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This review summarizes the applications of multifunctional nanomaterials for synergistic photothermal antibacterial therapy and discusses the mechanism of the two treatment methods in antibacterial therapy.

Type V collagen (collagen V) is one of the important components of extracellular matrix (ECM) in pancreas. We previously reported that pre-coating collagen V on the culture dishes enhanced insulin production in INS-1 rat pancreatic β cells. In this study, we investigate the underlying mechanism.Insulin biosynthesis and secretion are both increased in INS-1 cells cultured on collagen V-coated dishes, accompanied by the reduced nuclear translocation of Yes-associated protein (YAP), a transcriptional co-activator. YAP, the downstream effector of Hippo signaling pathway, plays an important role in the development and function of pancreas. Inhibition of YAP activation by verteporfin further up-regulates insulin biosynthesis and secretion. Silencing large tumor suppressor (LATS), a core component of Hippo pathway which inhibits activity of YAP by phosphorylation, by siRNA transfection inhibits both insulin biosynthesis and secretion. In the present study, the protein level of insulin-like growth factor 1 receptor (IGF-1 R), detected as the upstream molecule of YAP, is reduced in the INS-1 cells cultured on the dishes coated with collagen V. The silencing of IGF-1 R by siRNA transfection further enhances insulin biosynthesis and secretion. IGF-1 treatment reduces collagen V-induced up-regulation of insulin biosynthesis and secretion, accompanying the increased nuclear YAP.Inhibition of IGF-1 R/YAP signal pathway is involved in collagen V-induced insulin biosynthesis and secretion in INS-1 cells.

Type I collagen (collagen I) is the most abundant component of the extracellular matrix (ECM) in the pancreas. We previously reported that collagen I-coated culture dishes enhanced proliferation of rat pancreatic β cell line, INS-1 cells, via up-regulation of β-catenin nuclear translocation. In this study, we further investigated the effects of collagen I on insulin production of INS-1 cells. The results indicate that insulin synthesis as well as cell proliferation is increased in the INS-1 cells cultured on the dishes coated with collagen I. Up-regulation of insulin-like growth factor 1 receptor (IGF-1R) on the INS-1 cells cultured on the collagen-coated dishes is involved in up-regulation of cell proliferation and increase of insulin biosynthesis; however, up-regulation of insulin secretion in the INS-1 cells on collagen I-coated dishes was further enhanced by inhibition of IGF-1R. Autophagy of INS-1 cells on collagen I-coated dishes was repressed via IGF-1R upregulation, and inhibition of autophagy with 3MA further enhanced cell proliferation and insulin biosynthesis but did not affect insulin secretion. E-cadherin/β-catenin adherent junction complexes are stabilized by autophagy. That is, autophagy negatively regulates the nuclear translocation of β-catenin that leads to insulin biosynthesis and cell proliferation. In conclusion, IGF-1R/downregulation of autophagy/nuclear translocation of β-catenin is involved in collagen I-induced INS-1 cell proliferation and insulin synthesis.

Purpose: The mechanism of cytotoxicity of silibinin on two human hepatocellular carcinoma (HCC) cell lines, HepG2 (p53 wild-type) and Hep3B cells (p53 null), is examined in relation with the induction of autophagy and phosphorylation of AMP-activated protein kinase (p-AMPK). Materials and Methods: Levels of apoptosis in relation to the levels of autophagy and those of glycolysis-related proteins, glucose transporter 1/4 (Glut1/4) and hexokinase-II (HK2), in HepG2 and Hep3B cells were examined. Results: Silibinin-induced apoptosis was incomplete for HCC cell death in that up-regulated autophagy and/or reduced level of glycolysis, which are induced by silibinin treatment, antagonized silibinin-induced apoptosis. Inhibition of autophagy with 3-methyl adenine (3MA) or blocking of AMP-activated protein kinase (AMPK) activation with Compound C (CC) enhanced silibinin-induced apoptosis. The results confirm that AMPK involved in autophagy as well as in glycolysis remaining with silibinin is responsible for attenuation of silibinin-induced apoptosis. Blocking of AMPK or autophagy contributes to the enhancement of silibinin’s cytotoxicity to HepG2 and Hep3B cells. Conclusion: This study shows that incomplete apoptosis of HCC by silibinin treatment becomes complete by repression of autophagy and/or glycolysis.

