Jujuboside B alleviates acetaminophen-induced hepatotoxicity in mice by regulating Nrf2-STING signaling pathway.

BACKGROUND: Jujuboside B (JuB) is the main bioactive saponin component of Chinese anti-insomnia herbal medicine Ziziphi Spinosae Semen, which has been reported to possess varied pharmacological functions. Even though it has been traditionally used to treat inflammation- and toxicity-related diseases, the effects of JuB on acetaminophen (APAP) overdose-induced hepatotoxicity have not been determined yet. METHODS: C57BL/6 J mice were pre-treated with JuB (20 or 40 mg/kg) for seven days before APAP (400 mg/kg) injection. After 24 h of APAP treatment, serum, and liver tissues were collected to evaluate the therapeutic effects. To investigate whether the Nrf2-STING signaling pathway is involved in the protective effects of JuB against APAP-induced hepatotoxicity, the mice received the DMXAA (the specific STING agonist) or ML385 (the specific Nrf2 inhibitor) during the administration of JuB, and Hematoxylin-eosin staining, Real-time PCR, immunohistochemical, and western blot were performed. RESULTS: JuB pretreatment reversed APAP-induced CYP2E1 accumulations and alleviated APAP-induced acute liver injury. Furthermore, JuB treatment significantly inhibited oxidative stress and the pro-inflammatory cytokines, as well as alleviated hepatocyte apoptosis induced by APAP. Besides, our result also demonstrated that JuB treatment upregulated the levels of total Nrf2, facilitated its nuclear translocation, upregulated the expression of HO-1 and NQO-1, and inhibited the APAP-induced STING pathway activation. Finally, we verified that the beneficial effects of JuB were weakened by DMXAA and ML385. CONCLUSION: Our study suggested that JuB could ameliorate APAP-induced hepatic damage and verified a previously unrecognized mechanism by which JuB prevented APAP-induced hepatotoxicity through adjusting the Nrf2-STING pathway.

Network meta-analysis of different liver protective drugs in the treatment of drug-induced liver injury.

BACKGROUND: Currently, drug-induced liver injury (DILI) has become one of those public issues in society, which has added a huge burden to both the individuals and the society. In the current clinical stage, there are numerous drugs developed to treat this disease, and different drug treatment measures have been proven to achieve certain clinical efficacy in the corresponding randomized controlled trials. However, there are still many therapeutic drugs that have not been directly compared and studied. Therefore, it is difficult to directly compare the effectiveness and safety of various strategies for the treatment of DILI. In this regard, the present study collected the therapeutic efficacy of diverse treatments in DILI in recent years through network meta-analysis, evaluated and screened the existing optimal clinical therapeutic plan, and helped physicians formulate clinical therapeutic plans. METHODS: Databases, including the Chinese Journal Full-text Database, Wanfang Data Journal Paper Resources (Wangfang), VIP Chinese Science and Technology Journal Full-text Database, The Cochrane Library, PubMed, and EMBASE, were searched using keywords from inception to January 2023. Eligible randomized controlled trials were selected in line with eligibility criteria, and mesh meta-analysis of binary variables was carried out using Stata 16 software. CONCLUSION: In combination with alanine aminotransferase, aspartate aminotransferase, and total bilirubin, MI may be the intervention measure for minimizing alanine aminotransferase levels in patients after treatment. Besides, compound glycyrrhizin may be the intervention for minimizing aspartate aminotransferase levels in patients after treatment, and polyene phosphatidylcholine may be the intervention for minimizing total bilirubin levels in patients after treatment. Placebo is the potential intervention that has the least adverse reactions post-treatment, and RT has the second least adverse reactions. Moreover, hepatocyte growth-promoting factors may be the most effective intervention after treatment. RESULTS: To sum up, the present work compared the clinical effects of 13 liver protective drugs through meta-analysis and provided a systematic understanding of commonly used drugs for the treatment of DILI in clinical practice.

Melatonin exhibits partial protective effects against gemcitabine- and cisplatin-induced kidney and reproductive injuries in mice.

