Factors influencing implementation of a care coordination intervention for cancer survivors with multiple comorbidities in a safety-net system: an application of the Implementation Research Logic Model.

BACKGROUND: Under- and uninsured cancer survivors have significant medical, social, and economic complexity. For these survivors, effective care coordination between oncology and primary care teams is critical for high-quality, comprehensive care. While evidence-based interventions exist to improve coordination between healthcare teams, testing implementation of these interventions for cancer survivors seen in real-world safety-net settings has been limited. This study aimed to (1) identify factors influencing implementation of a multicomponent care coordination intervention (nurse coordinator plus patient registry) focused on cancer survivors with multiple comorbidities in an integrated safety-net system and (2) identify mechanisms through which the factors impacted implementation outcomes. METHODS: We conducted semi-structured interviews (patients, providers, and system leaders), structured observations of primary care and oncology operations, and document analysis during intervention implementation between 2016 and 2020. The practice change model (PCM) guided data collection to identify barriers and facilitators of implementation; the PCM, Consolidated Framework for Implementation Research, and Implementation Research Logic Model guided four immersion/crystallization data analysis and synthesis cycles to identify mechanisms and assess outcomes. Implementation outcomes included appropriateness, acceptability, adoption, and penetration. RESULTS: The intervention was appropriate and acceptable to primary care and oncology teams based on reported patient needs and resources and the strength of the evidence supporting intervention components. Active and sustained partnership with system leaders facilitated these outcomes. There was limited adoption and penetration early in implementation because the study was narrowly focused on just breast and colorectal cancer patients. This created barriers to real-world practice where patients with all cancer types receive care. Over time, flexibility intentionally designed into intervention implementation facilitated adoption and penetration. Regular feedback from system partners and rapid cycles of implementation and evaluation led to real-time adaptations increasing adoption and penetration. DISCUSSION: Evidence-based interventions to coordinate care for underserved cancer survivors across oncology and primary care teams can be implemented successfully when system leaders are actively engaged and with flexibility in implementation embedded intentionally to continuously facilitate adoption and penetration across the health system.

Dietary Taurine Improves Growth Performance and Intestine Health via the GSH/GSSG Antioxidant System and Nrf2/ARE Signaling Pathway in Weaned Piglets.

Early weaning of piglets was prone to increase reactive oxygen species, disrupt the redox balance, decrease antioxidant capacity, cause oxidative stress and intestinal oxidative damage, and lead to diarrhea in piglets. This research aimed to study dietary taurine (Tau) supplementation at a level relieving intestinal oxidative damage in early-weaned piglets. A total of 48 piglets were assigned to four groups of 12 individuals and fed a basal diet with 0.0% Tau (CON), 0.2% Tau (L-Tau), 0.3% Tau (M-Tau), or 0.4% Tau (H-Tau), respectively. The animal experiment lasted 30 days. The final weight, weight gain, average daily gain, and feed conversion rate increased with the increase in dietary Tau (Linear, p < 0.05; Quadratic p < 0.05), while the diarrhea index of piglets decreased with the increase in dietary Tau (Linear, p < 0.05). Serum malondialdehyde, nitric oxide (NO), D-lactose, and oxidized glutathione (GSSG) concentrations decreased with the increase in dietary Tau (Linear, p < 0.05). The O2•- and •OH clearance rate in serum, liver, and jejunum mucosa increased with the increase in dietary Tau (Linear, p < 0.05). Serum superoxide dismutase (SOD) activity, glutathione peroxidase (GPX) activity, catalase (CAT) activity, and peroxidase (POD) activity and total antioxidant capacity increased with the increase in dietary Tau (Linear, p < 0.05). The serum glutathione (GSH) concentration and the ratio of GSH to GSSG increased with the increase in dietary Tau (Linear, p < 0.05). The POD and glutathione synthase activity in the liver and jejunum mucosa increased with the increase in dietary Tau (Linear, p < 0.05). The mRNA abundances of HO-1 and GPX1 in the H-Tau group were higher than that in the L-Tau, M-Tau, and CON groups (p < 0.05). The mRNA abundances of SOD1 and Nrf2 in the M-Tau and H-Tau groups were higher than in the L-Tau and CON groups (p < 0.05). The mRNA abundance of SOD2 in the L-Tau, M-Tau, and H-Tau groups was higher than in the CON group (p < 0.05). The VH and the ratio of VH to CD of jejunum and ileum increased with the increase in dietary Tau (Linear, p < 0.05). The mRNA abundances of occludens 1 and claudin 1 in the H-Tau group were higher than that in the CON, L-Tau, and M-Tau (p < 0.05). The mRNA abundance of occludin in the L-Tau, M-Tau, and H-Tau groups was higher than that in CON (p < 0.05). The abundance of Firmicutes increased with the increase in dietary Tau (Linear, p < 0.05), while Proteobacteria and Spirochaetota decreased with the increase in dietary Tau (Linear, p < 0.05). Collectively, dietary supplementation of 0.3% and 0.4% Tau in feed could significantly improve the growth performance and enhance the antioxidant capacity of piglets.

