Naringenin inhibits APAP-induced acute liver injury through activating PPARA-dependent signaling pathway.

Acute liver injury (ALI) refers to the damage to the liver cells of patients due to drugs, food, and diseases. In this work, we used a network pharmacology approach to analyze the relevant targets and pathways of the active ingredients in Citri Reticulatae Pericarpium (CRP) for the treatment of ALI and conducted systematic validation through in vivo and in vitro experiments. The network pharmacologic results predicted that naringenin (NIN) was the main active component of CRP in the treatment of ALI. GO functional annotation and KEGG pathway enrichment showed that its mechanism may be related to the regulation of PPARA signaling pathway, PPARG signaling pathway, AKT1 signaling pathway, MAPK3 signaling pathway and other signaling pathways. The results of in vivo experiments showed that (NIN) could reduce the liver lesions, liver adipose lesions, hepatocyte injury and apoptosis in mice with APAP-induced ALI, and reduce the oxidative stress damage of mouse liver cells and the inflammation-related factors to regulate ALI. In vitro experiments showed that NIN could inhibit the proliferation, oxidative stress and inflammation of APAP-induced LO2 cells, promote APAP-induced apoptosis of LO2 cells, and regulate the expression of apoptotic genes in acute liver injury. Further studies showed that NIN inhibited APAP-induced ALI mainly by regulating the PPARA-dependent signaling pathway. In conclusion, this study provides a preliminary theoretical basis for the screening of active compounds in CRP for the prevention and treatment of ALI.

The association between alcohol consumption and all-cause mortality: An umbrella review of systematic reviews using lifetime abstainers or low-volume drinkers as a reference group.

BACKGROUND AND AIMS: Systematic reviews of the relationship between alcohol consumption and all-cause mortality have reported different relative risk (RR) curves, possibly due to the choice of reference group. Results have varied from 'J-shaped' curves, where low-volume consumption is associated with reduced risk, to monotonically increased risk with increasing consumption. We summarised the evidence on alcohol consumption and all-cause mortality exclusively from systematic reviews using lifetime abstainers or low-volume/occasional drinkers as the reference group. METHODS: We conducted a systematic umbrella review of systematic reviews of the relationship between alcohol consumption and all-cause mortality in prospective cohort studies using a reference group of lifetime abstainers or low-volume/occasional drinkers. Several databases (PubMed/Medline/Embase/PsycINFO/Cochrane Library) were searched to March 2022. Reviews were assessed for risk of bias, and those with reference groups containing former drinkers were excluded. RESULTS: From 2149 articles retrieved, 25 systematic reviews were identified, and five did not include former drinkers in the reference group. Four of the five included reviews had high risk of bias. Three reviews reported a J-shaped relationship between alcohol consumption and all-cause mortality with significant decreased risk for low-volume drinking (RR range 0.84 to 0.95), while two reviews did not. The one review at low risk of bias reported monotonically increased risk with greater consumption (RRs = 1.02, 1.13, 1.33 and 1.52 for low-, medium-, high- and higher-volume drinking, respectively, compared with occasional drinking). All five reviews reported significantly increased risk with higher levels of alcohol consumption (RR range 1.28 to 3.70). Sub-group analyses were reported by sex and age; however, there were evidence gaps for many important factors. Conversely, 17 of 20 excluded systematic reviews reported decreased mortality risk for low-volume drinking. CONCLUSIONS: Over 70% of systematic reviews and meta-analyses published to March 2022 of all-cause mortality risk associated with alcohol consumption did not exclude former drinkers from the reference group and may therefore be biased by the 'sick-quitter effect'.

SIRT6 activates PPARα to improve doxorubicin-induced myocardial cell aging and damage.