Cisplatin has the potential to cause kidney and reproductive organ injuries, prompting the search for protective agents against cisplatin-induced toxicity. Melatonin, an antioxidant hormone, has shown promise in mitigating oxidative stress in various organs. However, its protective effects on cisplatin-induced kidney and reproductive injuries have not been extensively investigated. The aim of this study was to explore the potential protective effects of melatonin on cisplatin-induced kidney and reproductive injuries when administered in combination with gemcitabine in mice. Male C57BL/6 mice were subjected to a seven-week treatment with gemcitabine plus cisplatin, with or without melatonin intervention. The testis, epididymis, and kidney were assessed through histological analysis and measurement of blood parameters. Treatment with cisplatin led to a significant reduction in testicular weight, histological abnormalities, and alterations in reproductive hormone levels. Melatonin exhibited a slight protective effect on the testis, with higher doses of melatonin yielding better outcomes. However, melatonin did not reverse the effects of cisplatin on the epididymis. Administration of melatonin before and during treatment with cisplatin plus gemcitabine in mice demonstrated a modest protective effect on testicular injuries, while showing limited effects on epididymal injuries. Serum creatinine levels in the group treated with gemcitabine plus cisplatin treatment and high-dose melatonin approached those of the control group, indicating a protective effect on the kidney. These findings underscore the potential of melatonin as a protective agent against cisplatin-induced kidney and reproductive injuries and emphasize the need for further research to optimize its dosage and evaluate its long-term effects.

Effective protective agents against organ toxicity of deoxynivalenol and their detoxification mechanisms: A review.

Deoxynivalenol (DON) is one of the most prevalent mycotoxins in feed, which causes organ toxicity in animals. Therefore, reducing DON-induced organ toxicity can now be accomplished effectively using protective agents. This review provides an overview of multiple studies on a wide range of protective agents and their molecular mechanisms against DON organ toxicity. Protective agents include plant extracts, yeast products, bacteria, peptides, enzymes, H2, oligosaccharides, amino acids, adsorbents, vitamins and selenium. Among these, biological detoxification of DON using microorganisms to reduce the toxicity of DON without affecting the growth performance of pigs may be the most promising detoxification strategy. This paper also evaluates future developments related to DON detoxification and discusses the detoxification role and application potential of protective agents. This paper provides new perspectives for future research and development of safe and effective feed additives.

Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects / Efectos Protectores y Mecanismos de la Decocción de Huangqi Contra los Efectos Secundarios Inducidos por la Radiación

SUMMARY: The 12C6+ heavy ion beam irradiation can cause bystander effects. The inflammatory cytokines, endocrine hormones and apoptotic proteins may be involved in 12C6+ irradiation-induced bystander effects. This study characterized the protective effects and mechanisms of Huangqi decoction (HQD) against 12C6+ radiation induced bystander effects. Wistar rats were randomly divided into control, 12C6+ heavy ion irradiation model, and high-dose/medium-dose/low-dose HQD groups. HE staining assessed the pathological changes of brain and kidney. Peripheral blood chemical indicators as well as inflammatory factors and endocrine hormones were detected. Apoptosis was measured with TUNEL. Proliferating cell nuclear antigen (PCNA) expression was determined with real-time PCR and Western blot.Irradiation induced pathological damage to the brain and kidney tissues. After irradiation, the numbers of white blood cells (WBC) and monocyte, and the expression of interleukin (IL)-2, corticotropin-releasing hormone (CRH) and PCNA decreased. The damage was accompanied by increased expression of IL-1β, IL-6, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) as well as increased neuronal apoptosis. These effects were indicative of radiation-induced bystander effects. Administration of HQD attenuated the pathological damage to brain and kidney tissues, and increased the numbers of WBC, neutrophils, lymphocyte and monocytes, as well as the expression of IL-2, CRH and PCNA. It also decreased the expression of IL-1β, IL-6, CORT and ACTH as well as neuronal apoptosis. HQD exhibits protective effects against 12C6+ radiation-induced bystander effects. The underlying mechanism may involve the promotion of the production of peripheral blood cells, inhibition of inflammatory factors and apoptosis, and regulation of endocrine hormones.

La irradiación con haz de iones pesados 12C6+ puede provocar efectos secundarios. Las citoquinas inflamatorias, las hormonas endocrinas y las proteínas apoptóticas pueden estar involucradas en los efectos secundarios inducidos por la irradiación 12C6+. Este estudio caracterizó los efectos y mecanismos protectores de la decocción de Huangqi (HQD) contra los efectos externos inducidos por la radiación 12C6+. Las ratas Wistar se dividieron aleatoriamente en grupos control, modelo de irradiación de iones pesados 12C6+ y grupos de dosis alta/media/baja de HQD. La tinción con HE evaluó los cambios patológicos del cerebro y el riñón. Se detectaron indicadores químicos de sangre periférica, así como factores inflamatorios y hormonas endocrinas. La apoptosis se midió con TUNEL. La expresión del antígeno nuclear de células en proliferación (PCNA) se determinó mediante PCR en tiempo real y transferencia Western blot. La irradiación indujo daños patológicos en los tejidos cerebrales y renales. Después de la irradiación, disminuyó el número de glóbulos blancos (WBC) y monocitos, y la expresión de interleucina (IL)-2, hormona liberadora de corticotropina (CRH) y PCNA. El daño estuvo acompañado por una mayor expresión de IL-1β, IL-6, corticosterona (CORT) y hormona adrenocorticotrópica (ACTH), así como un aumento de la apoptosis neuronal. Estas alteraciones fueron indicativas de efectos inducidos por la radiación. La administración de HQD atenuó el daño patológico a los tejidos cerebrales y renales, y aumentó el número de leucocitos y monocitos, así como la expresión de IL-2, CRH y PCNA. También disminuyó la expresión de IL-1β, IL-6, CORT y ACTH, así como la apoptosis neuronal. HQD exhibe mecanismos protectores contra los efectos externos inducidos por la radiación 12C6+. El mecanismo subyacente puede implicar la promoción de la producción de células sanguíneas periféricas, la inhibición de factores inflamatorios y la apoptosis y la regulación de hormonas endocrinas.

