Extending the Grading of Recommendations Assessment, Development and Evaluation (GRADE) in Traditional Chinese Medicine (TCM): The GRADE-TCM.

AIM: To extend and form the "Grading of Recommendations Assessment, Development and Evaluation in Traditional Chinese Medicine" (GRADE-TCM). METHODS: Methodologies were systematically reviewed and analyzed concerning evidence-based TCM guidelines worldwide. A survey questionnaire was developed based on the literature review and open-end expert interviews. Then, we performed expert consensus, discussion meeting, opinion collection, external examination, and the GRADE-TCM was formed eventually. RESULTS: 265 Chinese and English TCM guidelines were included and analyzed. Five experts completed the open-end interviews. Ten methodological entries were summarized, screened and selected. One round of consensus was conducted, including a total of 22 experts and 220 valid questionnaire entries, concerning 1) selection of the GRADE, 2) GRADE-TCM upgrading criteria, 3) GRADE-TCM evaluation standard, 4) principles of consensus and recommendation, and 5) presentation of the GRADE-TCM and recommendation. Finally, consensus was reached on the above 10 entries, and the results were of high importance (with voting percentages ranging from 50 % to 81.82 % for "very important" rating) and strong reliability (with the Cr ranging from 0.93 to 0.99). Expert discussion meeting (with 40 experts), opinion collection (in two online platforms) and external examination (with 14 third-party experts) were conducted, and the GRADE-TCM was established eventually. CONCLUSION: GRADE-TCM provides a new extended evidence-based evaluation standard for TCM guidelines. In GRADE-TCM, international evidence-based norms, characteristics of TCM intervention, and inheritance of TCM culture were combined organically and followed. This is helpful for localization of the GRADE in TCM and internationalization of TCM guidelines.

Application of Maillard Reaction Products Derived Only from Enzymatically Hydrolyzed Sesame Meal to Enhance the Flavor and Oxidative Stability of Sesame Oil.

The low-temperature roasting of sesame oil has become increasingly popular because of its nutritional benefits; however, the flavor is reduced. In order to improve the quality of sesame oil without exogenous addition, sesame meal was hydrolyzed and further used to prepare Maillard reaction products (MRPs) while protease hydrolysis (PH) and glucoamylase-protease hydrolysis (GPH) were used, and their respective Maillard products (PHM and GPHM) were added in the oils for reducing sugar and total sugar content determination, free amino acid determination, and color and descriptive sensory analysis, as well as electronic nose, SPME-GC-MS, odor activity value, and oxidative stability analyses. Results showed that the MRPs could be produced using the enzymatically hydrolyzed sesame meal without exogenous addition, and the oil flavor blended with GPHM (GPHM-SO) was significantly (p < 0.05) improved with the best sensory quality. The composition of pyrazines (119.35 µg/mL), furans (13.95 µg/mL), and sulfur substances (6.25 µg/mL) contributed positively to sensory properties in GPHM-SO, and 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, and 2,3-dimethylpyrazine were characterized as the key flavor compounds with odor activity values of 7.01, 14.80, and 31.38, respectively. Furthermore, the oxidative stability of the oil was significantly improved with the addition of MRPs, and the shelf life of GPHM-SO was predicted to be extended by 1.9 times more than that of the crude oil based on the accelerated oxidation fitting analysis. In general, the MRPs derived only from sesame meal can enhance the flavor and oxidative stability of sesame oil and can be applied in the oil industry.

Improving the circulation time and renal therapeutic potency of extracellular vesicles using an endogenous ligand binding strategy.