Objectives Previous studies have suggested that spinosin (SPI) exerted neuroprotective effects through inhibition of oxidative damage, but the underlying mechanisms are still unclear. Herein, the mechanisms underlying the protective effects of SPI against oxidative stress induced by hydrogen peroxide (H2O2) were examined in neuro-2a (N2a) mouse neuroblastoma cells. Methods N2a cells were pretreated with H2O2 for 2 h, followed by a 24-h incubation with SPI. Intracellular reactive oxygen species (ROS) production was analysed by flow cytometry. Levels of Aβ1-42 production were determined by ELISA assay. Levels of expression of c-Jun N-terminal kinase (JNK), p-JNK, extracellular signal-regulated kinase (ERK), p-ERK, p38 mitogen-activated protein kinase (p38MAPK), p-p38MAPK, p-Tau (Ser199), p-Tau (Ser202), p-Tau (Ser396), synaptophysin (SYP) and postsynaptic scaffold postsynaptic density-95 (PSD-95) were detected by Western blot analysis. Key findings Our results showed that H2O2 treatment enhanced intracellular ROS production in N2a cells. SPI prevented H2O2-induced oxidative damage via inhibiting Aβ1-42 production, decreasing Tau phosphorylation and improving synaptic structural plasticity. Notably, H2O2-increased p38MAPK activation was attenuated by SPI administration, and p38MAPK inhibitor BIRB796 markedly reduced H2O2-induced oxidative damage in N2a cells. Conclusions Our findings suggest that SPI protects N2a cells from H2O2-induced oxidative damage through inactivation of p38MAPK.

The present research work primarily investigated whether spinosin has the potential of improving the pathogenesis of Alzheimer’s disease (AD) driven by β-amyloid (Aβ) overproduction through impacting the procession of amyloid precursor protein (APP). Wild type mouse Neuro-2a cells (N2a/WT) and N2a stably expressing human APP695 (N2a/APP695) cells were treated with spinosin for 24 h. The levels of APP protein and secreted enzymes closely related to APP procession were examined by western blot analysis. Oxidative stress related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were detected by immunofluorescence assay and western blot analysis, respectively. The intracellular reactive oxygen species (ROS) level was analyzed by flow cytometry, the levels of Aβ1-42 were determined by ELISA kit, and Thioflavin T (ThT) assay was used to detect the effect of spinosin on Aβ1-42 aggregation. The results showed that ROS induced the expression of ADAM10 and reduced the expression of BACE1, while spinosin inhibited ROS production by activating Nrf2 and up-regulating the expression of HO-1. Additionally, spinosin reduced Aβ1-42 production by impacting the procession of APP. In addition, spinosin inhibited the aggregation of Aβ1-42. In conclusion, spinosin reduced Aβ1-42 production by activating the Nrf2/HO-1 pathway in N2a/WT and N2a/ APP695 cells. Therefore, spinosin is expected to be a promising treatment of AD.

A dry socket is one of the most common complications after tooth extraction. The main etiologies are the loss of blood clots in the socket and the inflammation reaction caused by infection. Current studies on how to prevent dry sockets could not solve these two etiologies at the same time. Recent studies have demonstrated the anti-inflammation role of silibinin. In this study, silibinin was engineered into GelMA hydrogels (Sil-GelMA) with a concentration of 30 mM. The surface characteristics were observed by scanning electron microscopy and the successful loading of silibinin was detected by FTIR spectrometry. The Sil-GelMA hydrogels presented the sustained release ability of silibinin and slow degradation performance of GelMA. Furthermore, silibinin inhibited the inflammatory reaction by inducing M2-type macrophage polarization, promoting the secretion of anti-inflammatory factors (CD206, IL-10) and inhibiting the secretion of anti-inflammatory factors (IL-1β, iNOS). Silibinin also increased the secretion of vascularization-related factor VEGF and promoted vascularization

Silibinin, a major component of milk thistle extract silymarin, promotes hypoglycemia by activating estrogen receptor (ER) α and β-mediated pathways in pancreatic β-cells. Glucagon-like peptide-1 (GLP-1) is the enteroendocrine peptide produced in L-cells, and it controls glucose homeostasis through multiple pathways. The effect of silibinin on L-cell mass and function is still unknown.The protective effect of silibinin on palmitate (PA)-treated intestinal L-cell line GLUTag cells and the SHRSP•Z-Leprfa/Izm-Dmcr (SP•ZF) diabetic rat model was investigated in current study.After pre-incubation with 50 μM silibinin for 4 h, GLUTag cells were treated with 0.125 mM PA. MTT, Annexin V/PI apoptosis, Hoechst 33342 staining, western blot, DCFH-DA, GLP-1 ELISA, qRT-PCR and immunofluorescence analyses were undertaken to determine ER-dependent protection of silibinin against PA-induced cellular damage. The differential protein expression of GLUTag cells under different treatments was examined by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). The SP•ZF diabetic rat model was chosen for in vivo study. After 4 weeks of gastric gavage with 100 or 300 mg kgThe current study showed that the GLUTag cells preincubated with silibinin activated the transcription factor nuclear erythroid-2 like factor-2 (Nrf2)-antioxidant pathway, reduced reactive oxygen species (ROS) generation, and improved cell survival and GLP-1 content, while the antioxidative effect of silibinin was blocked by the selective ERα antagonist MPP or ERβ antagonist PHTPP in GLUTag cells. Our proteomics data further revealed that ERα or β inactivation reduced glutathione peroxide and proteins associated with endocytosis and reproduction, thus at least partially reversing the protective effect of silibinin. SP•ZF rats received silibinin treatment showed increased serum GLP-1 content and improved glucose homeostasis. Furthermore, silibinin upregulated ERα and β levels and reduced the level of 8-OHdG in GLP-1-positive cells.Our study showed that silibinin improved L-cell mass and function through an ER-mediated antioxidant pathway, and the proteomics analysis revealed for the first time the differential regulation of proteins by PA and silibinin in GLUTag cells.