Polar microalgae extracts protect human HaCaT keratinocytes from damaging stimuli and ameliorate psoriatic skin inflammation in mice.

BACKGROUND: Polar microalgae contain unique compounds that enable them to adapt to extreme environments. As the skin barrier is our first line of defense against external threats, polar microalgae extracts may possess restorative properties for damaged skin, but the potential of microalgae extracts as skin protective agents remains unknown. PURPOSE: This study aimed to analyze compound profiles from polar microalgae extracts, evaluate their potential as skin epithelial protective agents, and examine the underlying mechanisms. METHODS: Six different polar microalgae, Micractinium sp. (KSF0015 and KSF0041), Chlamydomonas sp. (KNM0029C, KSF0037, and KSF0134), and Chlorococcum sp. (KSF0003), were collected from the Antarctic or Arctic regions. Compound profiles of polar and non-polar microalgae extracts were analyzed using gas chromatography-mass spectrometry (GC-MS). The protective activities of polar microalgae extracts on human keratinocyte cell lines against oxidative stress, radiation, and psoriatic cytokine exposure were assessed. The potential anti-inflammatory mechanisms mediated by KSF0041, a polar microalga with protective properties against oxidative stress, ultraviolet (UV) B, and an inflammatory cytokine cocktail, were investigated using RNA-sequencing analysis. To evaluate the therapeutic activity of KSF0041, an imiquimod-induced murine model of psoriatic dermatitis was used. RESULTS: Polar microalgae contain components comparable to those of their non-polar counterparts, but also showed distinct differences, particularly in fatty acid composition. Polar microalgae extracts had a greater ability to scavenge free radicals than did non-polar microalgae and enhanced the viability of HaCaT cells, a human keratinocyte cell line, following exposure to UVB radiation or psoriatic cytokines. These extracts also reduced barrier integrity damage and decreased mRNA levels of inflammatory cytokines in psoriatic HaCaT cells. Treatment with KSF0041 extract altered the transcriptome of psoriatic HaCaT cells toward a more normal state. Furthermore, KSF0041 extract had a therapeutic effect in a mouse model of psoriasis. CONCLUSIONS: Bioactive compounds from polar microalgae extracts could provide novel therapeutics for damaged and/or inflamed skin.

