Insights into Ganoderma fungi meroterpenoids opening a new era of racemic natural products in mushrooms.

Ganoderma meroterpenoids (GMs) containing 688 structures to date were discovered to have multiple remarkable biological activities. 65.6% of meroterpenoids featuring stereogenic centers from Ganoderma species are racemates. Further, GMs from different Ganoderma species seem to have their own characteristics. In this review, a comprehensive summarization of GMs since 2000 is presented, including GM structures, structure corrections, biological activities, physicochemical properties, total synthesis, and proposed biosynthetic pathways. Additionally, we especially discuss the racemic nature, species-related structural distribution, and structure-activity relationship of GMs, which will provide a likely in-house database and shed light on future studies on GMs.

Heat stress upregulates arachidonic acid to trigger autophagy in sertoli cells via dysfunctional mitochondrial respiratory chain function.

As a key factor in determining testis size and sperm number, sertoli cells (SCs) play a crucial role in male infertility. Heat stress (HS) reduces SCs counts, negatively impacting nutrient transport and supply to germ cells, and leading to spermatogenesis failure in humans and animals. However, how HS affects the number of SCs remains unclear. We hypothesized that changes in SC metabolism contribute to the adverse effects of HS. In this study, we first observed an upregulation of arachidonic acid (AA), an unsaturated fatty acid after HS exposure by LC-MS/MS metabolome detection. By increasing ROS levels, expression of KEAP1 and NRF2 proteins as well as LC3 and LAMP2, 100 µM AA induced autophagy in SCs by activating oxidative stress (OS). We observed adverse effects of AA on mitochondria under HS with a decrease of mitochondrial number and an increase of mitochondrial membrane potential (MMP). We also found that AA alternated the oxygen transport and absorption function of mitochondria by increasing glycolysis flux and decreasing oxygen consumption rate as well as the expression of mitochondrial electron transport chain (ETC) proteins Complex I, II, V. However, pretreatment with 5 mM NAC (ROS inhibitor) and 2 µM Rotenone (mitochondrial ETC inhibitor) reversed the autophagy induced by AA. In summary, AA modulates autophagy in SCs during HS by disrupting mitochondrial ETC function, inferring that the release of AA is a switch-like response, and providing insight into the underlying mechanism of high temperatures causing male infertility.

Melatonin or vitamin C attenuates lead acetate-induced testicular oxidative and inflammatory damage in mice by inhibiting oxidative stress mediated NF-κB signaling.

Lead (Pb) acts as an environmental endocrine disruptor and has negative effects in animals; excessive accumulation of lead causes reproductive dysfunction in male animals. Oxidative stress plays a vital role in Pb-induced injury. However, the mechanisms underlying chronic testicular toxicity of Pb remain unclear. In this study, we aimed to determine the effects of lead acetate on reproductive function in male mice, identify the underlying mechanisms, and test counter measures to alleviate the toxic effects. Male mice were dosed with lead acetate (500 mg/L) in free drinking water for 12 weeks, and administered melatonin (5 mg/kg) or vitamin C (500 mg/kg) by intraperitoneal injection. Blood from the eyeball, testicles, and sperm from the caudal epididymis were collected after 12 weeks and analyzed. Pb exposure reduced sperm count and motility, increased sperm malformation (P < 0.01), disrupted testicular morphology and structure, and decreased the expression of steroid hormone synthesis-related enzymes and serum testosterone concentration (P < 0.01). Pb also increased the number of inflammatory cells and the levels of the pro-inflammatory cytokines TNF-α and IL-6 (P < 0.01), and activated NF-κB signaling. Furthermore, the ROS yield and oxidation indicators LPO and MDA were significantly increased (P < 0.01), and the antioxidant indicators T-AOC, SOD, and GSH were significantly reduced (P < 0.01). Treatment with melatonin or vitamin C reversed the effects of lead acetate; vitamin C was more effective in restoring SOD activity (P < 0.01) and enhancing ZO-1 protein levels (P < 0.01). Thus, long-term exposure to lead acetate at low concentrations could adversely affect sperm quality and induce inflammatory damage by oxidative stress mediated NF-κB signaling. Vitamin C could act as a protective agent and improve reproductive dysfunction in male animals after lead accumulation.