The effect of theabrownins on the amino acid composition and antioxidant properties of hen eggs.

Pu-erh tea theabrownins (TBs) exert beneficial effect on egg quality and antioxidant properties of eggs, but the underlying mechanisms behind this response are unclear. In this study, we investigate the effect of TBs on egg antioxidative activity, amino acid and fatty acid profiles, and the underlying relationship between the TBs and oxidant-sensitive Nrf2 signaling pathway in laying hens. Eighty layers were fed a basal diet (control) and 400 mg/kg of TBs supplemented diet for 12 wk. TBs led to an increase in albumen height and Haugh unit (P < 0.05). The albumen lysine, valine, and tryptophan were higher in layers fed TBs, whereas yolk tryptophan, methionine, vitamin A, and α-tocopherol content were enhanced by TBs (P < 0.05). Eggs albumen and yolk showed higher total antioxidant capacity (T-AOC), reducing power (RP), and the scavenging rate of 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH), and lower MDA content than those of eggs from the control group (P < 0.05). Also, magnum Nrf2, hemeoxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and Bcl2 expression were up-regulated by TBs, whereas magnum proapoptotic gene (Bax, caspase 3, Cyt C) were down-regulated by TBs (P < 0.05). Our findings suggest that TBs improved egg albumen quality and antioxidant activity, and the Nrf2-ARE pathway were found to be involved in this process.

[Heat-tonifying acupuncture relieves pain and synovial inflammatory injury by regulating Keap1-Nrf2/ARE/ HO-1 signaling pathway in rabbits with cold syndrome type rheumatoid arthritis].

OBJECTIVE: To observe the effect of heat-tonifying needling on Keap1-Nrf2/ARE/HO-1 signal transduction pathway in knee synovium in rabbits with cold syndrome type rheumatoid arthritis (RA), so as to explore its mechanisms underl-ying improvement of RA. METHODS: New Zealand rabbits were randomly divided into normal control, RA model, uniform reinforcing-reducing acupuncture, twisting reinforcing acupuncture and heat-tonifying acupuncture groups, with 6 rabbits in each group. The cold syndrome type RA model was established by subcutaneous injection of mixture fluid of ovalbumin and Freund's complete adjuvant at the shoulder-back as well as injection of mixture of ovalbumin and normal saline into knee-joint cavity combined with ice-compress freezing. Acupuncture stimulation (uniform reinforcing-reducing, or twisting reinforcing or heat-tonifying) was applied to bilateral "Zusanli"(ST36) for 1 min with the needle retained for 30 min, once a day for 7 consecutive days. The general conditions of rabbits in each group were recorded, the thermal pain threshold (TPT) and perimeter of knee joints was measured. Conditions of the synovium in the knee cavity, hydrops, blood flow signal, articular surface, and related muscles were observed by using a color Doppler ultrasonic diagnostic apparatus, and the blood flow signals inside the synovium (image scores) were divided into 0 (no signals), I (1 or 2 dot-like signal), II (less than half) ad III (more than half). After H.E. staining, the pathological changes (0-3 points) were assessed according to the state of inflammatory cell infiltration, and hyperplasia of synovial matrix and coating cells. The expression levels of Keap1, Nrf2, HO-1 and GSH-PX1 mRNAs in the knee synovium were detected by quantitative real-time PCR, and the expression of knee synovial HO-1 protein was measured by Western blot. RESULTS: In comparison with the normal control group, the model group had a significant increase in the perimeter, pathological score, expression of Nrf2, HO-1 mRNAs and HO-1 protein (P<0.05), and an obvious decrease in the TPT, expression levels of Keap1 and GSH-PX1 mRNAs (P<0.05). Relevant to the model group, all the three acupuncture maneuvers reversed modeling-induced increase of perimeter and pathological score (P<0.05), decrease of TPT and expression of GSH-PX1 mRNA(P<0.05), further down-regulated expression of Keap1 mRNA (P<0.05), further up-regulated the expression of Nrf2, HO-1 mRNAs and HO-1 protein (P<0.05). The heat-reinforcing manipulation was significantly superior to uniform reinforcing-reducing and twirling reinforcing manipulations in up-regulating TPT, and expression of Nrf2 mRNA, GSH-PX1 mRNA, HO-1 mRNA and protein (P<0.05), and in down-regulating pathological score and Keap1 mRNA expression (P<0.05). CONCLUSION: Heat-tonifying, uniform reinforcing-reducing and twirling reinforcing needling manipulations may relieve pain and improve pathological state in RA rabbits, which may be associated with their functions in raising the ability of anti-oxidative stress by regulating Keap1-Nrf2/ARE/ HO-1 signaling pathway, the therapeutic effect of heat-tonifying needling is superior to that of uniform reinforcing-reducing and twirling reinforcing needling.