Nephroprotective plant species used in traditional Mayan Medicine for renal-associated diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: The prevalence of kidney disease has increased rapidly in recent years and has emerged as one of the leading causes of mortality worldwide. Natural products have been suggested as valuable nephroprotective agents due to their multi-target and synergistic effects on modulating important proteins involved in kidney injury. There is a large number of plant species that have been used traditionally for kidney-related conditions in Mesoamerican medicine by different cultural groups that could provide a valuable source of nephroprotective therapeutic candidates and could lead to potential drug discovery. AIM OF REVIEW: This review aims to provide an overview of the currently known efficacy of plant species used traditionally in Mesoamerica by Mayan groups to treat kidney-related conditions and to analyze the phytochemical, pharmacological, molecular, toxicological, and clinical evidence to contribute to public health efforts and for directing future research. METHODS: Primary sources of plant use reports for traditional kidney-related disorders in Mesoamerica were searched systematically from library catalogs, theses, and scientific databases (PubMed, Google Scholar; and Science Direct), and were filtered according to usage frequency in Mayan groups and plant endemism. The database of traditional plants was further analyzed based on associations with published reports of the phytochemical, pharmacological, molecular, toxicological, and clinical evidence. RESULTS: The most reported kidney-related conditions used traditionally in Mayan medicine involve reducing renal damage (a cultural interpretation that considers an inflammatory or infectious condition), cleaning or purifying the blood and kidney, reducing kidney pain, and eliminating kidney stones. A total of 208 plants used for kidney-related problems by 10 Mayan groups were found, representing 143 native species, where only 42 have reported pharmacological activity against kidney damage, mainly approached by in vitro and in vivo models of chemical- or drug-induced nephrotoxicity, diabetes nephropathy, and renal injury produced by hypertension. Nephroprotective effects are mainly mediated by reducing oxidative stress, inflammatory response, fibrosis mechanisms, and apoptosis in the kidney. The most common nephroprotective compounds associated with traditional Mayan medicine were flavonoids, terpenoids, and phenolic acids. The most widely studied traditional plants in terms of pharmacological evidence, bioactive compounds, and mechanisms of action, are Annona muricata L., Carica papaya L., Ipomoea batatas (L.) Lam., Lantana camara L., Sechium edule (Jacq.) Sw., Tagetes erecta L., and Zea mays L. Most of the plant species with reported pharmacological activity against kidney damage were considered safe in toxicological studies. CONCLUSION: Available pharmacological reports suggest that several herbs used in traditional Mayan medicine for renal-associated diseases may have nephroprotective effects and consistent pharmacological evidence, nephroprotective compounds, and mechanisms of action in different models of kidney injury. However, more research is required to fully understand the potential of traditional Mayan medicine in drug discovery given the limited ethnobotanical studies and data available for most species with regards to identification on bioactive components, pharmacological mechanisms, and the scarce number of clinical studies.

Research Progress on the Role of Pyroptosis in Myocardial Ischemia-Reperfusion Injury.

Myocardial ischemia-reperfusion injury (MIRI) results in the aggravation of myocardial injury caused by rapid recanalization of the ischemic myocardium. In the past few years, there is a growing interest in investigating the complex pathophysiological mechanism of MIRI for the identification of effective targets and drugs to alleviate MIRI. Currently, pyroptosis, a type of inflammatory programmed death, has received greater attention. It is involved in the MIRI development in combination with other mechanisms of MIRI, such as oxidative stress, calcium overload, necroptosis, and apoptosis, thereby forming an intertwined association between different pathways that affect MIRI by regulating common pathway molecules. This review describes the pyroptosis mechanism in MIRI and its relationship with other mechanisms, and also highlights non-coding RNAs and non-cardiomyocytes as regulators of cardiomyocyte pyroptosis by mediating associated pathways or proteins to participate in the initiation and development of MIRI. The research progress on novel small molecule drugs, clinical drugs, traditional Chinese medicine, etc. for regulating pyroptosis can play a crucial role in effective MIRI alleviation. When compared to research on other mature mechanisms, the research studies on pyroptosis in MIRI are inadequate. Although many related protective drugs have been identified, these drugs generally lack clinical applications. It is necessary to further explore and verify these drugs to expand their applications in clinical setting. Early inhibition of MIRI by targeted regulation of pyroptosis is a key concern that needs to be addressed in future studies.

Hawk Tea Flavonoids as Natural Hepatoprotective Agents Alleviate Acute Liver Damage by Reshaping the Intestinal Microbiota and Modulating the Nrf2 and NF-κB Signaling Pathways.

Hawk tea (Litsea coreana Levl. var. lanuginosa) is a traditional herbal tea in southwestern China, and was found to possess hepatoprotective effects in our previous study. However, it is unclear whether hawk tea flavonoids (HTF) can alleviate alcoholic liver damage (ALD). Firstly, we extracted and identified the presence of 191 molecules categorized as HTFs, with reynoutrin, avicularin, guaijaverin, cynaroside, and kaempferol-7-O-glucoside being the most prevalent. After taking bioavailability into consideration and conducting comprehensive sorting, the contribution of guaijaverin was the highest (0.016 mg/mice). Then, by daily intragastric administration of HTF (100 mg/kg/day) to the ALD mice, we found that HTF alleviated liver lipid deposition (inhibition of TG, TC, LDL-C) by reducing liver oxidative-stress-mediated inflammation (up-regulation NRF2/HO-1 and down-regulation TLR4/MyD88/NF-κB pathway) and reshaping the gut microbiota (Lactobacillus, Bifidobacterium, Bacillus increased). Overall, we found HTF could be a potential protective natural compound for treating ALD via the gut-liver axis and guaijaverin might be the key substance involved.

Scutellaria baicalensis and its constituents baicalin and baicalein as antidotes or protective agents against chemical toxicities: a comprehensive review.