Diabetic nephropathy (DN) with high morbidity and mortality is one of the most severe diabetes complications and affects nearly one-third of people with diabetes. Our present experiment was designed to assess the potential therapeutic of a polysaccharide purified from okra (OP) on DN in high-fat diet-fed and streptozotocin (STZ)-induced diabetic mice. We found that an 8-week treatment with OP could significantly decrease the 24-h urine protein (24-h UP), serum creatinine (Scr), serum urea nitrogen (SUN) and glycosylated hemoglobin (HbA1c) levels, which are regard as the biomarkers of renal injury. The results of immunohistochemical analysis and histopathological examination showed that the diabetic-induced microstructural changes and fibrosis in kidney can be alleviated by the administration of OP (400 mg/kg). Our immunofluorescences results demonstrated that OP (400 mg/kg) could greatly reduce the level of reactive oxygen species (ROS) in kidney. In addition, we also studied the level of SOD, GSH, CAT, HO-1, Nrf2, p-AMPK, PGC-1α, Sirt1, Bcl-2, cleaved caspase-3 and Bax in renal tissue by assay kit and western blot. Our results suggested that OP ameliorated DN in diabetic mice, which is possibly related to suppressing apoptosis and oxidative stress through activating AMPK-Sirt1-PGC-1α signaling axis.

Extracellular matrix (ECM) molecules have multiple functions; prevention of cytotoxicity, provision of mechanical support, cell adhesive substrates and structural integrity in addition to mediation of cellular signaling. In this study, we report that the proliferation of INS-1 cells cultured on collagen I-coated dishes is enhanced, but it is inhibited on collagen V-coated dishes. Inhibitory proliferation on collagen V-coated is not due to apoptosis induction. Silibinin decreases hepatic glucose production and protects pancreatic β-cells, as a potential medicine for type II diabetes. Silibinin up-regulates the proliferation of cells cultured on both collagen I- and V-coated dishes. Collagen-coating regulates gene expression of collagen in a collagen type-related manner. Silibinin increases mRNA expression of collagen I in the cells on collagen I- and V-coated dishes; however, silibinin decreases collagen V mRNA expression on collagen I- and V-coated dishes. Collagen I-coating significantly enhances nuclear translocation of β-catenin, while collagen V-coating reduces it. Differential effects of silibinin on collagen I mRNA and collagen V mRNA can be accounted for by the finding that silibinin enhances nuclear translocation of β-catenin on both collagen I- and V-coated dishes, since phenomenologically nuclear translocation of β-catenin enhances collagen I mRNA but represses collagen V mRNA. These results demonstrate that nuclear translocation of β-catenin up-regulates proliferation and collagen I gene expression, whereas it down-regulates collagen V gene expression of INS-1 cells. Differential gene expressions of collagen I and V by nuclear β-catenin could be important for understanding fibrosis where collagen I and V may have differential effects.

Amylin and amyloid-β (Aβ) were found to induce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in rat pancreatic β-cell line, INS-1 cells, leading to cell death. In this study, we report on reciprocal relationship between the expression of estrogen receptors (ERs) α and β (ERα and ERβ) and generation of ROS/RNS in amylin/Aβ1-42 -treated INS-1 cells. That is, pharmacological activation of ERs in INS-1 cells significantly decreases ROS/RNS generation, but blockage of ERs increases ROS/RNS generation. Silibinin is a natural polyphenolic flavonoid isolated from milk thistle with phytoestrogen activities, also known as silybin. Treatment with silibinin down-regulated ROS/RNS production induced by treatment with amylin/Aβ1-42 in the cells. Silencing ERs expression with siRNAs targeting ERs showed that the protective effect of silibinin was markedly weakened, indicating that silibinin protection is largely attributed to activation of ERs' signaling. The binding of silibinin to ERs implies that the protective effect of silibinin on amylin/Aβ1-42 -treated INS-1 cells owes to down-regulation of ROS/RNS through the activation of ERs phosphorylation. Amylin and Aβ1-42 cotreatment enhanced furthermore ROS/RNS generation and cytotoxicity through further down-regulation of ERs phosphorylation, and this was reversed by silibinin. Silibinin also protects INS-1 cells from amylin and Aβ1-42 cotreatment. These results indicate that protective effect of silibinin is mediated by enhancement of ERs phosphorylation that depresses ROS/RNS generation in amylin/Aβ1-42 -treated INS-1 cells.