Kidney diseases are a serious health issue worldwide, and novel therapeutics are urgently needed. Extracellular vesicles (EVs) have emerged as potent drug delivery systems (DDSs), but their therapeutic potential is limited by short circulation times and insufficient renal retention. Here, we report that endogenous ligand (albumin, ALB) binding is an efficient modification strategy to improve the therapeutic potency of EV-based DDSs for kidney diseases. Surface albumin-binding peptide (ABP)-displayed EVs (ABP-EVs) were produced by transfecting parent cells with the ABP-Lamp2b fusion plasmid. Compared with unmodified EVs (NC-EVs), ABP-EVs showed increased binding to ALB in vitro and elevated circulation time and multiple organ retention in vivo after systemic (iv) injection. Moreover, ABP-EVs had higher renal retention than NC-EVs in mice with acute kidney injury through a complex mechanism involving microvascular injury and megalin-mediated endocytosis. As a result, delivery of small molecule drugs (e.g., curcumin) or proteins (e.g., hepatocyte growth factor) by ABP-EVs had superior therapeutic (e.g., anti-apoptotic, antioxidant, anti-inflammatory) effects in vitro and in vivo. This study highlights that ABP-EVs are versatile DDSs for kidney diseases and provides insights into the new strategies of engineering EVs for drug delivery.

Research progress of anthocyanin prebiotic activity: A review.

BACKGROUND: Anthocyanins are a kind of flavonoids and natural water-soluble pigments, which endow fruits, vegetables, and plants with multiple colors. They are important source of new products with prebiotic activity. However, there is no systematic review documenting prebiotic activity of anthocyanins and their structural analogues. This study aims to fill this gap in literature. PURPOSE: The objective of this review is to summarize and evaluate the prebiotic activity of anthocyanin's, and discuss the physical and molecular modification methods to improve their biological activities. STUDY DESIGN AND METHODS: In this review, the databases (PubMed, Google Scholar, Web of Science, Researchgate and Elsevier) were searched profoundly with keywords (anthocyanin's, prebiotics, probiotics, physical embedding and molecular modification). RESULTS: A total of 34 articles were considered for reviewing. These studies approved that anthocyanins play an important role in promoting the proliferation of probiotics, inhibiting the growth of harmful bacteria and improving the intestinal environment. In addition, physical embedding and molecular modification have also been proved to be effective methods to improve the prebiotic activity of anthocyanins. Anthocyanins could promote the production of short chain fatty acids, accelerate self degradation and improve microbial related enzyme activities to promote the proliferation of probiotics. They inhibited the growth of harmful bacteria by inhibiting the expression of harmful bacteria genes, interfering with the role of metabolism related enzymes and affecting respiratory metabolism. They promoted the formation of a complete intestinal barrier and regulated the intestinal environment to keep the body healthy. Physical embedding, including microencapsulation and colloidal embedding, greatly improved the stability of anthocyanins. On the other hand, molecular modification, especially enzymatic modification, significantly improved the biological activities (antioxidant, prebiotic activity and so on) of anthocyanins. CONCLUSION: All these research results displayed by this review indicate that anthocyanins are a useful tool for developing prebiotic products. The better activities of the new anthocyanins formed by embedding and modification may make them become more effective raw materials. Our review provides a scientific basis for the future research and application of anthocyanins.

Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury.

Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)-induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)-induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO-1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti-inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8-OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti-inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.

Phloretin ameliorates hyperuricemia-induced chronic renal dysfunction through inhibiting NLRP3 inflammasome and uric acid reabsorption.

BACKGROUND: Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown. PURPOSE: This study aims to evaluate the therapeutic effect of phloretin on HUA-induced renal injury in mice and to reveal its underlying mechanism. METHODS: Mice were induced hyperuricemic by oral gavage of adenine/potassium oxonate. The effects of phloretin on renal function, fibrosis, oxidative stress, inflammation, and UA metabolism in HUA mice were evaluated. The effect of phloretin on NLRP3 pathway was analyzed in human renal tubular cell lines (HK-2). RESULTS: HUA mice showed renal dysfunction with increased renal fibrosis, inflammation and mitochondrial stress. By contrast, phloretin reduced the level of serum blood urea nitrogen (BUN), urinary albumin to creatinine ratio (UACR), tubular necrosis, extracellular matrix (ECM) deposition and interstitial fibroblasts in HUA mice. The renal infiltration of inflammatory cells, cytokines such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1ß (IL-1ß) release, mitochondrial reactive oxygen species (ROS) and morphological lesions in HUA mice also decreased. Furthermore, phloretin partly inhibited renal glucose transporter 9 (GLUT9) and promoted urinary UA excretion in HUA mice. In vitro, phloretin suppressed the NLPR3 pathway under LPS or UA stimulation in HK-2 cells. CONCLUSIONS: Phloretin could effectively attenuate UA-induced renal injury via co-inhibiting NLRP3 and UA reabsorption, and thus it might be a potential therapy to hyperuricemia-related renal diseases.