Scutellaria baicalensis (SB), also known as the Chinese skullcap, has a long history of being used in Chinese medicine to treat a variety of conditions ranging from microbial infections to metabolic syndrome and malignancies. Numerous studies have reported that treatment with total SB extract or two main flavonoids found in its root and leaves, baicalin (BA) and baicalein (BE), can prevent or alleviate the detrimental toxic effects of exposure to various chemical compounds. It has been shown that BA and BE are generally behind the protective effects of SB against toxicants. This paper aimed to review the protective and therapeutic effects of SB and its main components BA and BE against chemical compounds that can cause intoxication after acute or chronic exposure and seriously affect different vital organs including the brain, heart, liver, and kidneys. In this review paper, we had a look into a total of 221 in vitro and in vivo studies from 1995 to 2021 from the scientific databases PubMed, Scopus, and Web of Science which reported protective or therapeutic effects of BA, BE, or SB against drugs and chemicals that one might be exposed to on a professional or accidental basis and compounds that are primarily used to simulate disease models. In conclusion, the protective effects of SB and its flavonoids can be mainly attributed to increase in antioxidants enzymes, inhibition of lipid peroxidation, reduction of inflammatory cytokines, and suppression of apoptosis pathway.

Aspergillus awamori attenuates ochratoxin A-induced renal and cardiac injuries in rabbits by activating the Nrf2/HO-1 signaling pathway and downregulating IL1ß, TNFα, and iNOS gene expressions.

Ochratoxin A (OTA) is one of the most dangerous and that pollute agricultural products, inducing a variety of toxic effects in humans and animals. The current study explored the protective effect of different concentrations of Aspergillus awamori (A. awamori) against OTA (0.3 mg/kg diet) induced renal and cardiac damage by exploring its mechanism of action in 60 New Zealand white male rabbits. Dietary supplementation of A. awamori at the selected doses of 50, 100, and 150 mg/kg diet, respectively, for 2 months significantly improved the rabbit's growth performance; modulated the suppressed immune response and restored the altered hematological parameters; reduced the elevated levels of renal injury biomarkers such as urea, creatinine, and alkaline phosphatase; and increased serum total proteins concentrations. Moreover, it also declined enzymatic activities of cardiac injury biomarkers, including AST, LDH, and CK-MB. A. awamori alleviated OTA-induced degenerative and necrotic changes in the kidney and heart of rabbits. Interestingly, A. awamori upregulated Nrf2/OH-1 signaling pathway. Therefore enhanced TAC, CAT, and SOD enzyme activities and reduced OTA-induced oxidative and nitrosative stress by declining iNOS gene expression and consequently lowered MDA and NO levels. In addition to attenuating renal and cardiac inflammation via reducing IL-1ß, TNF-α gene expressions in a dose-dependent response. In conclusion,this is the first report to pinpoint that dietary incorporation of A. awamori counteracted OTA-induced renal and cardiac damage by potentiating the rabbit's antioxidant defense system through its potent antioxidant, free radical scavenging, and anti-inflammatory properties in a dose-dependent response. Based on our observations, A. awamori could be utilized as a natural protective agent against ochratoxicosis in rabbits.

In vitro comparison of various antioxidants and flavonoids from Rooibos as beta cell protectants against lipotoxicity and oxidative stress-induced cell death.

Oxidative stress and lipotoxicity effects on pancreatic ß cells play a major role in the pathogenesis of type 2 diabetes (T2D). Flavonoids and antioxidants are under study for their cytoprotective effects and antidiabetic potential. In this study, we aimed to compare the protective effect of the Rooibos components aspalathin, isoorientin, 3-hydroxyphloretin (3-OH) and green Rooibos extract (GRT) itself, and exendin-4 and N-acetylcysteine (NAC) as reference molecules, against lipotoxicity and oxidative stress. The insulin-producing ß cell line INS1E was exposed to hydrogen peroxide or streptozotocin (STZ) to induce oxidative stress, and palmitate to induce lipotoxicity. Cell viability was assessed by a MTS cell viability assay. Antioxidant response and antiapoptotic gene expression was performed by qRT-PCR. Glucose transporter 2 (GLUT 2) transporter inhibition was assessed through 2-NBDG uptake. GRT and the flavonoids aspalathin and 3-hydroxyphloretin offered significant protection against oxidative stress and lipotoxicity. GRT downregulated expression of pro-apoptotic genes Txnip and Ddit3. The flavonoids aspalathin and 3-hydroxyphloretin also downregulated these genes and in addition upregulated expression of antioxidant response genes Hmox1, Nqo1 and Sod1. Isoorientin gave no cytoprotection. Cytoprotection by Rooibos components was significantly higher than by NAC or exendin-4. Rooibos components strongly protect INS1E ß cells against diabetogenic stress. Cytoprotection was associated with the upregulation of antioxidant response genes of the NRF2/KEAP1 pathway or suppression of the TXN system. The Rooibos molecules offered better protection against these insults than exendin-4 and NAC, making them interesting candidates as ß cell cytoprotectants for therapeutic or nutraceutical applications.