Moschus exerted protective activity against H2O2-induced cell injury in PC12 cells through regulating Nrf-2/ARE signaling pathways.

The pivotal characteristics of Alzheimer's disease (AD) are irreversible memory loss and progressive cognitive decline, eventually causing death from brain failure. In the various proposed hypotheses of AD, oxidative stress is also regarded as a symbolic pathophysiologic cascade contributing to brain diseases. Using Chinese herbal medicine may be beneficial for treating and preventing AD. As a rare and valuable animal medicine, Moschus possesses antioxidant and antiapoptotic efficacy and is extensively applied for treating unconsciousness, stroke, coma, and cerebrovascular diseases. We aim to evaluate whether Moschus protects PC12 cells from hydrogen peroxide (H2O2)-induced cellular injury. The chemical constituents of Moschus are analyzed by GC-MS assay. The cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP) levels, oxidative stress-related indicators, and apoptotic proteins are determined. Through GC-MS analysis, nineteen active contents were identified. The cell viability loss, lactate dehydrogenase releases, MMP levels, ROS productions, and Malondialdehyde (MDA) activities decreased, and BAX, Caspase-3, and Kelch-like ECH-associated protein 1 expression also significantly down-regulated and heme oxygenase 1, nuclear factor erythroid-2-related factor 2 (Nrf-2), and quinine oxidoreductase 1 expression upregulated after pretreatment of Moschus. The result indicated Moschus has neuroprotective activity in relieving H2O2-induced cellular damage, and the potential mechanism might be associated with regulating the Nrf-2/ARE signaling pathway. A more in-depth and comprehensive understanding of Moschus in the pathogenesis of AD will provide a fundamental basis for in vivo AD animal model research, which may be able to provide further insights and new targets for AD therapy.

Bambusa vulgaris leaves reverse mitochondria dysfunction in diabetic rats through modulation of mitochondria biogenic genes.

OBJECTIVES: There is evidence that mitochondrial dysfunction mediated by hyperglycemia increases the incidence of diabetes and age-related insulin resistance. Thus, maintaining mitochondrial integrity may provide alternative therapeutic approach in diabetes treatment. This study aimed to evaluate the effect of Bambusa vulgaris leaf extract on mitochondrial biogenesis in the pancreas of diabetic rats. METHODS: 11 weeks old male rats (n=30) were purchased, and sorted into the following groups: control, diabetic control, diabetes + metformin (100 mg/kg), diabetes + Aq. B. vulgaris (100 mg/kg), diabetes + Aq. B. vulgaris (200 mg/kg), and diabetes + Aq. B. vulgaris (300 mg/kg). Diabetes was induced in the rats by a single dose of 65 mg/kg streptozotocin (STZ). The mRNA expression of genes related to mitochondria biogenesis (pgc-1α, Nrf2, GSK3ß, AMPK and SIRT2) and genes of Nrf2-Keap1-ARE signaling pathway were determined by reverse transcriptase polymerase chain reaction. Molecular docking studies including lock and key docking and prime MM-GBSA were incorporated to identify the lead chemical compounds in Bambusa vulgari. RESULTS: The results showed that B. vulgaris leaf extract promotes mitochondrial biogenesis via altering the mRNA expression of mitochondrial master regulator pgc-1α, other upstream genes, and the Nrf2-Keap1-ARE antioxidant pathway. Through molecular docking results, cryptochlorogenic acid, hesperidin, orientin, vitexin, scopolin, and neochlorogenic were found as the crucial chemicals in B. vulgaris with the most modulating effect on PGC-1α, AMPK, and GSK3. CONCLUSIONS: This study thus suggests that B. vulgaris leaf extract restores the integrity of mitochondria in diabetic rats.

