blood glucose, which might be accompanied by high and low blood glucose levels, and the postoperative brain glucose uptake rate of POCD patients is significantly reduced. Recent studies have also found that hyperglycemia during extracorporeal circulation is a risk factor for POCD (Feinkohl et al., 2017b, Jones, 2008). Therefore, study on the mechanism of POCD caused by abnormal glucose metabolism is of important guiding significance for perioperative clinical intervention. Studies have shown that glucose metabolism disorder is an important pathological mechanism of cognitive impairment (Diaz-Venegas et al., 2017). McNay et al. found that hippocampal-dependent learning and memory function is related to brain glucose metabolism using brain microdialysis technique (McNay and Recknagel, 2011). The mechanisms of abnormal glucose metabolism leading to POCD involve increased insulin resistance, abnormal insulin signaling pathway, enhanced oxidative stress response, increased advanced glycation end products (AGE), abnormal blood-brain barrier, and glucose transporter-4 metabolic disorders, among which, the insulin signaling pathway IRS-PI3K-AKT-GLUT4 disorder may exert influence on neuronal glucose metabolism and cognitive function changes (Rizzo et al., 2014, Pearson-Leary and McNay, 2016, Yaffe et al., 2011). At present time, diagnosis methods for POCD is insufficient. 18F-FDG (18F-fluorodeoxyglucose) PET/CT is an effective approach in detecting brain glucose metabolism-related damage in neurodegenerative dementia. Normal brain cells have high metabolism rate of 18F-FDG uptake, with standard uptake value. Standard Uptake Value (SUV) is a quantitative indicator that reflects the level of glucose concentration in brain cells, which functionally reflects the metabolic level of brain cells (Banzo et al., 2014, Jimenez-Bonilla et al., 2016). In addition, lipopolysaccharide (LPS) is the main bacterial toll-like receptor 4 (TLR4) ligand that actuates the immune system to respond to infection. Previous studies have shown that surgery in adult rats with intraperitoneal injection of LPS might trigger more serious neurodegenerative diseases, which suggests that adult rats are more prone to cognitive disorders when they have received surgery. This simulates the cognitive function of surgical infection status in young patients in clinical settings (Sochocka et al., 2017, Fischer et al., 2011). In this study, adult rats that have unilateral nephrectomy and have been treated with LPS intraperitoneal injection were used to cause adult rat cognitive dysfunction model. 18F-FDG PET/CT photo copies were used to record and test the changing of brain glucose metabolism of the rats with cognitive dysfunction. Molecular biological techniques were adapted to detect the changes of INSR-PI3K-AKT-GLUT4 of the insulin signaling pathway. Apart from the above, those techniques were helpful to explain the mechanism of glucose metabolism changes of POCD in adult rats, and to provide reference for preventing and treating POCD.

The precise characterization and quantification of oxidative protein damage is a significant challenge due to the low abundance, large variety, and heterogeneity of modifications. Mass spectrometry (MS)-based techniques at the peptide level (proteomics) provide a detailed but limited picture due to incomplete sequence coverage and imperfect enzymatic digestion. This is particularly problematic with oxidatively modified and cross-linked/aggregated proteins. There is a pressing need for methods that can quantify large numbers of modified amino acids, which are often present in low abundance compared to the high background of non-damaged amino acids, in a rapid and reliable fashion. We have developed a protocol using zwitterionic ion-exchange chromatography coupled with LC-MS to simultaneously quantify both parent amino acids and their respective oxidation products. Proteins are hydrolyzed with methanesulfonic acid in the presence of tryptamine and purified by strong cation exchange solid phase extraction. The method was validated for the common amino acids (excluding Gln, Asn, Cys) and the oxidation products 3-chlorotyrosine (3-ClTyr), 3-nitrotyrosine (3-NO2Tyr), di-tyrosine, Nε-(1-carboxymethyl)-l-lysine, o,o’-di-tyrosine, 3,4,-dihydroxyphenylalanine, hydroxy-tryptophan and kynurenine. Linear standard curves were observed over ~3 orders of magnitude dynamic range (2–1000 pmol for parent amino acids, 80 fmol–20 pmol for oxidation products) with limit-of-quantification values as low as 200 fmol (o,o’-di-tyrosine). The validated method was used to quantify Tyr and Trp loss, and formation of 3-NO2Tyr on the isolated protein anastellin treated with peroxynitrous acid, and for 3-ClTyr formation (over a 2 orders of magnitude range) in cell lysates and complex protein mixtures treated with hypochlorous acid., Graphical abstract Image 1, Highlights • Identification and quantification of oxidative protein damage is a major challenge. • A versatile LC-MS assay is reported that involves hydrolysis to free amino acids. • Quantification is possible for both parent amino acids and products in single runs. • A dynamic range of 2-3 orders of magnitude is available for most analytes. • Example of use with pure proteins, extracellular matrix and cell lysates are given.

Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF‐Leprfa/fa and 16 ZDF-Lepr+/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial)., Graphical abstract fx1, Highlights • Hyperglycemia induces vascular complications and cardiovascular disease. • Empagliflozin reduces hyperglycemia and cardiovascular mortality (EMPA-REG trial). • Here, empagliflozin normalized vascular function and oxidative stress in ZDF rats. • Here, empagliflozin reduced AGE/RAGE signaling, inflammation and oxidative stress. • Here, empagliflozin conferred glycemic control, epigenetic and pleiotropic effects.

Bisphosphonates are commonly used in patients with metastatic bone disease to prevent skeletal related events. Atypical femur fracture is a known complication of long-term bisphosphonate use but the incidence in cancer patients and pathogenesis are not well known. Several mechanisms of pathogenesis have been proposed including altered angiogenesis, altered bone mechanical properties, micro damage and bone remodeling suppression. Atypical femur fractures are atraumatic or minimally traumatic fractures in the sub trochanteric region or the femoral shaft. Awareness of atypical femur fractures is critical to diagnose and treat them in a timely manner. There is a paucity of data regarding the management of atypical femur fracture in patients with malignancy. Management options of atypical femur fractures include stopping bisphosphonates, initiating calcium/vitamin D supplementation and either surgery with internal fixation or conservative management. In the future, it will be important to explore the effect of continuous vs. intermittent exposure, cumulative dose and length of exposure on the incidence of this complication. Herein, we review the epidemiology, risk factors, management options and proposed mechanisms of pathogenesis of atypical femur fractures. Keywords: Atypical femur fracture, Bisphosphonates, Bone remodeling, Bone metastasis, Denosumab

Graphical abstract, Highlights • COVID-19 has led to serious death and lacks treatment strategies. • Lianhua Qingwen is a commonly used Chinese patent medicine to treat viral infection. • Lianhua Qingwen has antiviral, anti-inflammatory and immunoregulatory activities. • Lianhua Qingwen combined with conventional treatment obviously improved COVID-19. • Lianhua Qingwen can be a complementary strategy for treating COVID-19., Background An outbreak of Coronavirus Disease 2019 (COVID-19) which was infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is still spreading and has led to unprecedented health emergency over the world. Though no specific drug has been developed so far, emerging agents have been confirmed effective or potentially beneficial to restrain it. Lianhua Qingwen (LHQW) is a commonly used Chinese medical preparation to treat viral influenza, including in the fight against SARS in 2002–2003 in China. Recent data also showed that LHQW played a vigorous role in COVID-19 treatment. Purpose This review will elucidate the pre-clinical and clinical evidence of LHQW in lung protection and antiviral activities, and provide timely data delivery for the exploration of effective treatment strategies in the therapy of COVID-19. Study design and method The research data were obtained from the academic databases (up to August 8, 2020) including Pubmed, CNKI and Web of Science, on ethnobotany and ethno medicines. The search keywords for screening the literature information were “virus”, “COVID-19”, or “SARS-CoV-2”, and “Lianhua Qingwen”. The documents were filtered and summarized for final evaluation. Results The collected evidence demonstrated that LHQW exhibited benefits against COVID-19. Impressively, LHQW in conjunction with conventional treatment could significantly improve COVID-19 patients as a synergetic strategy. The mechanisms were mainly involved the antiviral activity, and regulation of inflammation response as well as immune function. Conclusion Although the data were far from adequate, the latest advances had shown the benefits of LHQW in COVID-19, especially in combination with other antiviral drugs. This review provides comprehensive evidence of LHQW as a complementary strategy for treating COVID-19. Nevertheless, imperious researches should be conducted to clarify the unconfirmed effects, regulatory mechanisms and adverse reactions of LHQW in treating COVID-19 by means of well designed randomized controlled trials.