Schisandra chinensis Oil Attenuates Aristolochic Acid I-Induced Nephrotoxicity in vivo and in vitro.

OBJECTIVE: To investigate the protective effects of Schisandra chinensis oil (SCEO) against aristolochic acid I (AA I)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism. METHODS: C57BL/6 mice were randomly divided into 5 groups according to a random number table, including control group, AA I group, and AA I +SCEO (0.25, 0.5 and 1 g/kg) groups (n=5 per group). Pretreatment with SCEO was done for 2 days by oral administration, while the control and AA I groups were treated with sodium carboxymethyl cellulose. Mice of all groups except for the control group were injected intraperitoneally with AA I (5 mg/kg) from day 3 until day 7. Histopathological examination and apoptosis of kidney tissue were observed by hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (SCr), as well as renal malondialdehyde (MDA), glutathione, r-glutamyl cysteingl+glycine (GSH), and superoxide dismutase (SOD) were analyzed using enzyme-linked immunosorbent assay (ELISA). Expressions of hepatic cytochrome P450 1A1 (CYP1A1), CYP1A2, and nad(p)hquinonedehydrogenase1 (NQO1) were analyzed using ELISA, quantitative real-time polymerase chain reaction (qPCR) and Western blot, respectively. In vitro, SCEO (40 µ g/mL) was added 12 h before treatment with AA I (40 µ mol/mL for 48 h) in human renal proximal tubule cell line (HK-2), then apoptosis and reactive oxygen species (ROS) were analyzed by flow cytometry. RESULTS: SCEO 0.5 and 1 g/kg ameliorated histopathological changes and TUNEL+ staining in the kidney tissues of mice with AA I-induced nephrotoxicity, and reduced serum levels of ALT, AST, BUN and SCr (P<0.01 or P<0.05). SCEO 0.5 and 1 g/kg alleviated the ROS generation in kidney, containing MDA, GSH and SOD (P<0.01 or P<0.05). SCEO 1 g/kg increased the expressions of CYP1A1 and CYP1A2 and decreased NQO1 level in the liver tissues (P<0.01 or P<0.05). Besides, in vitro studies also demonstrated that SCEO 40 µ g/mL inhibited apoptosis and ROS generation (P<0.05 or P<0.01). CONCLUSIONS: SCEO can alleviate AA I-induced kidney damage both in vivo and in vitro. The protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and ROS production.

Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential.

Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate (Punica granatum L.) and in wood and bark of some tree species. Structurally, EA is a dilactone of hexahydroxydiphenic acid (HHDP), a dimeric gallic acid derivative, produced mainly by hydrolysis of ellagitannins, a widely distributed group of secondary metabolites. EA is attracting attention due to its antioxidant, anti-inflammatory, antimutagenic, and antiproliferative properties. EA displayed pharmacological effects in various in vitro and in vivo model systems. Furthermore, EA has also been well documented for its antiallergic, antiatherosclerotic, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties. This review reports on the health-promoting effects of EA, along with possible mechanisms of its action in maintaining the health status, by summarizing the literature related to the therapeutic potential of this polyphenolic in the treatment of several human diseases.

Inhibitory effects and underlying mechanisms of Artemisia capillaris essential oil on melanogenesis in the B16F10 cell line.

The present study investigated the anti­melanogenic activity of 10 essential oils using the B16F10 cell model. Initially, a wide range of concentrations of these essential oils were screened in order to determine their toxicity levels. The assigned non­toxic concentrations of the tested essential oils were then used to evaluate their effects on melanogenesis. The effects of the essential oils with potent anti­melanogenic activity on cell proliferation, protection against H2O2­induced cell death and the expression of certain melanogenesis­related genes, including MITF, tyrosinase, tyrosinase related protein (TRP)­1 and TRP­2 were also evaluated. The results revealed that the essential oils extracted from Citrus unshiu, Juniperus chinensis L., Zanthoxylum piperitum and Artemisia capillaris (A. capillaris) inhibited melanogenesis. However, among these four extracts, only A. capillaris extract enhanced cell proliferation, exhibited anti­H2O2 activities and decreased the expression level of TRP­1. It was demonstrated that A. capillaris extract inhibited melanin synthesis via the downregulation of the TRP­1 translational level. These essential oil extracts, particularly that of A. capillaris, may thus be used as natural anti­melanogenic agents for therapeutic purposes and in the cosmetic industry for skin whitening effects with beneficial proliferative properties. However, further studies using in vivo models are required to validate these findings and to examine the effects of these extracts on various molecular pathways.