The Sirtuins family, formally known as the Silent Information Regulator Factors, constitutes a highly conserved group of histone deacetylases. Recent studies have illuminated SIRT6's role in doxorubicin (DOX)-induced oxidative stress and apoptosis within myocardial cells. Nevertheless, the extent of SIRT6's impact on DOX-triggered myocardial cell aging and damage remains uncertain, with the associated mechanisms yet to be fully understood. In our research, we examined the influence of SIRT6 on DOX-induced cardiomyocyte senescence using ß-galactosidase and γ-H2AX staining. Additionally, we gauged the mRNA expression of senescence-associated genes, namely p16, p21, and p53, through Real-time PCR. Employing ELISA assay kits, MDA, and total SOD activity assay kits, we measured inflammatory factors TNF-α, IL-6, and IL-1ß, alongside oxidative stress-related indicators. The results unequivocally indicated that SIRT6 overexpression robustly inhibited DOX-induced cardiomyocyte senescence. Furthermore, we established that SIRT6 overexpression suppressed the inflammatory response and oxidative stress induced by DOX in cardiomyocytes. Conversely, silencing SIRT6 exacerbated DOX-induced cardiomyocyte injury. Our investigations further unveiled that SIRT6 upregulated the expression of genes CD36, CPT1, LCAD, MCAD associated with fatty acid oxidation through its interaction with PPARα, thereby exerting anti-aging effects. In vivo, the overexpression of SIRT6 was observed to restore DOX-induced declines in EF and FS to normal levels in mice. Echocardiography and HE staining revealed the restoration of cardiomyocyte alignment, affording protection against DOX-induced myocardial senescence and injury. The findings from this study suggest that SIRT6 holds significant promise as a therapeutic target for mitigating DOX-induced cardiomyopathy.

PARP-2 mediates cardiomyocyte aging and damage induced by doxorubicin through SIRT1 Inhibition.

Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.

Progress of research on the role of active ingredients of Citri Reticulatae Pericarpium in liver injury.

BACKGROUND: Liver is a vital organ responsible for metabolizing and detoxifying both endogenous and exogenous substances in the body. However, it is susceptible to damage from chemical and natural toxins. The high incidence and mortality rates of liver disease and its associated complications impose a significant economic burden and survival pressure on patients and their families. Various liver diseases exist, including cholestasis, viral and non-viral hepatitis, fatty liver disease, drug-induced liver injury, alcoholic liver injury, and severe end-stage liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and cholangiocellular carcinoma (CCA). Recent research has shown that flavonoids found in Citri Reticulatae Pericarpium (CRP) have the potential to normalize blood glucose, cholesterol levels, and liver lipid levels. Additionally, these flavonoids exhibit anti-inflammatory properties, prevent oxidation and lipid peroxidation, and reduce liver toxicity, thereby preventing liver injury. Given these promising findings, it is essential to explore the potential of active components in CRP for developing new drugs to treat liver diseases. OBJECTIVE: Recent studies have revealed that flavonoids, including hesperidin (HD), hesperetin (HT), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangerine (TN), and erodcyol (ED), are the primary bioactive components in CRP. These flavonoids exhibit various therapeutic effects on liver injury, including anti-oxidative stress, anti-cytotoxicity, anti-inflammatory, anti-fibrosis, and anti-tumor mechanisms. In this review, we have summarized the research progress on the hepatoprotective effects of HD, HT, NIN, NOB, NRG, TN, ED and limonene (LIM), highlighting their underlying molecular mechanisms. Despite their promising effects, the current clinical application of these active ingredients in CRP has some limitations. Therefore, further studies are needed to explore the full potential of these flavonoids and develop new therapeutic strategies for liver diseases. METHODS: For this review, we conducted a systematic search of three databases (ScienceNet, PubMed, and Science Direct) up to July 2022, using the search terms "CRP active ingredient," "liver injury," and "flavonoids." The search data followed the PRISMA standard. RESULTS: Our findings indicate that flavonoids found in CRP can effectively reduce drug-induced liver injury, alcoholic liver injury, and non-alcoholic liver injury. These therapeutic effects are mainly attributed to the ability of flavonoids to improve liver resistance to oxidative stress and inflammation while normalizing cholesterol and liver lipid levels by exhibiting anti-free radical and anti-lipid peroxidation properties. CONCLUSION: Our review provides new insights into the potential of active components in CRP for preventing and treating liver injury by regulating various molecular targets within different cell signaling pathways. This information can aid in the development of novel therapeutic strategies for liver disease.

Baicalin inhibits pressure overload-induced cardiac hypertrophy by regulating the SIRT3-dependent signaling pathway.