Isolation and Characterization of trans-p-Hydroxycinnamoyl Meroterpenoids from Ganoderma sinensis.

Zizhines V, W, Y, Z, (±)-zizhines X, and Z1-Z3, and (±)-ganosinensol L, thirteen new compounds including four pairs of enantiomers and a known compound (-)-ganosinensol L, were isolated from the fruiting bodies of Ganoderma sinensis. Their structures were identified by spectroscopic, computational methods, and CD (circular dichroism spectroscopy) comparisons. Zizhines V-Z and Z1-Z3 are meroterpenoids consisting of the phenolic and the terpenoidal parts. All the compounds except zizhine Z3 bear a common trans-p-hydroxycinnamoyl group. Biological evaluation shows that (-)-zizhine Z1 inhibits cell migration in the MDA-MB-231 cell lines. The present study discloses the chemical profiling of G. sinensis and paves the way for its development as functional products to benefit chronic disorders.

Ectopic expression of a combination of 5 genes detects high risk forms of T-cell acute lymphoblastic leukemia.

BACKGROUND: T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment by using a specific pipeline designed to discover aberrantly active gene. RESULTS: The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes, the latter characterizing high risk forms in adult patients. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients. CONCLUSION: Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.

Melatonin alleviates the heat stress-induced impairment of Sertoli cells by reprogramming glucose metabolism.

Sertoli cells (SCs) provide structural and nutritional support for developing germ cells. Normal glucose metabolism of SCs is necessary for spermatogenesis. Melatonin could alleviate the effects of heat stress on spermatogenesis. However, the influences of heat stress on glucose metabolism in SCs remain unclear, and the potential protective mechanisms of melatonin on SCs need more exploration. In this study, boar SCs were treated at 43°C for 30 min, and different concentrations of melatonin were added to protect SCs from heat stress-induced impairment. These results showed that heat stress-induced oxidative stress caused cell apoptosis, inhibited the pentose phosphate pathway, and decreased the ATP content. Furthermore, heat stress increased the expressions of glucose intake- and glycolytic-related enzymes, which enhanced the glycolysis activity to compensate for the energy deficit. Melatonin relieved heat stress-induced oxidative stress and apoptosis by activating the Kelch-like ECH-associated protein 1 (KEAP1)/NF-E2-related factor 2 signaling pathway to increase the capacity of antioxidants. In addition, melatonin enhanced heat-shock protein 90 (HSP90) expression through melatonin receptor 1B (MTNR1B), thereby stabilizing hypoxia-inducible factor-1α (HIF-1α). Activation of the HIF-1α signaling pathway enhanced glycolysis, promoted the pentose phosphate pathway, and increased cell viability. Our results suggest that melatonin reprograms glucose metabolism in SCs through the MTNR1B-HSP90-HIF-1α axis and provides a theoretical basis for preventing heat stress injury.

17ß-estradiol rescues the damage of thiazolidinedione on chicken Sertoli cell proliferation via adiponectin.