Diosmin, a citrus fruit-derived phlebotonic bioflavonoid protects rats from chronic kidney disease-induced loss of bone mass and strength without deteriorating the renal function.

Kidney Disease Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline has recommended treatment decisions for patients with chronic kidney disease (CKD) with osteoporosis and/or high risk of fracture. Bisphosphonates, the first-line anti-osteoporosis drugs have the concern of worsening kidney functions. Moreover, despite impaired bone formation in CKD patients, teriparatide, the formation-stimulating drug is not recommended. Thus, there is an urgent need for safe and effective treatment of osteoporosis in CKD patients. Here, in CKD rats, we tested the osteoprotective effect of diosmin, a citrus-derived bioflavonoid used as a phlebotonic in chronic venous insufficiency and has a renoprotective effect. CKD was developed by 5/6th nephrectomy and diosmin at the human equivalent dose (100 mg kg-1) did not advance renal failure but reduced blood pressure to the level of sham control. Fibroblast growth factor-23 and parathyroid hormone were increased in CKD and diosmin suppressed both. CKD reduced bone mass and deteriorated the microarchitecture of trabecular bones, and diosmin maintained both to control levels. Bone formation and strength were impaired in the CKD and diosmin maintained these levels to control levels. Nanoindentation of bone showed that diosmin significantly increased tissue hardness over the control. Diosmetin, the metabolic surrogate of diosmin had comparable pharmacokinetic profiles between the control and CKD groups. Furthermore, diosmetin (50 mg kg-1) protected against CKD-induced bone loss. These data suggest that diosmin and its metabolic surrogate, diosmetin protect against CKD-induced osteopenia. Since diosmin has no renal adverse effect and protected bone mass and strength in CKD rats, we propose assessing its anti-osteoporosis effect in CKD patients.

Isoxanthanol has protective and anti-inflammatory effects on subchondral bone deterioration in experimental osteoarthritic rat model.

In the present study isoxanthanol was investigated for treatment of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in vivo. The study demonstrated that isoxanthanol inhibited excessive release of interleukin-6, NO and PGE2 in RAW264.7 cells treated with LPS in dose dependent manner. The effects of isoxanthanol were examined in a rat model of osteoarthritis (OA) and observed to amelio-rate inflammatory damage and protect against OA. Moreover, in vivo data also confirmed inhibition of interleukin-6, NO and PGE2 levels in LPS-induced OA-rats. Deterioration of knee subchondral bone in LPS-induced OA-rats was also prevented effectively by isoxanthanol-treatment. Therefore, isoxanthanol prevents subchondral bone deterioration in OA rats via targeting inflammatory processes.

Integrated lipidomics and network pharmacology analysis of the protective effects and mechanism of Yuanzhi San on rats with cognitive impairment.

Cognitive impairment (CI) can seriously affect people's mental and physical health. Yuanzhi San (YZS) is a classic prescription for treating CI, but the mechanisms need further exploration. The aim of this study is to explore the effect of YZS on promoting the learning and memory ability of CI rats induced by d-galactose combined with aluminum chloride. Behavioral experiments had been used to comprehensively evaluate the established CI model. Brain histological morphology and the expressions of calcium ion signaling pathway related factors in serum were used to evaluate the effect of YZS against CI. Lipids in rat serum were analyzed by ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS) and chemical pattern recognition methods. Network pharmacology was used to find potential chemical compounds, targets, and related signaling pathways against CI with treatment of YZS. The integrated lipidomics and network pharmacology analysis were conducted by Cytoscape software. The results showed that YZS could alleviate neurodegenerative impairment. It was verified that model rats had longer latency time, shorter exploration paths, lower new objects recognition indexes, and shorter exercise time and distances compared with the normal rats in behavioral experiments, indicating that the model rats were successfully established. Rats of YZS 6.67 had significant differences in retention time (p < 0.05), number of entrances (p < 0.01), new object recognition indexes (p < 0.05, p < 0.01), exercise time (p < 0.05), and content of Ca [2]+, CAM, APP, CREB (p < 0.01), CAMK2 (p < 0.05). Rats of YZS 6.67 had five cell layers in hippocampus histological morphology. Behavioral experiments results showed that YZS had an active effect on CI rats. From lipidomics analysis, 129 lipids were screened out by conditions of VIP > 1 and p < 0.05, and 17 lipid markers were identified from the databases, which were divided mainly into five types. Pathway analysis indicated that linoleic acid, α-linolenic acid, arachidonic acid, and glycerophospholipid metabolisms were potential target pathways closely involved in the mechanism YZS's effects against CI. Network pharmacology focused on 84 chemical compounds, 130 intersection targets, and 10 hub genes of YZS's effects against CI. Six hub genes and four lipid compounds had intrinsic contact with arachidonic acid metabolism, glycerophospholipid metabolism and linoleate metabolism. The study revealed that YZS could improve animal cognitive behaviors, the expression of factors associated with memory in serum and the histological morphology of hippocampus. Four lipid compounds, three metabolic pathways, and six hub genes of YZS could effectively modulated CI. These results collectively suggest that the main mechanism of YZS in improving CI involves lipid metabolism, which affects biological processes and targets of action in the body.