In this study, we combined two enemin-type diterpenoid derivatives with two well-established hydrogen sulfide moieties via ester or different anhydride linkers, to search apoptosis inducing drug candidate capable of hydrogen sulfide generating. Therefore, a series of hybrids were synthesized and superior antiproliferative efficacy accompanied with enhanced selectivity was observed under extensive pharmacological evaluations. A standard methylene blue (MB+) method was applied to measure the capacity for the hydrogen sulfide generation of all the target derivatives. One particular molecule A1, which contained α-thioctic acid moiety for hydrogen sulfide donating, manifested more potent antiproliferative activity. It exerted inhibitory effects against Bel-7402, SGC-7901 and A549 cell lines with IC50 values of 2.16, 5.07 and 6.98 μM respectively. While it exacted relatively low effects over human normal cell lines L-02 and PBMC with IC50 values of 15.81 μM for the prior and 14.15 μM for the latter, and displayed better selectivity index (SI) than parent diterpenoids. A high dosage of H2S release was also recorded. Hence, A1 was most suitable for mechanistic exploration on account of both safety and efficacy. The ensuing biological assays revealed central role of apoptosis in A1’s mode of action for antiproliferative efficacy, which led to further confirmation of G1 phase cell cycle arrest, mitochondria membrane potential collapse and apoptotic activation in Bel-7402 cells. Further western blot assay on intrinsic mitochondria pathway unlocked intricate interplay among a series of apoptotic related proteins in which Bax, caspase-3 and cytochrome c went through up-regulation, while Bcl-2, Bcl-xL and procaspase-3 undergone down-regulation. In a nutshell, a hydrogen sulfide releasing hybrid A1 was synthesized and antiproliferative evaluation identified it to be a worthy drug candidate for future in depth study.

Alzheimer's disease (AD), a neurodegenerative disease, is diagnosed by impaired learning and memory in elderly individuals. Tectochrysin (TEC) is a flavonoid compound isolated from Alpinia Oxyphylla Miq., which has been traditionally used for the treatment of diarrhea, salivation, diuresis and dementia. In our study, model mice with AD induced by intracerebroventricular injection of Aβ1–42 were used to determine the role of TEC on memory retrieval. The results revealed that AD mice received intracerebroventricular injection of TEC (140 µg/kg) showed improved spatial memory performance and down-regulated expressions of β-secretase and accumulation of Aβ1–42 in brain tissues. TEC also decreased the concentration of malondialdehyde and total cholinesterase, and increased activities of both antioxidant superoxide dismutase and glutathione peroxidase in hippocampal and cortex. In addition, Aβ1–42 induced injury of neurons in hippocampal CA1 layer was rehabilitated in TEC treated mice. These findings highlight the beneficial role of TEC in amnestic mice induced by Aβ1–42 through the down-regulation of Aβ1–42 accumulation, oxidative stress, and total cholinesterase. Our study indicated a therapeutic potential of TEC in the treatment of AD.

Extracellular matrix (ECM) plays an important role in tissue repair, cell proliferation, and differentiation. Our previous study showed that collagen I and collagen V differently regulate the proliferation of rat pancreatic β cells (INS-1 cells) through opposite influences on the nuclear translocation of β-catenin. In this study, we investigated the β-catenin pathway in INS-1 cells on dishes coated with collagen I or V. We found that nuclear translocation of the transcription factor Yes-associated protein (YAP) was enhanced by collagen I and suppressed by collagen V, but had no effect on INS-1 cell proliferation. Morphologically, INS-1 cells on collagen V-coated dishes showed stronger cell-to-cell adhesion, while the cells on collagen I-coated dishes showed weaker cell-to-cell adhesion in comparison with the cells on non-coated dishes. E-cadherin played an inhibitory role in the proliferation of INS-1 cells cultured on collagen I or collagen V coated dishes via regulation of the nuclear translocation of β-catenin. Integrin β1 was enhanced with collagen I, while it was repressed with collagen V. The integrin β1 pathway positively regulated the cell proliferation. Inhibition of integrin β1 pathway restored the protein level of E-cadherin and inhibited the nuclear translocation of β-catenin in the cells on collagen I-coated dishes, but no effect was observed in the cells on collagen V-coated dishes. In conclusion, collagen I enhances the proliferation of INS-1 cells via the integrin β1 and E-cadherin/β-catenin signaling pathway. In INS-1 cells on collagen V-coated dishes, both integrin β1 and E-cadherin/β-catenin signal pathways are involved in the inhibition of proliferation.