Thiazolidinedione (TZD) is an oral anti-diabetic drug that exhibits some side effects on the male reproductive system by interfering with the steroidogenesis and androgenic activity and also shows anti-proliferative effect on several cell types. This study investigated the effect of TZD on immature chicken Sertoli cell (SC) proliferation and the potential mechanism by which 17ß-estradiol regulated this process. Chicken SC viability was investigated under different treatment concentration and time of TZD. 17ß-estradiol (0.001 µM, 24 h) was added to analyze its effects on TZD-mediated cell viability, cell metabolic activity, cell growth, cell cycle progression, reactive oxygen species (ROS) level, antioxidant enzyme activity, mitochondria activity, oxygen consumption rate, adenosine triphosphate (ATP) level, and mitochondrial respiratory chain enzyme activity, adiponectin expression and several cell proliferation-related genes mRNA and protein levels. We performed the microRNA (miRNA) array to find TZD-induced differentially expressed miRNAs and validated whether miR-1577 can target on adiponectin via the dual luciferase reporter assay, as well as verified the effect of adiponectin addition with different concentrations on the SC viability. Further, SCs were transfected with miR-1577 agomir (a double-stranded synthetic miRNA mimic) in the presence or absence of TZD and antagomir (a single-stranded synthetic miRNA inhibitor) in the presence or absence of 17ß-estradiol to analyze whether miR-1577 was involved in TZD-mediated SC proliferation and whether 17ß-estradiol regulated this process. Results showed that TZD significantly inhibited SC viability, cell metabolic activity, cell growth, and cell cycle progression, while increased adiponectin level and ROS generation. TZD-treated SCs presented decreases of antioxidant enzyme activity, mitochondria activity, basal and maximal respiration, ATP production and level, mitochondrial respiratory chain enzyme activity, and mRNA and protein expressions of several cell proliferation-related genes, as well as the significant alteration of miRNA expressions (a total number of 55 miRNAs were up-regulated whereas 53 miRNAs down-regulated). Whereas, 17ß-estradiol played a positive role in chicken SC proliferation and rescued the damage of TZD on SC proliferation by up-regulating miR-1577 expression whose target gene was validated to be the adiponectin. In addition, exogenous adiponectin (more than 1 µg/ml) treatment exhibited a significant inhibition on the SC viability. Transfection of miR-1577 agomir promoted the SC proliferation via down-expressed adiponectin, and increased the mitochondrial function and cell proliferation-related gene expression, while TZD weakened the positive effect of miR-1577 agomir on SCs. On the other hand, transfection of miR-1577 antagomir inhibited SC proliferation by producing the opposite effects on above parameters, while 17ß-estradiol attenuated the negative effect of miR-1577 antagomir on SCs. These findings suggest down-expressed miR-1577 is involved in the regulation of TZD-inhibited SC proliferation through increasing adiponectin level, and this damage of TZD on the immature chicken SC proliferation can be ameliorated by appropriate dose of exogenous 17ß-estradiol treatment. This study provides an insight into the cytoprotective effect of 17ß-estradiol on TZD-damaged SC proliferation and may suggest a potential strategy for reducing the risk of SC dysfunction caused by the abuse of TZD.

Lucidumones B-H, racemic meroterpenoids that inhibit tumor cell migration from Ganoderma lucidum.

Seven new meroterpenoids, lucidumones B-H (1 and 3-8), along with one known meroterpenoid (2), were isolated from the fruiting bodies of Ganoderma lucidum. The structures of the new compounds were assigned by spectroscopic and computational methods. All the isolated compounds were tested for their inhibition on human cancer cell migration. It was found that compounds (-)-1, (+)-2, (-)-4, (+)-6, and (+)-8 could significantly inhibit cell migration in KYSE30 cell line. Further examination disclosed that cell migration inhibition of (+)-6 and (+)-8 might be related with downregulation of N-cadherin.

Renoprotective ganodermaones A and B with rearranged meroterpenoid carbon skelotons from Ganoderma fungi.

Two structurally novel meroterpenoids, ganodermaones A (1) and B (2), were isolated from Ganoderma fungi (G. cochlear and G. lucidum). The structures of 1 and 2 were assigned by spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 represent the first examples of meroterpenoids in Ganoderma fungal species featuring with carbon migration. The plausible biosynthetic pathway for 1 was proposed. Biological evaluation showed that both 1 and 2 could inhibit renal fibrosis in TGF-ß1-induced kidney proximal tubular cells.

Petchiether A attenuates obstructive nephropathy by suppressing TGF-ß/Smad3 and NF-κB signalling.

Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-ß1 (TGF-ß1)/Smad3-driven renal fibrosis is the common pathogenesis of obstructive nephropathy. In this study, we identified petchiether A (petA), a novel small-molecule meroterpenoid from Ganoderma, as a potential inhibitor of TGF-ß1-induced Smad3 phosphorylation. The obstructive nephropathy was induced by unilateral ureteral obstruction (UUO) in mice. Mice received an intraperitoneal injection of petA/vehicle before and after UUO or sham operation. An in vivo study revealed that petA protected against renal inflammation and fibrosis by reducing the infiltration of macrophages, inhibiting the expression of proinflammatory cytokines (interleukin-1ß and tumour necrosis factor-α) and reducing extracellular matrix deposition (α-smooth muscle actin, collagen I and fibronectin) in the obstructed kidney of UUO mice; these changes were associated with suppression of Smad3 and NF-κB p65 phosphorylation. Petchiether A inhibited Smad3 phosphorylation in vitro and down-regulated the expression of the fibrotic marker collagen I in TGF-ß1-treated renal epithelial cells. Further, we found that petA dose-dependently suppressed Smad3-responsive promoter activity, indicating that petA inhibits gene expression downstream of the TGF-ß/Smad3 signalling pathway. In conclusion, our findings suggest that petA protects against renal inflammation and fibrosis by selectively inhibiting TGF-ß/Smad3 signalling.

Specific Chicken Egg Yolk Antibody Improves the Protective Response against Gallibacterium anatis Infection.

Gallibacterium anatis is a pathogen associated with peritonitis and salpingitis in chickens and other avian species. Novel safety prevention strategies are urgently needed because of widespread multidrug resistance and antigenic diversity. The objective of this study was to produce a specific chicken egg yolk antibody and evaluate its protective response against a G. anatis infection model in 4-week-old chicks. Enzyme-linked immunosorbent assays showed that hens immunized with the recombinant N terminus of Gallibacterium toxin A (GtxA-N) had significantly increased antibody titers against GtxA-N in serum and egg yolk IgY. Western blotting showed that IgY antibody had specificity against GtxA-N in the egg yolks of immunized hens. The growth of G. anatis in brain heart infusion (BHI) broth and agar was significantly inhibited by the GtxA-N-specific IgY antibody. The protective effects of the specific IgY antibody were evaluated in G. anatis-infected chicks after intramuscular injection (10 mg/ml). The anti-GtxA-N antibody titers in the sera of G. anatis-challenged chicks following an injection of specific IgY antibody were significantly higher than those of the control and the nonspecific IgY groups, but lower lesion scores for the peritoneum, liver, and duodenum were found after specific IgY antibody treatment. The results from this study suggest that the GtxA-N-specific IgY antibody could potentially improve the protective response against G. anatis infection in chicks.

Identification of microRNAs for regulating adenosine monophosphate-activated protein kinase expression in immature boar Sertoli cells in vitro.

Adenosine monophosphate-activated protein kinase (AMPK) plays a key role in cellular energy homeostasis and cell proliferation. MicroRNAs (miRNAs) function as posttranscriptional regulators of gene expression in biological processes. It is unclear to whether miRNAs are involved in AMPK-regulated Sertoli cell (SC) proliferation. To further understand the regulation of miRNAs in the immature boar SC proliferation, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) was added to activate AMPK. By an Illumina small RNA deep sequencing, we obtained sequences and relative expression levels of 272 known mature miRNAs, among which 9 miRNAs were significantly upregulated whereas 16 miRNAs were downregulated following the AICAR treatment. The results identified 38 conserved miRNAs, with 8 significantly downregulated miRNAs whereas no upregulated miRNAs. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggested that miR-1285 was involved in many activities and pathways associated with cell proliferation via targeting on AMPKα2. We validated that AICAR significantly downregulated miR-1285 level in SCs. Transfection of miR-1285 mimic increased the SC viability and cell cycle progression but reduced AMPKα2 mRNA and protein levels, indicating that miR-1285 is involved in the immature boar SC proliferation via downregulating AMPKα2 expression.

MiR-8-3p regulates hyperthermia-induced lactate secretion by targeting PPP2R5B in boar Sertoli cells.