Icariin attenuates thioacetamide­induced bone loss via the RANKL­p38/ERK­NFAT signaling pathway.

There is an increasing incidence of destructive bone disease caused by osteoclast proliferation. This is characterized by reduced bone mass and imbalance of bone homeostasis. Icariin (ICA), a flavonoid compound isolated from Epimedium, has anti­osteoporosis activity and inhibits the formation of osteoclasts and bone resorption. The purpose of the present study was to investigate the protective effect of ICA on osteoclastic differentiation induced by thioacetamide (TAA) and its possible mechanism in Sprague Dawley (SD) rats. In the present study, SD rats were intraperitoneally injected with TAA (300 mg/kg) for the bone loss model, treated with ICA (600 mg/kg, intragastric gavage) in the ICA group and TAA+ICA group for treatment of bone loss for 6 weeks. Indexes associated with bone metabolism, such as alkaline phosphatase, N­terminal telopeptide of type­I collagen (NTX­I), calcium (Ca), phosphorus (P) and magnesium (Mg) in the serum, were detected. Osteoclast differentiation of femoral tissues was detected by hematoxylin and eosin and tartrate­resistant acid phosphatase staining. The femoral bone mass was evaluated using a three­point bending test and micro computed tomography. Western blotting was used to detect the expression levels of osteoclast­related proteins in each group. In the rats treated with TAA, the serum concentrations of Ca, P and Mg were decreased, the serum concentration of NTX­I was increased, osteoclast differentiation of the femur was increased, femur bone stress and bone mass were decreased and the bone loss and osteoclast formation were reduced after ICA treatment. In addition, ICA inhibited the protein expression of receptor activator of nuclear factor κ­Β ligand (RANKL), receptor activator of nuclear factor κ­B (RANK), p38, ERK, c­Fos and nuclear factor of activated T cells 1 (NFATc1) in the femur of rats treated with TAA. The results suggested that ICA may inhibit osteoclast differentiation by downregulating the RANKL­p38/ERK­NFAT signaling pathway and prevent TAA­induced bone loss. The results are helpful to understand the mechanism of osteoclast differentiation induced by TAA, as well as the antiresorptive activity and molecular mechanism of ICA, and to provide new ideas for the treatment of osteolytic diseases.

Hepatoprotective effects of sea cucumber ether-phospholipids against alcohol-induced lipid metabolic dysregulation and oxidative stress in mice.

Sea cucumber is widely consumed as food and folk medicine in Asia, and its phospholipids are rich sources of dietary eicosapentaenoic acid enriched ether-phospholipids (ether-PLs). Emerging evidence suggests that ether-PLs are associated with neurodegenerative disease and steatohepatitis. However, the function and mechanism of ether-PLs in alcoholic liver disease (ALD) are not well understood. To this end, the present study sought to investigate the hepatoprotective effects of sea cucumber ether-PLs, including plasmenyl phosphatidylethanolamine (PlsEtn) and plasmanyl phosphatidylcholine (PlsCho), and their underlying mechanisms. Our results showed that compared with EtOH-induced mice, ether-PL treated mice showed improved liver histology, decreased serum ALT and AST levels, and reduced alcohol metabolic enzyme (ALDH2 and ADH1) expressions. Mechanistic studies showed that ether-PLs attenuated "first-hit" hepatic steatosis and lipid accumulation evoked by alcohol administration. Moreover, PlsEtn more effectively restored endogenous plasmalogen levels than PlsCho, thereby enhancing hepatic antioxidation against "second-hit" reactive oxygen species (ROS) due to the damaged mitochondria and abnormal ethanol metabolism. Taken together, sea cucumber ether-PLs show great potential to become a natural functional food against chronic alcohol-induced hepatic steatosis and lipid metabolic dysregulation.