Resveratrol exerts dose-dependent anti-fibrotic or pro-fibrotic effects in kidneys: A potential risk to individuals with impaired kidney function.

BACKGROUND: Renal fibrosis is the pathological feature of chronic kidney disease (CKD) which leads to end-stage renal disease (ESRD) and renal failure. Resveratrol [3,5,4'-trihydroxy-trans-stilbene (RSV)] has shown benefits for metabolic diseases and anti-cancer therapy, but its potential risk on renal health has not been fully evaluated. PURPOSE: To investigate the global effects of RSV on renal fibrosis in human tubular epithelial cell (TEC) line HK-2, and in mice with unilateral ureteral obstruction (UUO). METHODS: A TGF-ß-induced in vitro model of epithelial-mesenchymal transition (EMT) in TEC was established. The effects of RSV on cell viability, pro-fibrotic factors, oxidative stress, mitochondria function, and underlying pathway proteins were analyzed. In vivo, the effects of RSV on renal function and fibrosis were assayed in UUO mice. RESULTS: Our results showed that low concentrations of RSV (5-20 µM) decreased TGF-ß-induced EMT via Sirt1-dependent deacetylation of Smad3/Smad4 mechanism. By contrast, long-term (72 h) exposure to high concentrations of RSV (≥ 40 µM) promoted EMT in HK-2 cells via mitochondrial oxidative stress and ROCK1-mediated disordered cytoskeleton remodeling. In vivo, low-dose treatment of RSV (≤ 25 mg/kg) partly improved renal function, whereas high-dose treatment of RSV (≥ 50 mg/kg) lost its anti-fibrotic role and even aggravated renal fibrosis. However, mice with UUO were more susceptible to high RSV-induced renal injury than normal mice. CONCLUSION: Dependent on dose, RSV activated either anti-fibrotic or pro-fibrotic effects in kidneys. The risk of RSV consumption in individuals with impaired kidney function should be carefully considered.

[Effect of Electroacupuncture on Expression of Catechol-O-methyltransferase in the Inferior Colliculus and Auditory Cortex in Age-related Hearing Loss Guinea Pigs].

OBJECTIVE: To observe the expression of catechol-O-methyltransferase (COMT) in inferior colliculus and auditory cortex of guinea pigs with age-related hearing loss(AHL) induced by D-galactose, so as to explore the possible mechanism of electroacupuncture(EA) underlying preventing AHL. METHODS: Thirty 3-month-old guinea pigs were randomly divided into control group, model group and EA group(n=10 in each group), and ten 18-month-old guinea pigs were allocated as elderly group. The AHL model was established by subcutaneous injection of D-galactose. EA was applied to bilateral "Yifeng"(SJ 17) and "Tinggong"(SI 19) for 15 min in the EA group while modeling, once daily for 6 weeks. After treatment, the latency of auditory brainstem response(ABR) Ⅲ wave was measured by a brain-stem evoked potentiometer. The expressions of COMT in the inferior colliculus and auditory cortex were detected by Western blot. RESULTS: Compared with the control group, the latencies of ABR Ⅲ wave were significantly prolonged and the expressions of COMT in the inferior colliculus and auditory cortex were significantly decreased in the model group and the elderly group(P<0.05). After the treatment, the latency of ABR Ⅲ wave was significantly shortened and the expressions of COMT in the inferior colliculus and auditory cortex were significantly increased in the EA group in comparison with the model group (P<0.05). CONCLUSIONS: EA at "Yifeng" (SJ 17) and "Tinggong" (SI 19) can improve the hearing of age-related deafness in guinea pigs, which may contribute to its effect in up-regulating the expression of COMT in the inferior colliculus and auditory cortex.