Lactate produced by glycolysis in Sertoli cells (SCs) is the main energy substrate for developing germ cells and plays a vital role in spermatogenesis. MicroRNAs (miRNAs) function as posttranscriptional regulators of gene expression in biological processes. We have previously shown that hyperthermia (43°C, 30 min) promotes lactate secretion by inhibiting phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in cultured immature boar SCs. However, it is unclear whether miRNAs are involved in AMPK-modulated glycolysis in SCs. In the present study, we identified 349 miRNAs (227 upregulated and 122 downregulated) in hyperthermia-treated boar SCs by next-generation high-throughput RNA sequencing. MiR-8-3p, which was found to be a novel upregulated miRNA in hyperthermia-treated SCs, suppressed the expression of AMPK upstream genes (protein phosphatase 2 subunit B, PPP2R5B), and further downregulated the expression of p-AMPK. The miR-8-3p mimic upregulated expression of glucose transporter 3, lactate dehydrogenase A and monocarboxylate transporter 1, and increased lactic acid dehydrogenase activity, lactate secretion, and ATP depletion in SCs; the miR-8-3p inhibitor had the opposite effects on these parameters. Our findings indicate that miR-8-3p acts as a novel regulator of AMPK-modulated lactate secretion by targeting PPP2R5B in hyperthermic boar SCs.

Meroterpenoids from the Fungus Ganoderma sinensis and First Absolute Configuration Clarification of Zizhine H.

Five new meroterpenoids, zizhines P-S and U (1-4,7), together with two known meroterpenoids (5 and 6) were isolated from Ganoderma sinensis. Their structures including absolute configurations were assigned by using spectroscopic, computational, and chemical methods. Racemics zizhines P and Q were purified by HPLC on chiral phase. Biological evaluation found that 4, 5 and 6 are cytotoxic toward human cancer cells (A549, BGC-823, Kyse30) with IC50 values in the range of 63.43-80.83 µM towards A549, 59.2 ± 2.73 µM and 64.25 ± 0.37 µM towards BGC-823, 76.28 ± 1.93 µM and 85.42 ± 2.82 µM towards Kyse30.

SALL4 suppresses reactive oxygen species in pancreatic ductal adenocarcinoma phenotype via FoxM1/Prx III axis.

Pancreatic ductal adenocarcinoma (PDAC) is a major malignant phenotype in pancreatic cancer, which is one of the most death causes by cancer in the world. PDAC developed from pancreatic intra-epithelial neoplasms (PanINs) and poorly diagnosed at early stages. Beside of high drug resistance, metastasis is the great concern during pancreatic cancer treatment. SALL4 expression is inherent in the upregulations of endothelial mesenchymal transition (EMT) genes and therefore promoting cancer metastasis. Furthermore, some of evidences indicated reactive oxygen species (ROS) is also influent to metastasis and self-antioxidant capacity seems a gold standard for successful metastasis rate. In this study, we have found the role Spalt like protein 4 (SALL4) to PDAC proliferation, mobility and its regulation to mitochondrial ROS via FoxM1/Prx III axis. It is possible that SALL4 mainly induces endothelial-mesenchymal transition (EMT) phenotype and favors ROS loss to facilitate metastasis efficiency in PDAC cells. Therefore, SALL4 might be a promising marker for PDAC treatment and targeting SALL4 would benefit anti-proliferative and anti-metastasis therapies.

Innovative Approach of Non-Thermal Plasma Application for Improving the Growth Rate in Chickens.

As an innovative technology in biological applications-non-thermal plasma technique-has recently been applied to living cells and tissues. However, it is unclear whether non-thermal plasma treatment can directly regulate the growth and development of livestock. In this study, we exposed four-day-incubated fertilized eggs to plasma at 11.7 kV for 2 min, which was found to be the optimal condition in respect of highest growth rate in chickens. Interestingly, plasma-treated male chickens conspicuously grew faster than females. Plasma treatment regulated the reactive oxygen species homeostasis by controlling the mitochondrial respiratory complex activity and up-regulating the antioxidant defense system. At the same time, growth metabolism was improved due to the increase of growth hormone and insulin-like growth factor 1 and their receptors expression, and the rise of thyroid hormones and adenosine triphosphate levels through the regulation of demethylation levels of growth and hormone biosynthesis-related genes in the skeletal muscles and thyroid glands. To our knowledge, this study was the first to evaluate the effects of a non-thermal plasma treatment on the growth rate of chickens. This safe strategy might be beneficial to the livestock industry.