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H2S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation. Similarly, inhibition of endogenous H2S production also suppresses tumor proliferation. Accordingly, H2S biosynthesis inhibitors and H2S supplementation (H2S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H2S on pancreatic cancer has not been studied so far. However, H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H2S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H2S donors and NO–H2S dual donors on pancreatic cancer were summarized in this paper. Exogenous H2S donors may be promising compounds for pancreatic cancer treatment., Graphical abstract The review summarizes the antitumor mechanisms of H2S donating derivatives against pancreatic cancer by modulating signaling pathways, including PI3K/AKT/mTOR, SHH, NF-κB, MAPK, NOTCH, STAT3, DR4, etc. Perspectives on future directions and challenges are also discussed.Image 1

Hydrogen sulfide (H2S) is considered as a novel second-messenger molecule associated with the modulation of various physiological and pathological processes. In the field of antitumor research, endogenous H2S induces angiogenesis, accelerates the cell cycle and inhibits apoptosis, which results in promoting oncogenesis eventually. Interestingly, high concentrations of exogenous H2S liberated from donors suppress the growth of various tumors via inducing cellular acidification and modulating several signaling pathways involved in cell cycle regulation, proliferation, apoptosis and metastasis. The selective release of certain concentrations of H2S from H2S donors in the target has been considered as an alternative tumor therapy strategy. Triple-negative breast cancer (TNBC), an aggressive subtype with less than one year median survival time, is known to account for approximately 15–20% of all breast cancers. Due to the lack of approved targeted therapy, the clinical treatment of TNBC is still hindered by metastasis as well as recurrence. Significant efforts have been spent on developing novel treatments of TNBC, and remarkable progress in the control of TNBC by H2S donors and their derivatives have been made in recent years. This review summarizes various pathways involved in antitumor and anti-metastasis effects of H2S donors and their derivatives on TNBC, which provides novel insights for TNBC treatment.

A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways., Graphical Abstract

Previous studies have shown that spinosin was implicated in the modulation of sedation and hypnosis, while its effects on learning and memory deficits were rarely reported. The aim of this study is to investigate the effects of spinosin on the improvement of cognitive impairment in model mice with Alzheimer's disease (AD) induced by Aβ₁₋₄₂ and determine the underlying mechanism. Spontaneous locomotion assessment and Morris water maze test were performed to investigate the impact of spinosin on behavioral activities, and the pathological changes were assayed by biochemical analyses and histological assay. After 7 days of intracerebroventricular (ICV) administration of spinosin (100 µg/kg/day), the cognitive impairment of mice induced by Aβ₁₋₄₂ was significantly attenuated. Moreover, spinosin treatment effectively decreased the level of malondialdehyde (MDA) and Aβ₁₋₄₂ accumulation in hippocampus. Aβ₁₋₄₂ induced alterations in the expression of brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), as well as inflammatory response in brain were also reversed by spinosin treatment. These results indicated that the ameliorating effect of spinosin on cognitive impairment might be mediated through the regulation of oxidative stress, inflammatory process, apoptotic program and neurotrophic factor expression, suggesting that spinosin might be beneficial to treat learning and memory deficits in patients with AD via multi-targets.

Silibinin, a flavonolignan derived from milk thistle (Silybum marianum), has been revealed to have a beneficial effect on improving diabetes-impaired glycemic control. However, the underlying mechanism is still unclear. In the present study, to evaluate whether the gut-brain-liver axis, an important neural pathway for the control of hepatic glucose production, is involved in silibinin-regulated glucose homeostasis, the expression of glucagon-like peptide-1 receptor (GLP1R) in the duodenum, activation of neurons in the nucleus of the solitary tract (NTS), as well as glycogen accumulation and expression of gluconeogenic enzymes in the livers of diabetic SHRSP·Z-Leprfa/IzmDmcr (SP·ZF) rats with 4-week oral administration of silibinin (100 and 300 mg kg-1 day-1) were evaluated. Common hepatic branch vagotomy was further conducted in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic SD rats to confirm the role of the gut-brain-liver axis in silibinin-improved glycemic control. The results revealed a significant inhibition of fasting blood glucose after SP·ZF rats were administrated with silibinin for 4 weeks. The expression of GLP1R in the duodenum and the activation of neurons in the NTS increased, while hepatic glucose production decreased on silibinin administration. However, the hypoglycemic effect of silibinin was reversed by common hepatic branch vagotomy in diabetic SD rats. Our study suggested that silibinin may be useful as a potential functional food ingredient against diabetes by triggering the gut-brain-liver axis.

The sesquiterpene nootkatone (NKT), isolated from Alpiniae oxyphyllae Fructus, was shown to possess protective effects on neurons. In our study, by using an Alzheimer’s disease (AD) model of mice induced by intracerebroventricular (i.c.v.) injection of Aβ1–42 oligomers, we investigated the effects of NKT on memory impairment and further evaluated the pathological changes of mice. AD mice were treated by i.c.v. injection of NKT (at a dose of 0.02 mg/kg and 0.20 mg/kg) or vehicle (PBS) into the lateral ventricle once daily for 5 consecutive days. The behavioral tasks were performed, and levels of some biochemical indicators and histopathological changes of the brain were evaluated to elucidate the mechanism of NKT in the treatment of AD. The results revealed that NKT significantly improved the neurobehavioral performance of the AD mice in the Y-maze and Morris water maze tests. More importantly, NKT treatment decreased the malondialdehyde (MDA), Aβ as well as the acetylcholin esterase (AChE) levels in the mice brain, while increased the glutathione peroxidase (GSH-Px) levels with improved histopathological changes in the hippocampus. These findings provided evidences for the beneficial role of NKT in Aβ1–42-induced mice AD model linking to anti-oxidative and anti-AChE activities with inhibitory effect against Aβ accumulation.