BACKGROUND: The conserved sirtuin protein sirtuin 3 (SIRT3) is a vital protective protein for cardiac hypertrophy. Inhibition of SIRT3 accelerated the development of heart hypertrophy. On the other hand, myocardial hypertrophy was prevented by overexpressing SIRT3. SIRT3 has been proposed as a potential therapeutic target for managing or averting heart hypertrophy. Baicalin, a flavonoid extracted from the Scutellaria baicalensis plant, has anti-cardiovascular properties, including protection against cardiac hypertrophy. However, the molecular mechanism of the anti-hypertrophic effect of baicalin is not well known. PURPOSE: In this study, we aim to investigate the effect of baicalin on cardiac hypertrophy and explored its underlying molecular mechanisms. STUDY-DESIGN/METHODS: Abdominal aortic constriction (AAC)-induced mouse cardiac hypertrophy and angiotensin II (Ang II)-induced cardiomyocyte hypertrophy models were established. After baicalin treatment, cardiac hypertrophy was monitored by detecting the expression of hypertrophic genes and cell surface area. Echocardiogram was performed to check the heart function in vivo. Moreover, the protein expression of the SIRT3-dependent pathway was detected by Western blotting. RESULTS: In this work, we demonstrated that baicalin might suppress the cell surface area and the expression of the Ang II -induced myosin heavy chain ß (ß-MHC), brain natriuretic polypeptide (BNP), and atrial natriuretic factor (ANF). Additionally, it reduced the AAC rats' hypertrophic impact. We also found that baicalin prevents cardiac hypertrophy by regulating SIRT3/LKB1/AMPK signaling pathway. Moreover, we showed that baicalin upregulated the SIRT3 protein expression by inhibiting proteasome and by the activation of 20 S proteasome subunit beta type-5 (PSMB5). CONCLUSION: These results offer the first proof that baicalin inhibits cardiac hypertrophy due to its effect on the SIRT3-dependent signaling pathway, indicating its potential for treating cardiac hypertrophy and heart failure. The present study provides a preliminary experimental basis for the clinical application of baicalin and baicalin-like compounds.

Research on the impact mechanism of environmental regulation on green total factor productivity from the perspective of innovative human capital.

Green total factor productivity (GTFP) improvement is an important way to achieve sustainable development, and how to improve GTFP has become the focus of attention of governments and scholars. This paper constructs a GTFP evaluation index system to characterize social, economic, ecological, cultural, and politically sustainable development, and analyzes the impact of environmental regulations on GTFP in the context of increasing innovative labor force. The results of the study are as follows: Firstly, China's GTFP continues to improve, with a decrease in low-value provinces and an increase in high-value provinces; there is an agglomeration effect of GTFP in the eastern and western regions. Secondly, under the role of innovative human capital, the threshold effect of China and the eastern and western regions is significantly positive in the first stage and insignificant in the second stage. The threshold effect of the central region is not significant in the first stage, but significantly negative in the second stage (- 11.650); the effect of environmental regulation in the eastern region is the strongest. Thirdly, the control variables in the upper period GTFP, national and eastern R&D investment, level of foreign openness, local fiscal expenditure, central and western information construction, western tertiary industry development, urbanization, foreign direct investment, level of foreign openness, and local fiscal expenditure can increase GTFP. In this regard, the government should adhere to innovative talent cultivation and investment in science and technology to build a talent ecological environment for regional sustainable development, adjust environmental regulations in time to meet the demand for sustainable development to realize the GTFP regional linkage enhancement.

Role of curcumin in the treatment of acute kidney injury: research challenges and opportunities.