Shenling Baizhusan Improves Spermatogenesis in Hyperuricemia Oligoasthenospermia Mice by Regulating Nrf2/ARE Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect and mechanism of Shenling Baizhusan on the treatment of oligoasthenospermia with hyperuricemia （HUA）. MethodThirty-two male Kunming （KM） mice were randomly divided into blank group （n=6）， model group （n=6）， high-dose Shenling Baizhusan group （n=7）， low-dose Shenling Baizhusan group （n=7）， and febuxostat group （n=6）. Except for the blank group， all other groups received intraperitoneal injection of potassium oxazinate suspension （600 mg·kg-1） for 7 days. After modeling， the high-dose Shenling Baizhusan group and the low-dose Shenling Baizhusan group were orally administered with 20.14 g·kg-1 and 10.07 g·kg-1 of Shenling Baizhusan， respectively. The Febuxostat group was orally administered with 0.25 g·kg-1 of Febuxostat， while the blank group and model group were orally administered with the same volume of physiological saline. Oral administration was performed once a day for 14 consecutive days， after which samples were collected. Biochemical methods were used to measure serum uric acid （UA）， superoxide dismutase （SOD） and malondialdehyde （MDA） in testicular tissue. Hematoxylin-eosin （HE） staining was used to observe the histopathological changes in testicular tissue and evaluate the spermatogenesis function. Automated sperm analyzer was used to measure sperm density and motility. Single-cell gel electrophoresis （SCGE） was used to assess sperm DNA integrity. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling （TUNEL） was used to detect testicular cell apoptosis rate. Western blot analysis was performed to measure the protein expression levels of Kelch-like ECH-associated protein 1 （Keap1）， nuclear factor E2-related factor 2 （Nrf2）， heme oxygenase-1 （HO-1）， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and Caspase-3 in testicular tissue. Real-time polymerase chain reaction （PCR） was conducted to evaluate the mRNA expression levels of Keap1， Nrf2， and HO-1 in testicular tissue. ResultCompared with the blank group， the model group showed elevated serum UA level （P<0.01）， decreased testicular spermatogenesis function， sperm density， and motility （P<0.01）， and increased sperm trailing rate and testicular cell apoptosis rate （P<0.01）. Compared with the model group， the high-dose Shenling Baizhusan group showed significant improvements in the above-mentioned indicators （P<0.05， P<0.01）. Additionally， the expression levels of Keap1， Bax， and Caspase-3 in testicular tissue were reduced， while the expression levels of Nrf2， HO-1， and Bcl-2 increased （P<0.05， P<0.01）. The mRNA level of Keap1 decreased （P<0.05， P<0.01）， while the mRNA levels of Nrf2 and HO-1 increased （P<0.05， P<0.01）. ConclusionShenling Baizhusan can significantly improve HUA oligoasthenospermia， and its mechanism may be related to the Nrf2/antioxidant response element （ARE） signaling pathway.

Modified Qing'e Formula protects against UV-induced skin oxidative damage via the activation of Nrf2/ARE defensive pathway.

Exposure to ultraviolet (UV) light triggers the rapid generation and accumulation of reactive oxygen species (ROS) in skin cells, which increases oxidative stress damage and leads to photoaging. Nuclear factor E2-related factor 2 (Nrf2) modulates the antioxidant defense of skin cells against environmental factors, especially ultraviolet radiation. Natural products that target Nrf2-regulated antioxidant reactions are promising candidates for anti-photoaging. The aim of this study was to investigate the protective effect of Modified Qing'e Formula (MQEF) on UV-induced skin oxidative damage and its molecular mechanisms. In this study, the photoaging models of human keratinocytes (HaCaT) and ICR mice were established by UV irradiation. In vitro models showed that MQEF displayed potent antioxidant activity, significantly increased cell viability and reduced apoptosis and excess ROS levels. Meanwhile, the knockdown of Nrf2 reversed the antioxidant and anti-apoptotic effects of MQEF. In vivo experiments indicated that MQEF could protect the skin against UV-exposed injury which manifested by water loss, sensitivity, tanning, wrinkling, and breakage of collagen and elastic fibers. The application of MQEF effectively increased the activity of antioxidant enzymes and reduced the content of malondialdehyde (MDA) in mice. In addition, MQEF was able to activate Nrf2 nuclear translocation in mouse skin tissue. In summary, MQEF may attenuate UV-induced photoaging by upregulating Nrf2 expression and enhancing antioxidant damage capacity. MQEF may be a potential candidate to prevent UV-induced photoaging by restoring redox homeostasis.

Wedelolactone facilitates the early development of parthenogenetically activated porcine embryos by reducing oxidative stress and inhibiting autophagy.