Effect of Electroacupuncture on Visceral and Hepatic Fat in Women with Abdominal Obesity: A Randomized Controlled Study Based on Magnetic Resonance Imaging.

OBJECTIVE: Visceral adipose tissue (VAT) and hepatic fat deposition are the most important risk factors for women's health. Acupuncture, including electroacupuncture (EA), is used to treat obesity throughout the world. The effect of EA is evaluated mainly by body mass index (BMI) and waist circumference (WC). Few studies have assessed its effect in reducing VAT volume and hepatic fat fraction (HFF) based on an exact measurement method such as magnetic resonance imaging (MRI). This study aimed to resolve this issue. METHODS: Thirty subjects were randomly divided into two groups. The control group (n = 15) did not receive any intervention and maintained a normal diet and their usual exercise habits. The treatment group (n = 15) received EA three times a week for 3 months. BMI and WC were measured using different devices. VAT and HFF were measured by MRI and calculated by related software before and after the intervention. RESULTS: A marked difference was evident in group that received EA treatment in the following tests. The differences in BMI (U = 21.00, p < 0.001), WC (U = 40.50, p = 0.002), VAT volume (U = 13.00, p < 0.001), and mean HFF (U = 0.00, p < 0.001) before and after the intervention in the treatment group were distinct and significant compared with those of the control group. Three months later, the treatment group showed a lower BMI (W = 91.00, p = 0.001), WC (t = 4.755, p < 0.001), VAT volume (t = 5.164, p < 0.001), and mean HFF (W = 120.00, p = 0.001) compared with pretreatment levels. Compared with the control group, the treatment group showed a lower VAT volume (t = 60.00, p = 0.029) after 3 months of treatment. After 3 months, the control group showed higher mean HFF (t = -2.900, p = 0.012) and VAT volume (W = 11.50, p = 0.006) compared with their initial levels. CONCLUSION: Based on MRI evaluation, this randomized controlled study proved that EA treatment reduces BMI and WC as well as VAT volume and HFF in women with abdominal obesity.

Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway.

Vasculopathy is a major complication of diabetes. Impaired mitochondrial bioenergetics and biogenesis due to oxidative stress are a critical causal factor for diabetic endothelial dysfunction. Sirt1, an NAD+-dependent enzyme, is known to play an important protective role through deacetylation of many substrates involved in oxidative phosphorylation and reactive oxygen species generation. Mesenchymal stem cell-conditioned medium (MSC-CM) has emerged as a promising cell-free therapy due to the trophic actions of mesenchymal stem cell (MSC)-secreted molecules. In the present study, we investigated the therapeutic potential of MSC-CMs in diabetic endothelial dysfunction, focusing on the Sirt1 signalling pathway and the relevance to mitochondrial function. We found that high glucose-stimulated MSC-CM attenuated several glucotoxicity-induced processes, oxidative stress and apoptosis of endothelial cells of the human umbilical vein. MSC-CM perfusion in diabetic rats ameliorated compromised aortic vasodilatation and alleviated oxidative stress in aortas. We further demonstrated that these effects were dependent on improved mitochondrial function and up-regulation of Sirt1 expression. MSC-CMs activated the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), leading to direct interaction between Akt and Sirt1, and subsequently enhanced Sirt1 expression. In addition, both MSC-CM and Sirt1 activation could increase the expression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), as well as increase the mRNA expression of its downstream, mitochondrial, biogenesis-related genes. This indirect regulation was mediated by activation of AMP-activated protein kinase (AMPK). Overall our findings indicated that MSC-CM had protective effects on endothelial cells, with respect to glucotoxicity, by ameliorating mitochondrial dysfunction via the PI3K/Akt/Sirt1 pathway, and Sirt1 potentiated mitochondrial biogenesis, through the Sirt1/AMPK/PGC-1α pathway.