Thunbergia laurifolia

Leaves of Thunbergia laurifolia (TL) have been reported to have antioxidation, anti-inflammatory, detoxifying, and hepatoprotective effects. However, studies relating to antifibrotic activity have not been reported. Currently, there is no standard treatment for hepatic fibrosis. This study aimed to investigate the antifibrotic activity of TL in human hepatic stellate LX-2 cells. Results from cell viability and cell death assays showed that the extract at high concentrations was toxic to LX-2 cells. TL extract reversed the transformation of LX-2 cells to myofibroblast-like characteristics in response to stimulation by transforming growth factor-beta 1. This action may be associated with the effect of TL in suppressing α-SMA and collagen-I production observed by immunofluorescence study and western blot analysis. Additionally, TL extract significantly decreased MMP-9 activity which is consistent with the reduction of MMP-9, MMP-2, and TIMP-1 gene expression. The effect of TL in suppressing fibrosis may be associated with its ability to inhibit the activation of p38 MAPK and Erk1/2 kinases as examined by western blot analysis. Our study provides convincing evidence that TL possesses antifibrotic activity which may be through the suppression of TGF-β1-mediated production of MMPs, collagen-1, and α-SMA in hepatic stellate cells

Alpinetin Suppresses Effects of TGF-β1 on Stimulating the Production and Organization of Fibrotic Markers in Human Primary Dermal Fibroblasts

Overgrowths of dermal fibroblasts and myofibroblast phenoconversion in response to TGF-β stimulation are the hallmarks of skin fibrosis. Constitutive activation of dermal fibroblasts by TGF-β induces the excessive production of extracellular matrix as well as certain key intracellular proteins which form a complex interaction network. Current therapies include monoclonal anti-bodies against TGF-β and surgery, but these treatments generally elicit a limited effect on certain kinds of skin fibrosis. In the current study, we investigated the effects of alpinetin (AP) on human primary dermal fibroblasts (HPDFs) stimulated with TGF-β1. Results demonstrated that AP exhibited strong inhibitory effects on TGF-β1-induced proliferation and migration of HPDFs. AP also inhibited TGF-β1-induced morphological changes of fibroblasts to myofibroblasts, and these were found to be from its effects on blocking actin stress fiber formation and organization. The expression of major fibrotic molecules including α-SMA and type I collagen upon TGF-β1 stimulation was also inhibited by AP. In addition, AP attenuated TGF-β1-induced production and organization of vimentin, β-catenin, and N-cadherin, important for the pathophysiology of skin fibrosis. In conclusion, we revealed that AP has an ability to reverse the fibrotic effects of TGF-β1 at the cellular level, and this discovery suggests the therapeutic potential of AP for skin fibrosis

Molecular Targets of Pinocembrin Underlying Its Regenerative Activities in Human Keratinocytes

Pinocembrin is one of the well-known compounds in the group of flavonoids. The pharmacological activities of pinocembrin in association with wound-healing activities have been reported. However, its effects on the aspect of cellular interaction underlying growth and survival are still unidentified in human keratinocytes. Our previous study reported that Boesenbergia rotunda potently stimulated survival and proliferation of a human keratinocyte cell line (HaCaT). On the basis that pinocembrin is revealed to be one of the major constituents of this plant, we aimed to define the survival- and proliferation-enhancing effects of this compound at the cellular level. Results from the current study confirmed that pinocembrin induced an increase in HaCaT cell number. At the signaling perspective, we identified that pinocembrin significantly triggered ERK1/2 and Akt activation. The stimulating effects of pinocembrin were clearly inhibited by MEK and PI3K inhibitors authenticating that proliferation- and survival-promoting activities of pinocembrin were mainly acted on these two signaling cascades. Altogether, we successfully identified that pinocembrin functions to induce keratinocyte proliferation and survival, at least by provoking MAPK and PI3K pathways. Our study encourages the fact that pinocembrin is one of the interesting natural flavonoid compounds to be developed as a wound closure-promoting agent

Oxyresveratrol Inhibits TNF-α-Stimulated Cell Proliferation in Human Immortalized Keratinocytes (HaCaT) by Suppressing AKT Activation

Psoriasis is a complex inflammatory disease characterized by hyperproliferative keratinocyte caused by active PI3K/AKT signaling. TNF-α concentrated in the psoriatic lesions stimulates AKT activation. We previously discovered that oxyresveratrol inhibited inflammation via suppressing AKT phosphorylation, therefore oxyresveratrol may possess a conserved property to block AKT activation and proliferation in keratinocyte in response to TNF-α. Our current study proved that oxyresveratrol exhibited potent anti-proliferative effects against TNF-α. These effects are explained by the findings that oxyresveratrol could potentially inhibit TNF-α-stimulated AKT and GSK3-β activation in a dose-dependent manner, and its inhibitory pattern was comparable to that of a specific PI3K inhibitor. Results from immunofluorescence supported that oxyresveratrol effectively inhibited AKT and GSK3-β activation in individual cells upon TNF-α stimulation. Furthermore, functional assay confirmed that oxyresveratrol repressed the expansion of the HaCaT colony over 3 days, and this was caused by the ability of oxyresveratrol to induce cell cycle arrest at S and G2/M phases and the reduction in the expression of a proliferative marker (Ki-67) and a survival marker (MCL-1). Given the importance of TNF-α and the PI3K/AKT pathway in the psoriatic phenotype, we anticipate that oxyresveratrol, which targets the TNF-α-stimulated PI3K/AKT pathway, would represent a promising psoriasis therapy in the near future