Wedelolactone (WDL) is a coumaryl ether compound extracted from the traditional Chinese medicinal plant, Eclipta prostrata L. It is a natural polyphenol that exhibits a variety of pharmacological activities, such as anti-inflammatory, anti-free radical, and antioxidant activities in the bone, brain, and ovary. However, its effect on embryonic development remains unknown. The present study explored the influence of WDL supplementation of porcine oocytes culture in vitro on embryonic development and the underlying mechanisms and its effect on the levels of Kelch-like ECH-associated protein 1/nuclear factor-erythroid 2-related factor 2/antioxidant response element (Keap1/Nrf2/ARE). The results showed that WDL (2.5 nM) significantly increased the blastocyst formation rate, mitochondrial activity, and proliferation ability while reducing the reactive oxygen species accumulation, apoptosis, and autophagy. These findings suggested that WDL can enhance the growth and development of early porcine embryos to alleviate oxidative stress and autophagy through regulating NRF2 and microtubule-associated protein 1 light chain 3 (MAP1LC3) gene expression levels.

Salvianolate ameliorates renal tubular injury through the Keap1/Nrf2/ARE pathway in mouse kidney ischemia-reperfusion injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute kidney injury (AKI) is a common clinical disease characterized by rapid loss of renal function. Salvianolate is a prescribed Chinese medicine derived from traditional Chinese medicine Salvia miltiorrhiza bunge that possesses many pharmacological effects, the active components extracted from Salvia miltiorrhiza bunge have been proved to protect ischemia-reperfusion (I/R)-AKI. AIM OF THE STUDY: This study aims to validate the therapeutic effect of SAL on I/R-AKI, and explore its potential pharmacological mechanism. MATERIALS AND METHODS: Mice were pretreated with/without salvianolate (10, 30, and 90 mg/kg) before renal ischemia-reperfusion operation. Serum creatinine, BUN, and H&E staining were performed to evaluate renal function. Immunofluorescence analysis was conducted to measure renal tubular injury including inflammatory factors and peroxide level. Apoptosis of the kidney tissues was determined by TUNEL assay. Keap1-Nrf2-ARE and apoptosis signaling pathways were measured by Western blot, RT-PCR, and YO-PRO-1 staining in kidneys or NRK52E cells. RESULTS: Pretreatment with SAL effectively alleviated renal function and ameliorated epithelial tubular injury, oxidative stress, and inflammatory response. Furthermore, the mechanistic study demonstrated that the SAL exerts anti-apoptotic effects through activation of the Keap1-Nrf2-ARE signaling pathway in renal tubular cells. CONCLUSION: These findings indicate the therapeutic benefit of salvianolate in the protection of renal injury from ischemia-reperfusion, and strengthen the evidence for the AKI treatment strategy by the anti-oxidative stress response, suggesting that SAL may be a potential agent for the treatment of AKI.

Shikonin Attenuates Cochlear Spiral Ganglion Neuron Degeneration by Activating Nrf2-ARE Signaling Pathway.

The molecular mechanisms that regulate the proliferation and differentiation of inner ear spiral ganglion cells (SGCs) remain largely unknown. Shikonin (a naphthoquinone pigment isolated from the traditional Chinese herbal medicine comfrey root) has anti-oxidation, anti-apoptosis and promoting proliferation and differentiation effects on neural progenitor cells. To study the protective effect of shikonin on auditory nerve damage, we isolated spiral ganglion neuron cells (SGNs) and spiral ganglion Schwann cells (SGSs) that provide nutrients in vitro and pretreated them with shikonin. We found that shikonin can reduce ouabain, a drug that can selectively destroy SGNs and induce auditory nerve damage, caused SGNs proliferation decreased, neurite outgrowth inhibition, cells apoptosis and mitochondrial depolarization. In addition, we found that shikonin can increase the expression of Nrf2 and its downstream molecules HO-1 and NQO1, thereby enhancing the antioxidant capacity of SGNs and SGSs, promoting cells proliferation, and inhibiting cells apoptosis by activating the Nrf2/antioxidant response elements (ARE) signal pathway. However, knockdown of Nrf2 rescued the protective effect of shikonin on SGNs and SGSs damage. In addition, we injected shikonin pretreatment into mouse that ouabain-induced hearing loss and found that shikonin pretreatment has a defensive effect on auditory nerve damage. In summary, the results of this study indicate that shikonin could attenuate the level of oxidative stress in SGNs and SGSs through the Nrf2-ARE signaling pathway activated, induce the proliferation and differentiation of SGNs, and thereby improve the neurological hearing damage in mice. Therefore, shikonin may be a candidate therapeutic drug for endogenous antioxidants that can be used to treat neurological deafness.

Randomized controlled trial of astaxanthin impacts on antioxidant status and assisted reproductive technology outcomes in women with polycystic ovarian syndrome.