A series of novel nitrogen mustard-evodiamine hybrids were synthesized and evaluated for their antitproliferative properties. The antiproliferative activities of 10a-d, 11a-d, and 12a-d against four different kinds of human cancer cell lines (PC-3, HepG2, THP-1 and HL-60) and human normal peripheral blood mononuclear cells (PBMC) were determined. The results showed that all the target hybrid compounds exhibited antiproliferative activities against tested human tumor cell lines to some extent and no antiproliferative activities (>200 μM) against human normal PBMC cells. The antiproliferative selectivity between tumorous and normal cells was very useful for further antitumor drug development. Among the target compounds, 12c showed the strongest cytotoxicity against two tumor cell lines (THP-1 and HL-60) with IC50 values of 4.05 μM and 0.50 μM, respectively, and selected for further mechanism study in HL-60 cells. The results showed that 12c could induce HL-60 cells apoptosis and arrest at G2 phase at low sub-micromolar concentrations via mitochondria-related pathways.

Depression is one of the most frequent psychiatric disorders of Alzheimer's disease (AD). Depression and anxiety are associated with increased risk of developing AD. Silibinin, a flavonoid derived from milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver diseases. In this study, the effect of silibinin on Aβ-induced anxiety/depression-like behaviors in rats was investigated. Silibinin significantly attenuated anxiety/depression-like behaviors caused by Aβ1-42-treatment as shown in tail suspension test (TST), elevated plus maze (EPM) and forced swimming tests (FST). Moreover, silibinin was able to attenuate the neuronal damage in the hippocampus of Aβ1-42-injected rats. Silibinin-treatment up-regulated the function through BDNF/TrkB pathway and attenuated autophagy in the hippocampus. Our study provides a new insight into the protective effects of silibinin in the treatment of anxiety/depression.

Hydrogen sulfide (H2S) has been recognized as the third endogenous signaling gasotransmitter following nitric oxide (NO) and carbon monoxide (CO), and exhibits antiproliferative activity against several cancer cells. In order to stably and controllably release H2S, H2S donating compound (ADT-OH) was used in the present study and 18H2S releasing natural ent-kaurane diterpenoid oridonin derivatives were designed and synthesized. Most derivatives showed more potent antiproliferative activities than oridonin against HepG2 and K562 cell lines, while they were lack of sensitivity to HCT-116 and B16 cells. In particular, 12b showed the most potent antiproliferative activities against HepG2, HCT-116 and K562 cells with IC50 values of 2.57, 5.81 and 0.95 μM, respectively. Through cell cycle analysis, 12b caused cell cycle arrest at S phase in K562 cells and G1 phase in HepG2 cells. In Hoechst 33258 staining assay, cell shrinkage and fragmentation of cell nuclei indicated apoptotic morphological changes. Considering the decline of mitochondrial membrane potential and changes in the levels of apoptosis-related proteins, 12b was shown to induce apoptosis through extrinsic and intrinsic apoptosis pathways.

The present research work primarily investigated whether spinosin has the potential of improving the pathogenesis of Alzheimer’s disease (AD) driven by β-amyloid (Aβ) overproduction through impacting the procession of amyloid precursor protein (APP). Wild type mouse Neuro-2a cells (N2a/WT) and N2a stably expressing human APP695 (N2a/APP695) cells were treated with spinosin for 24 h. The levels of APP protein and secreted enzymes closely related to APP procession were examined by western blot analysis. Oxidative stress related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were detected by immunofluorescence assay and western blot analysis, respectively. The intracellular reactive oxygen species (ROS) level was analyzed by flow cytometry, the levels of Aβ1-42 were determined by ELISA kit, and Thioflavin T (ThT) assay was used to detect the effect of spinosin on Aβ1-42 aggregation. The results showed that ROS induced the expression of ADAM10 and reduced the expression of BACE1, while spinosin inhibited ROS production by activating Nrf2 and up-regulating the expression of HO-1. Additionally, spinosin reduced Aβ1-42 production by impacting the procession of APP. In addition, spinosin inhibited the aggregation of Aβ1-42. In conclusion, spinosin reduced Aβ1-42 production by activating the Nrf2/HO-1 pathway in N2a/WT and N2a/APP695 cells. Therefore, spinosin is expected to be a promising treatment of AD.