Diabetes mellitus is one of the most common chronic diseases in the United States and peripheral neuropathy (PN) affects at least 50% of diabetic patients. Medications available for patients ameliorate symptoms (pain), but do not protect against cellular damage and come with severe side effects, leading to discontinued use. Our research group uses differentiated SH-SY5Y cells treated with advanced glycation end products (AGE) as a model to mimic diabetic conditions and to study the mechanisms of oxidative stress mediated cell damage and antioxidant protection. N-acetylcysteine (NAC), a common antioxidant supplement, was previously shown by our group to fully protect against AGE-induced damage. We have also shown that 3H-1,2-dithiole-3-thione (D3T), a cruciferous vegetable constituent and potent inducer of nuclear factor (erythroid-derived 2)- like 2 (Nrf2), can significantly increase cellular GSH concentrations and protect against oxidant species–induced cell death. Paradoxically, D3T conferred no protection against AGE-induced cell death or neurite degeneration. In the present study we establish a mechanism for this paradox by showing that D3T in combination with AGE increased oxidant species generation and depleted GSH via inhibition of glutathione reductase (GR) activity and increased expression of the NADPH generating enzyme glucose-6-phosphate dehydrogenase (G6PD). Blocking NADPH generation with the G6PD inhibitor dehydroepiandrosterone was found to protect against AGE-induced oxidant species generation, loss of viability, and neurite degeneration. It further reversed the D3T potentiation effect under AGE-treated conditions. Collectively, these results suggest that strategies aimed at combating oxidative stress that rely on upregulation of the endogenous antioxidant defense system via Nrf2 may backfire and promote further damage in diabetic PN., Graphical abstract fx1, Highlights • Glutathione(GSH) is key to protecting peripheral neurons from diabetes-induced damage. • Inducers of Nrf2 usually upregulate glutathione biosynthesis and reduction. • Paradoxically a Nrf2 inducer exacerbates diabetes-induced damage via GSH oxidation. • Diminished GSH reductase activity, despite induction, appears to account for paradox.

The extracellular matrix is engaged in an ever-evolving and elegant ballet of dynamic reciprocity that directly and bi-directionally regulates cell behavior. Homeostatic and pathophysiological changes in cell-matrix signaling cascades manifest as complex matrix phenotypes. Indeed, the extracellular matrix can be implicated in virtually every known human disease, thus, making it the most critical and dynamic “organ” in the human body. The overall goal of this Special Issue is to provide an accurate and inclusive functional definition that addresses the inherent complexity of matrix phenotypes. This goal is summarily achieved via a corpus of expertly written articles, reviews and original research, focused at answering this question empirically and fundamentally via state-of-the-art methods and research strategies., Highlights • ECM is the most important “organ” of the body; virtually all pathologies emanate from aberrant cell-matrix interactions • Matrix phenotypes manifest from ECM molecules and signaling into the cell nucleus as a form of “dynamic reciprocity” • This review focuses on the complexity of matrix phenotypes as diverse as the extracellular matrix itself • State-of-the-art methods, from ex vivo to next generation “omics” assays, bring intricate matrix phenotypes into focus • Deciphering the complexity of matrix phenotypes will uncover novel therapeutics and biomarkers to diagnose and treat disease

The presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP), a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS) generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE) by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage., Graphical abstract, Highlights • Short time exposure of pancreatic β-cells to low hIAPP aggregate amounts is studied. • NADPH oxidase activity is increased after 3 h treatment with 60 nM hIAPP aggregates. • RAGE engagement by aggregates increases Nox1 expression. • Reduced lipoperoxidation and increased antioxidant enzymes were observed. • A protective hormetic response via RAGE-Nox1 is proposed.

Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.

Obesity is an energy balance disorder associated with dyslipidemia, insulin resistance and diabetes type 2, also summarized with the term metabolic syndrome or syndrome X. Increasing evidence points to “adipocyte dysfunction”, rather than fat mass accretion per se, as the key pathophysiological factor for metabolic complications in obesity. The dysfunctional fat tissue in obesity characterizes a failure to safely store metabolic substrates into existing hypertrophied adipocytes and/or into new preadipocytes recruited for differentiation. In this review we briefly summarize the potential of redox imbalance in fat tissue as an instigator of adipocyte dysfunction in obesity. We reveal the challenge of the adipose redox changes, insights in the regulation of healthy expansion of adipose tissue and its reduction, leading to glucose and lipids overflow., Graphical abstract, Highlights • Adipose tissue (AT) buffers nutrient excess determining overall metabolic health. • Redox insight in lipid storage and adipogenesis of AT is reviewed. • Redox modulation of AT as therapeutic target in obesity/syndrome X is considered.