PURPOSE: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is typically accompanied by a defective oxidative defense system. Here, we investigated the effect of astaxanthin (AST) as a powerful antioxidant on the oxidative stress (OS) response and assisted reproductive technology (ART) outcomes in PCOS patients. METHODS: In this double-blind, randomized, placebo-controlled trial, PCOS patients were randomly assigned into two groups. The intervention group received 8 mg AST, and the control group received the placebo daily for 40 days. The primary outcomes were the serum and follicular fluid (FF) levels of the OS biomarkers and the expression levels of the specific genes and proteins in the oxidative stress response pathway. The secondary outcomes were considered ART outcomes. RESULTS: According to our findings, a 40-day course of AST supplementation led to significantly higher levels of serum CAT and TAC in the AST group compared to the placebo group. However, there were no significant intergroup differences in the serum MDA and SOD levels, as well as the FF levels of OS markers. The expression of Nrf2, HO-1, and NQ-1 was significantly increased in the granulosa cells (GCs) of the AST group. Moreover, the MII oocyte and high-quality embryo rate were significantly increased in the AST group compared to the placebo group. We found no significant intergroup difference in the chemical and clinical pregnancy rates. CONCLUSION: AST treatment has been shown to increase both serum TAC levels and activation of the Nrf2 axis in PCOS patients' GCs. TRIAL REGISTRATION: ClincialTrials.gov Identifier: NCT03991286.

Coffee-Derived Phenolic Compounds Activate Nrf2 Antioxidant Pathway in I/R Injury In Vitro Model: A Nutritional Approach Preventing Age Related-Damages.

Age-related injuries are often connected to alterations in redox homeostasis. The imbalance between free radical oxygen species and endogenous antioxidants defenses could be associated with a growing risk of transient ischemic attack and stroke. In this context, a daily supply of dietary antioxidants could counteract oxidative stress occurring during ischemia/reperfusion injury (I/R), preventing brain damage. Here we investigated the potential antioxidant properties of coffee-derived circulating metabolites and a coffee pulp phytoextract, testing their efficacy as ROS scavengers in an in vitro model of ischemia. Indeed, the coffee fruit is an important source of phenolic compounds, such as chlorogenic acids, present both in the brewed seed and in the discarded pulp. Therefore, rat brain endothelial cells, subjected to oxygen and glucose deprivation (OGD) and recovery (ogR) to mimic reperfusion, were pretreated or not with coffee by-products. The results indicate that, under OGD/ogR, the ROS accumulation was reduced by coffee by-product. Additionally, the coffee extract activated the Nrf2 antioxidant pathway via Erk and Akt kinases phosphorylation, as shown by increased Nrf2 and HO-1 protein levels. The data indicate that the daily intake of coffee by-products as a dietary food supplement represents a potential nutritional strategy to counteract aging.

Vitamin D supplementation improves testicular function in aging rats induced by D-galactose / 中华内分泌代谢杂志

Objective:To investigate the effects and potential mechanism of vitamin D supplementation on testicular function in aging rats induced by D-galactose.Methods:The aging rats were induced by D-galactose with subcutaneous injection. The animals were randomly divided into 6 groups: aging rats (DG), aging rats with low-dose vitamin D supplementation (LD), aging rats with high-dose vitamin D supplementation (HD), normal control rats(NC), normal rats with low-dose vitamin D supplementation(LN), normal rats with high-dose vitamin D supplementation (HN). The body weight, testicular weight, serum testosterone concentrations and sperm quality of the rats in each group were measured. The testis morphological changes were detected using light microscopy. The activity of superoxide dismutase (SOD) and level of malondialdehyde(MDA) were determined with spectrophotometer. The expression levels of Nrf2, GCLC, SOD2 and VDR in testis were detected by western blot.Results:At baseline, compared with NC group, testicular weight, serum testosterone level, SOD activity, Nrf2, GCLC and SOD2 expression levels were significantly decreased in DG group, while MDA level was significantly increased. After vitamin D supplementation, testicular weight, testosterone levels and SOD activity in both of HD and LD groups were significantly increased, while the MDA level was significantly decreased. The expression levels of Nrf2, GCLC, SOD2 and VDR were significantly increased.Conclusion:Vitamin D supplementation may enhance the testicular antioxidant capacity through activating Nrf2-ARE signaling pathway, and improve the testicular function in D-galactose-induced aging rats.