Green Extraction of Natural Antioxidants from the Sterculia nobilis Fruit Waste and Analysis of Phenolic Profile.

The waste of Sterculia nobilis fruit was massively produced during food processing, which contains lots of natural antioxidants. In this study, antioxidants in the Sterculia nobilis fruit waste were extracted using the green microwave-assisted extraction (MAE) technique. The effects of five independent variables (ethanol concentration, solvent/material ratio, extraction time, temperature, and microwave power) on extraction efficiency were explored, and three major factors (ethanol concentration, extraction time, and temperature) showing great influences were chosen to study their interactions by response surface methodology. The optimal conditions were as follows: 40.96% ethanol concentration, 30 mL/g solvent/material ratio, 37.37 min extraction time at 66.76 °C, and 700 W microwave power. The Trolox equivalent antioxidant capacity value obtained in optimal conditions was in agreement with the predicted value. Besides, MAE improved the extraction efficiency compared with maceration and Soxhlet extraction methods. Additionally, the phenolic profile in the extract was analyzed by UPLC-MS/MS, and eight kinds of phenolic compounds were identified and quantified, including epicatechin, protocatechuic acid, ferulic acid, gallic acid, p-coumaric acid, caffeic acid, quercetin, and p-hydroxycinnamic acid. This study could contribute to the value-added utilization of the waste from Sterculia nobilis fruit, and the extract could be developed as food additive or functional food.

Microwave-Assisted Extraction of Phenolic Compounds from Melastoma sanguineum Fruit: Optimization and Identification.

A microwave-assisted extraction (MAE) technology optimized by response surface methodology (RSM) was established to extract phenolic compounds from the fruit of Melastoma sanguineum. The effects of solvent composition, ratio of solvent to material, temperature, time and microwave power on phenol yield were evaluated in single-factor tests. The three parameters exerting main impacts on phenol yield were further optimized by RSM. Under optimal extraction conditions (31.33% ethanol, solvent/material ratio of 32.21 mL/g, 52.24 °C, 45 min and 500 W), the total phenolic content was 39.02 ± 0.73 mg gallic acid equivalent (GAE)/g dry weight (DW). This MAE method performed better in comparison with two conventional methods, those being maceration (25.79 ± 1.03 mg GAE/g DW) and Soxhlet extraction (18.40 ± 1.34 mg GAE/g DW), using lower process temperature, shorter irradiation time, and lower organic solvent consumption. In addition, five flavonoids (epicatechin gallate, epicatechin, rutin, pigallocatechin and quercetin) and two phenolic acids (protocatechuic acid and chlorogenic acid) in the extract were identified and quantified using UPLC-MS/MS.

Wogonin suppresses stem cell-like traits of CD133 positive osteosarcoma cell via inhibiting matrix metallopeptidase-9 expression.

BACKGROUND: Several efforts have been deployed to cure osteosarcoma, a high-grade malignant bone tumour in children and adolescents. However, some challenges such as drug resistance, relapse, and tumour metastasis remain owing to the existence of cancer stem cells (CSC). There is an urgent need to develop cost-effective and safe therapies. METHODS: Wogonin, an extract from the root of Scutellaria baicalensis, has long been considered as a promising natural and safe compound for anti-tumourigenesis, particularly to inhibit tumour invasion and metastasis. Hoechst 33,342 staining, wound healing assay, sphere formation assay, western blotting, and gelatin zymography assays were performed in CD133 positive osteosarcoma cell. RESULTS: In this study, we examined the effect of Wogonin on the mobility of human osteosarcoma CSC. Wogonin induces apoptosis of human osteosarcoma CSC, inhibits its mobility in vitro via downregulation of MMP-9 expression, and represses its renewal ability. CONCLUSIONS: We demonstrated that Wogonin decreases the renewal capacity of CSC. By inhibiting the formation of and reducing the size of spheres, Wogonin at a concentration of 40-80 µM effectively minimizes potential risk from CSC. Taken together, we have demonstrated a new approach for developing a potential therapy for osteosarcoma.

Effects of Melatonin on Liver Injuries and Diseases.

Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.