ObjectivesThe aim of this study was to investigate the molecular mechanisms of the efficacy of lignin compound dehydrodiconiferyl alcohol (DHCA) isolated from Silybum marianum (L.) Gaertn in improving wound healing. These findings preliminarily brought to light the promising therapeutic potential of DHCA in skin wound healing.MethodsFirst, the effect of DHCA on healing in vivo was studied using a full-thickness scalp wound model of mice by topical administration. Histopathological examinations were then conducted by haematoxylin and eosin (H&E), Masson’s trichrome staining and the immunofluorescence assay. Second, we further examined the anti-inflammatory mechanism of DHCA in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages by immunofluorescence assay and Western blot analysis.Key findingsDHCA could promote scalp wound healing in mice by enhancing epithelial cell proliferation and collagen formation and reducing inflammatory cells infiltration. Moreover, the NF-κB nuclear translocation was suppressed remarkably by DHCA administration in connective tissue of healing area. DHCA was also shown to inhibit production of nitric oxide (NO) and interleukin (IL)-1β with downregulated inducible nitric oxide synthase (iNOS) expression in LPS-induced RAW 246.7 cells. More importantly, DHCA administration upregulated p-IκBα expression and induced nuclear translocation of NF-κB without affecting its expression.ConclusionsOur study indicated that DHCA exerted anti-inflammatory activity through inactivation of NF-κB pathways in macrophages and subsequently improved wound healing.

Polysaccharide extracted from okra (Abelmoschus esculentus (L.) Moench), a traditional functional food, is a biologically active substance reported to possess hypoglycemic and anti-oxidative qualities. However, it is unknown which polysaccharides play a role and have the potential mechanism. This present study is to assess the possible impacts of a novel polysaccharide isolated from okra (OP) on mice fed with a high-fat diet (HFD) combined with an intraperitoneal injection (i.p.) of 100 mg/kg streptozotocin (STZ) twice, to induce type 2 diabetes mellitus (T2DM). We found that an eight-week administration of OP at 200 or 400 mg/kg body weight significantly alleviated the symptoms, with elevations in blood glucose, triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), as well as reducing high-density lipoprotein cholesterol (HDL-C), body weight, food, and water consumption. The OP treatment increased the hepatic glycogen and decreased the mussy hepatic cords and liver fibrosis in the T2DM mice. The decreases of ROS and MDA and the increases of SOD, GSH-Px and CAT in liver were observed after administration of OP. OP alleviated the T2DM characteristics through the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3β) pathway, and enhanced the nuclear factor erythroid-2 (Nrf2) expression and promoted Nrf2-medicated heme oxygenase-1(HO-1) and superoxide dismutase 2 (SOD2) expression. OP also relieved mitochondrial dysfunction by inhibiting NOX2 activation. Taken together, these findings suggest that a polysaccharide isolated from okra exerts anti-T2DM effects partly by modulating oxidative stress through PI3K/AKT/GSK3β pathway-medicated Nrf2 transport. We have determined that a polysaccharide possesses hypoglycemic activity, as well as its underlying mechanism.

High levels of circulating free fatty acids often trigger pancreatic β cell dysfunction during the development of type 2 diabetes. Silibinin, the main component of Silybum marianum fruit extract (silymarin), is reported to have anti-diabetic effect. This study is designed to determine the protective effect of silibinin on palmitic acid-induced damage in a rat pancreatic β-cell line, INS-1 cells. Our results demonstrate that silibinin improves cell viability, enhances insulin synthesis and secretion, and resumes normal mitochondrial function in palmitic acid-treated INS-1 cells. An accumulating body of evidence has shown that the estrogen receptors are key molecules involved in glucose and lipid metabolism. Our results suggest that silibinin upregulates ERα signaling pathway from the finding that ERα-specific inhibitors abolish the anti-lipotoxic effect of silibinin. In conclusion, these findings suggest that silibinin protects INS-1 cells against apoptosis and mitochondrial damage through upregulation of ERα pathway.

Glucagon-like peptide-1 (GLP-1), a glucagon-like peptide secreted mainly from intestinal L cells, possesses the functions of promoting synthesis and secretion of insulin in pancreatic β-cells, and maintaining glucose homeostasis in an insulin-independent manner. Silychristin A, a major flavonolignan from silymarin, was reported to protect pancreatic β-cells from oxidative damage in streptozotocin (STZ)-induced diabetic rats. However, the role of silychristin A in the protection of intestinal L-cells is still unknown. Our current study demonstrated that palmitate (PA) inhibited protein expression of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2), and subsequently increased reactive oxygen species level to induce apoptosis and decrease GLP-1 content in intestinal L-cell line GLUTag cells. Pre-incubation of silychristin A effectively reversed PA-inactivated Nrf2-HO-1/SOD2 antioxidative pathway accompanied with decreased apoptosis level and increased GLP-1 level in GLUTag cells. As a potential target of silychristin A, estrogen receptor α was shown to be downregulated by PA stimulation, and the expression of which was improved by silychristin A in a concentration-dependent manner. Further study revealed that the treatment of estrogen receptor α antagonist MPP induced apoptosis and blocked the stimulation of GLP-1 production by silychristin A through the activation of Nrf2-HO-1/SOD2 pathway in GLUTag cells. Taken together, our study found silychristin A activated estrogen receptor α-dependent Nrf2-HO-1/SOD2 pathway to decrease apoptosis and upregulate GLP-1 production in GLUTag cells.