Protective Mechanism of Total Flavonoids of Lavender Against Skin Photoaging in Mice / 中国实验方剂学杂志

ObjectiveTo study the protective effect of total flavonoids of lavender on skin photoaging induced by ultraviolet B （UVB） in mice and to explore its mechanism from the perspective of nuclear factor E2-related factor 2 （Nrf2） antioxidant pathway. MethodEighty-four female KM mice were randomly divided into seven groups， namely blank group， model group， solvent group， vitamin E （0.013 g·kg-1） group， as well as low-， middle-， and high-dose （0.25， 1.25， 2.50 g·kg-1） groups of total flavonoids of lavender. The naked skin on the back of mice was irradiated with UVB for inducing optical damage. Thirty minutes before irradiation， the skin was coated with the total flavonoids of lavender. After continuous irradiation for one week， the skin moisture and elasticity on the back of mice were evaluated， and the effects of total flavonoids of lavender on histopathological changes in mouse skin were investigated by hematoxylin-eosin （HE） and Van Gieson （VG） staining. The levels of malondialdehyde （MDA）， superoxide dismutase （SOD）， total antioxidant capacity （T-AOC）， nitric oxide synthase （NOS）， and glutathione peroxidase （GSH-Px） after skin homogenization were detected by colorimetry， the inflammatory factors interleukin-1 （IL-1）， interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） in skin tissue by enzyme-linked immunosorbent assay （ELISA）， and the mRNA expression levels of Nrf2， Kelch-like epichlorohydrin-associated protein 1 （Keap1）， BTB-CNC homology 1 （Bach1）， heme oxygenase-1 （HO-1）， quinone oxidoreductase 1 （NQO1）， and glutamate-cysteine ligase catalytic subunit （GCLC） by real-time polymerase chain reaction （Real-time PCR）. ResultCompared with the blank group， the model group exhibited significantly increased appearance score （P<0.01）， reduced skin moisture and elasticity （P<0.01）， pronounced pathological changes in the skin tissue like epidermal thickening， scabbing， small abscess， and severe injury， elevated MDA， NOS， IL-1， IL-6 and TNF-α （P<0.05， P<0.01）， lowered SOD， T-AOC， Nrf2， Keap1， NQO1 and GCLC mRNA expression （P<0.05，P<0.01）， and up-regulated Bach1 mRNA expression （P<0.01）. Compared with the model group， the total flavonoids of lavender at the low， middle， and high doses all remarkably reduced the appearance score （P<0.01）， enhanced the skin moisture and elasticity （P<0.01）， diminished the MDA， NOS， IL-1， IL-6， and TNF-α （P<0.05， P<0.01）， increased SOD， T-AOC， Nrf2， Keap1， NQO1， HO-1 and GCLC mRNA expression （P<0.05， P<0.01）， and down-regulated the expression of Bach1 mRNA （P<0.01）. ConclusionThe protective effect of the total flavonoids of lavender against skin photoaging in mice is significant， which may be related to its activation of Keap1/Nrf2/ARE signaling pathway， regulation of oxidative stress， and improvement of inflammatory response.

Hepatoprotective effect of acetovanillone against methotrexate hepatotoxicity: Role of Keap-1/Nrf2/ARE, IL6/STAT-3, and NF-κB/AP-1 signaling pathways.

This study targeted to examine the protective effects of acetovanillone (AV) against methotrexate (MTX)-induced hepatotoxicity. Thirty-two rats were allocated into four groups of eight animals; Group 1: Normal; Group 2: administered AV (100 ml/kg; P.O.) for 10 days; Group 3: challenged with MTX (20 mg/kg, i.p; single dose); Group 4: administered AV 5 days before and 5 days after MTX. For the first time, this study affords evidence for AV's hepatoprotective effects on MTX-induced hepatotoxicity. The underlined mechanisms behind its hepatic protection include counteracting MTX-induced oxidative injury via down-regulation of NADPH oxidase and up-regulation of Nrf2/ARE, SIRT1, PPARγ, and cytoglobin signals. Additionally, AV attenuated hepatic inflammation through down-regulation of IL-6/STAT-3 and NF-κB/AP-1 signaling. Network pharmacology analysis exhibited a high enrichment score between the interacting proteins and strongly suggested the intricate and essential role of the target proteins regulating MTX-induced oxidative damage and inflammatory perturbation. Besides, AV increased the in vitro cytotoxic activity of MTX toward PC-3, HeLa, and K562 cancer cell lines. On the whole, our investigation suggested that AV might be regarded as a promising adjuvant for the amelioration of MTX hepatotoxicity and/or increased its in vitro antitumor efficacy, and it could be used in patients receiving MTX.

Intralesional Agents in Dermatology: Pros and Cons.

Since introduced in 1961, intralesional (IL) agent has become an essential part of the dermatological practice. The term IL referred to the direct delivery of agent percutaneously into skin lesions. This therapeutic approach is relatively safe, easy to perform and applicable for a broad range of dermatological conditions. On the other hand, immediate side effects, including pain during administration, bleeding, high risk of infection and allergic reaction, and subsequent side effects involving skin changes such as atrophy, telangiectasia, pigmentary changes, and striae are usually associated with this modality. This review paper highlights the pros and cons of IL agents in modern dermatology practice.