BACKGROUND: Acute kidney injury (AKI) is a common complication in clinical inpatients, and it continues a high morbidity and mortality rate despite many clinical treatment measures. AKI is triggered by infections, surgery, heavy metal exposure and drug side effects, but current chemical drugs often fall short of expectations for AKI treatment and have toxic side effects. Therefore, finding new interventions and treatments, especially of natural origin, is of remarkable clinical significance and application. The herbal monomer curcumin is a natural phenolic compound extracted from the plant Curcuma longa and showed various biological activities, including AKI. Furthermore, recent studies have shown that curcumin restores renal function by modulating the immune system and the release of inflammatory mediators, scavenging oxygen free radicals, reducing apoptosis and improving mitochondrial dynamics. However, curcumin has a low bioavailability, which limits its clinical application. For this reason, it is essential to investigate the therapeutic effects and molecular mechanisms of curcumin in AKI, as well as to improve its bioavailability for curcumin formulation development and clinical application. PURPOSE: This review summarizes the sources, pharmacokinetics, and limitations in the clinical application of curcumin and explores methods to optimize its bioavailability using nanotechnology. In particular, the therapeutic effects and molecular mechanisms of curcumin on AKI are highlighted to provide a theoretical basis for AKI treatment in clinical practices. METHODS: This review was specifically searched by means of a search of three databases (Web of Science, PubMed and Science Direct), till December 2021. Search terms were "Curcumin", "Acute kidney injury", "AKI", " Pharmacokinetics", "Mitochondria" and "Nano formulations". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review) RESULTS: Studies have shown that curcumin responded to AKI-induced renal injury and restored renal tubular epithelial cell function by affecting multiple signaling pathways in AKI models induced by factors such as cisplatin, lipopolysaccharide, ischemia/reperfusion, gentamicin and potassium dichromate. Curcumin was able to affect NF-κB signaling pathway and reduce the expression of IL-1ß, IL-6, IL-8 and TNF-α, thus preventing renal inflammatory injury. In the prevention of renal tubular oxidative damage, curcumin reduced ROS production by activating the activity of Nrf2, HO-1 and PGC-1α. In addition, curcumin restored mitochondrial homeostasis by upregulating OPA1 and downregulating DRP1 expression, while reducing apoptosis by inhibiting the caspase-3 apoptotic pathway. In addition, due to the low bioavailability and poor absorption of curcumin in vivo, curcumin nanoformulations including nanoparticles, liposomes, and polymeric micelles are formulated to improve the bioavailability. CONCLUSION: This review provides new ideas for the use of curcumin in the prevention and treatment of AKI by modulating the molecular targets of several different cellular signaling pathways.

Sirtuins: Research advances on the therapeutic role in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI), a common multidisciplinary diagnostic clinical critical illness, eventually causes end-stage renal disease (ESRD). Although many clinical measures have been taken to prevent or treat AKI, high morbidity and death rates were recorded. Therefore, in-depth pathogenesis study and search for new therapeutic targets are in demand. Interestingly, the suirtuins family showed a significant protective effect in AKI. Sirtuins (SIRT1-7) is a family of seven proteins with NAD+-dependent type III histone deacetylase activity. Sirtuins family members were involved by AKI, and regulation of sirtuins activities significantly improved AKI-induced renal injury. Therefore, the therapeutic role and molecular mechanisms of the sirtuins family in AKI has important research implications for clinical applications or basic research. PURPOSE: This review summarizes recent advances in the roles and functions of the sirtuins family, discusses their therapeutic effects on AKI and related molecular mechanisms, and the mechanisms of action of small molecule specific activators or inhibitors sirtuins in the prevention and treatment of AKI were discussed. METHODS: The data in this review were retrieved from various scientific databases (PubMed, Google scholar, Science Direct, and Web of Science), till December 2021. The keywords were used as follows: "Sirtuins", "Acute kidney injury", "AKI", "Sirtuins modulators" and "Histone deacetylation". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review). RESULTS: Growing evidence indicates that members of the sirtuins family regulate the development and progression of different renal diseases, including AKI, through anti-inflammation, antioxidation, anti-apoptotic, and maintenance of mitochondrial homeostasis. The molecular mechanism of Sirtuins family on AKI mainly regulated NF-κB, JNK/ERK, and AMPK/mTOR signaling pathways, upregulated the expression of PGC-1α, HO-1, NRF2, Bcl-2, OPA1, and AMPK, and downregulated the expression of NRLP3, IL-1ß, TNF-α, IL-6, ROS, MFF, Drp1, Bax, ERK, and mTOR. In addition, the active ingredients of herbs (resveratrol, thujaplicins, huperzine, and curcumin) could activate the activity of SIRT1 or SIRT3, thereby improving AKI. Meanwhile, the synthetic Sirtuins inhibitor (AK-1) inhibited SIRT2 activity, thus alleviating AKI. In the future, more specific modulators will remain needed to enhance the clinical therapeutic role of the Sirtuins family in AKI. CONCLUSION: The sirtuins family is a promising type III histone deacetylase for AKI treatment. This review will provide insight into sirtuins family's therapeutic role in AKI and promote the clinical use of sirtuins modulators in AKI.