Based on the definite therapeutic benefits, such as neuroprotective, cardioprotective, anticancer, anti-diabetic and so on, the Panax genus which contains many valuable plants, including ginseng (Panax ginseng C.A. Meyer), notoginseng (Panax notoginseng) and American ginseng (Panax quinquefolius L.), attracts research focus. Actually, the biological and pharmacological effects of the Panax genus are mainly attributed to the abundant ginsenosides. However, the low membrane permeability and the gastrointestinal tract influence seriously limit the absorption and bioavailability of ginsenosides. The acid or base hydrolysates of ginsenosides, 20 (R,S)-panaxadiol and 20 (R,S)-protopanaxadiol showed improved bioavailability and diverse pharmacological activities. Moreover, relative stable skeletons and active hydroxyl group at C-3 position and other reactive sites are suitable for structural modification to improve biological activities. In this review, the pharmacological activities of panaxadiol, protopanaxadiol and their structurally modified derivatives are comprehensively summarized.

To get chelidonine derivatives with enhanced antiproliferative activity and selectivity, a series of nitric oxide donating derivatives (10a-f and 11a-j) were designed, synthesized and biologically evaluated. Compared with chelidonine, these compounds exhibited lower IC50 values against human hepatoma cells HepG2, breast cancer cells MCF-7, colon cancer cells HCT-116, as well as leukemia cells K562. Compound 11j displayed the strongest antiproliferative activity with IC50 values of 3.91, 6.90, 4.36 and 1.12 μM against the above four cells, respectively. Nevertheless, it showed an IC50 value >40 μM against human peripheral blood mononuclear cells (PBMCs), which demonstrated high selectivity between normal and cancer blood cells. In further mechanism studies, 11j showed the capability to induce K562 cells apoptosis, S phase cell cycle arrest and mitochondrial membrane potential disorder. Besides, 11j was found to be effective in promoting the expression of proapoptotic protein Bad and suppressing the expression of anti-apoptotic proteins Bcl-xL, catalase, survivin, claspin and clusterin.

The optimum extraction conditions of essential oil from Asarum heterotropoides var. Mandshuricum applied by an orthogonal L(9)(3(3)) test were a water-to-raw material ratio of 17, a particle size of D(95) ≤ 3.8 mm and an extraction time of 2 h. In ingredient analysis, gas chromatography/mass spectrometry analysis identified the main components of essential oil as methyl eugenol (45.95%), safrole (17.48%) and 3,5-dimethoxytoluene (10.30%) orderly. In vitro, the minimum inhibitory concentration and minimum bactericidal concentration of essential oil were 0.01 and 0.02% against F. nucleatum, 0.04 and 0.08% against P. intermedia, and 0.005 and 0.005% against P. gingivalis. In vivo, administration of essential oil significantly suppressed alveolar bone resorption induced by F. nucleatum, with bone levels remaining comparable to non-infected mice. These results of antibacterial activity of essential oil in vitro and in vivo show the inhibition of periodontal pathogens and therapy of alveolar bone resorption in mice, suggesting that its essential oil could be a potential natural therapeutic agent for treatment of periodontitis in human beings.

Alkaloids, a category of natural products with ring structures and nitrogen atoms, include most U.S. Food and Drug Administration approved plant derived anti-cancer agents. Evodiamine is an alkaloid with attractive multitargeting antiproliferative activity. Its high content in the natural source ensures its adequate supply on the market and guarantees further medicinal study. To the best of our knowledge, there is no systematic review about the antiproliferative effects of evodiamine derivatives. Therefore, in this article the review of the antiproliferative activities of evodiamine will be updated. More importantly, the antiproliferative activities of structurally modified new analogues of evodiamine will be summarized for the first time.

Amylin and amyloid-β (Aβ) were found to induce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in rat pancreatic β-cell line, INS-1 cells, leading to cell death. In this study, we report on reciprocal relationship between the expression of estrogen receptors (ERs) α and β (ERα and ERβ) and generation of ROS/RNS in amylin/Aβ

Alzheimer's disease (AD), a neurodegenerative disease, is diagnosed by impaired learning and memory in elderly individuals. Tectochrysin (TEC) is a flavonoid compound isolated from Alpinia Oxyphylla Miq., which has been traditionally used for the treatment of diarrhea, salivation, diuresis and dementia. In our study, model mice with AD induced by intracerebroventricular injection of Aβ