Panax ginseng and its ginsenosides: potential candidates for the prevention and treatment of chemotherapy-induced side effects.

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural non-toxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun N-terminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG.

Syringa microphylla Diels: A comprehensive review of its phytochemical, pharmacological, pharmacokinetic, and toxicological characteristics and an investigation into its potential health benefits.

BACKGROUND: Syringa microphylla Diels is a plant in the family Syringa Linn. For hundreds of years, its flowers and leaves have been used as a folk medicine for the treatment of cough, inflammation, colds, sore throat, acute hepatitis, chronic hepatitis, early liver cirrhosis, fatty liver, and oesophageal cancer. PURPOSE: For the first time, we have comprehensively reviewed information on Syringa microphylla Diels that is not included in the Pharmacopoeia, clarified the pharmacological mechanisms of Syringa microphylla Diels and its active ingredients from a molecular biology perspective, compiled in vivo and in vitro animal experimental data and clinical data, and summarized the toxicology and pharmacokinetics of Syringa microphylla Diels. The progress in toxicology research is expected to provide a theoretical basis for the development of new drugs from Syringa microphylla Diels, a natural source of compounds that are potentially beneficial to human health. METHODS: The PubMed, Google Scholar, China National Knowledge Infrastructure, Web of Science, SciFinder Scholar and Thomson Reuters databases were utilized to conduct a comprehensive search of published literature as of July 2021 to find original literature related to Syringa microphylla Diels and its active ingredients. RESULTS: To date, 72 compounds have been isolated and identified from Syringa microphylla Diels, and oleuropein, verbascoside, isoacteoside, echinacoside, forsythoside B, and eleutheroside B are the main active components. These compounds have antioxidant, antibacterial, anti-inflammatory, and neuroprotective effects, and their safety and effectiveness have been demonstrated in long-term traditional applications. Molecular pharmacology experiments have indicated that the active ingredients of Syringa microphylla Diels exert their pharmacological effects in various ways, primarily by reducing oxidative stress damage via Nrf2/ARE pathway regulation, regulating inflammatory factors and inducing apoptosis through the MAPK and NF-κB pathways. CONCLUSION: This comprehensive review of Syringa microphylla Diels provides new insights into the correlations among molecular mechanisms, the importance of toxicology and pharmacokinetics, and potential ways to address the limitations of current research. As Syringa microphylla Diels is a natural low-toxicity botanical medicine, it is worthy of development and utilization and is an excellent choice for treating various diseases.

Arsenic Trioxide Combining Leflunomide Activates Nrf2-ARE-HO-1 Signaling Pathway and Protects Heart Xenografts.

OBJECTIVE: To investigate the molecular mechanisms underlying the effects of arsenic trioxide (As2O3) in combination with leflunomide on the hamster-to-rat heart xenotransplant. METHODS: Transplantation of LVG hamster hearts to Lewis rats was performed by anastomosis of vessels in the neck using end-to-end anastomosis with a non-suture cuff technique. Four groups of recipient rats (n=6 in each) were treated with normal saline (control), As2O3 [5 mg/(kg·day) intraperitoneally], leflunomide [5 mg/(kg·d) orally], or leflunomide [5 mg/(kg·d)+As2O3 [5 mg/(kg·d)] in combination. Donor hearts and/or rat spleens were harvested and analyzed 4 days after transplantation. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis were performed to detect the expression of the nuclear factor erythroid-derived factor 2-related factor (Nrf2) and its target gene heme oxygenase-1 (HO-1), Treg cell marker fork-head Box P3 (FOXP3), apoptosis-associated proteins Bcl-2, Bax, and cleaved caspase-3. Immunohistochemical staining was used to detect the levels of inflammatory natural killer cell and macrophage infiltration, intercellular cell adhesion molecule-1 (ICAM-1) and complement C3. RESULTS: Expression of Nrf2-ARE-HO-1 signaling pathway was upregulated in heart xenografts in rats treated with As2O3 plus leflunomide compared with control rats or rats treated with either drug alone (P<0.01), and this was accompanied by an increased Treg cells in the recipient rat spleen (P<0.01). In contrast, the expressions of Bax, cleaved caspase-3, ICAM-1, and complement C3, and infiltration of inflammatory cells in the xenografts were inhibited by As2O3 plus leflunomide treatment (P<0.01). CONCLUSION: Combination treatment with As2O3 and leflunomide protected hamster heart-xenografts in recipient rats.