Ubiquilin Networking in Cancers

Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies

Anti-Inflammatory Activity of Essential Oil from <i>Zingiber ottensii</i> Valeton in Animal Models

Zingiber ottensii (ZO) Valeton, a local plant in Northern Thailand, has been widely used in traditional medicine. Many studies using in vitro models reveal its pharmacological activities, including the anti-inflammatory activity of ZO essential oil, extracted from ZO rhizomes. However, the scientific report to confirm its anti-inflammatory activity using animal models is still lacking. The present study aimed to evaluate the anti-inflammatory activity and explore the possible mechanisms of action of ZO essential oil in rats. The results revealed that ZO essential oil significantly reduced the ear edema formation induced by ethyl phenylpropiolate. Pre-treatment with ZO essential oil significantly reduced the carrageenan-induced hind paw edema and the severity of inflammation in paw tissue. In addition, pre-treatment with ZO essential oil exhibited decreased COX-2 and pro-inflammatory cytokine TNF-α expression in paw tissue, as well as PGE2 levels in serum. On this basis, our study suggests that ZO essential oil possesses anti-inflammatory activity in animal models. Its possible mechanisms of action may involve the inhibition of TNF-α expression as well as the inhibition of COX-2 and PGE2 production. These findings provide more crucial data of ZO essential oil that may lead to new natural anti-inflammatory product development in the future

Synergistic Effects of Some Methoxyflavones Extracted from Rhizome of Kaempferia parviflora Combined with Gentamicin against Carbapenem-Resistant Strains of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii

The present study aimed to investigate the antibacterial activity of ethanolic Kaempferia parviflora extracts and the combined effects of the plant&rsquo;s specific compounds with gentamicin against clinical strains of carbapenem-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The minimal inhibitory concentrations (MIC) of gentamicin and Kaempferia parviflora extracts against the tested bacterial strains were determined by using broth microdilution. The combined effects of Kaempferia parviflora extract and gentamicin were investigated by using a checkerboard assay and expressed as a fractional inhibitory concentration index (FICI). Crude ethanolic extract of Kaempferia parviflora showed the lowest median values of MIC towards the tested isolates (n = 10) of these tested bacteria at doses of 64 &micro;g/mL, compared to those of other Kaempferia extracts. Among the isolated compounds, only three compounds, namely 3,5,7-trimethoxyflavone, 3,5,7,3&prime;4&prime;-pentamethoxyflavone, and 5,7,4&prime;-trimethoxyflavone, were identified by NMR structural analysis. According to their FICIs, the synergistic effects of gentamicin combined with 3,5,7,3&prime;4&prime;-pentamethoxyflavone were approximately 90%, 90%, and 80% of tested carbapenem-resistant Klebsiella pneumoniae (CRKP), Pseudomonas aeruginosa (CRPA), and Acinetobacter baumannii (CRAB), respectively. The present study concluded that 3,5,7,3&prime;4&prime;-pentamethoxyflavone extracted from Kaempferia parviflora potentiated the antibacterial action of gentamicin to combat bacterial resistance against the tested bacteria

Anti-cancer effects of Kaempferia parviflora on ovarian cancer SKOV3 cells

Abstract Background Kaempferia parviflora (KP) is an herb found in the north of Thailand and used as a folk medicine for improving vitality. Current reports have shown the anti-cancer activities of KP. However, the anti-cancer effects of KP on highly aggressive ovarian cancer have not been investigated. Therefore, we determined the effects of KP on cell proliferation, migration, and cell death in SKOV3 cells. Methods Ovarian cancer cell line, SKOV3 was used to investigate the anti-cancer effect of KP extract. Cell viability, cell proliferation, MMP activity, cell migration, and invasion were measured by MTT assay, cell counting, gelatin zymography, wound healing assay, and Transwell migration and invasion assays, respectively. Cell death was determined by trypan blue exclusion test, AnnexinV/PI with flow cytometry, and nuclear staining. The level of ERK and AKT phosphorylation, and caspase-3, caspase-7, caspase-9 was investigated by western blot analysis. Results KP extract was cytotoxic to SKOV3 cells when the concentration was increased, and this effect could still be observed even though EGF was present. Besides, the cell doubling time was significantly prolonged in the cells treated with KP. Moreover, KP strongly suppressed cell proliferation, cell migration and invasion. These consequences may be associated with the ability of KP in inhibiting the activity of MMP-2 and MMP-9 assayed by gelatin zymography. Moreover, KP at high concentrations could induce SKOV3 cell apoptosis demonstrated by AnnexinV/PI staining and flow cytometry. Consistently, nuclear labelling of cells treated with KP extract showed DNA fragmentation and deformity. The induction of caspase-3, caspase-7, and caspase-9 indicates that KP induces cell death through the intrinsic apoptotic pathway. The antitumor activities of KP might be regulated through PI3K/AKT and MAPK pathways since the phosphorylation of AKT and ERK1/2 was reduced. Conclusions The inhibitory effects of KP in cell proliferation, cell migration and invasion together with apoptotic cell death induction in SKOV3 cells suggest that KP has a potential to be a new candidate for ovarian cancer chemotherapeutic agent

Alpinetin Suppresses Zika Virus-Induced Interleukin-1&beta; Production and Secretion in Human Macrophages

Zika virus (ZIKV) infection has been recognized to cause adverse sequelae in the developing fetus. Specially, this virus activates the excessive release of IL-1&beta; causing inflammation and altered physiological functions in multiple organs. Although many attempts have been invested to develop vaccine, antiviral, and antibody therapies, development of agents focusing on limiting ZIKV-induced IL-1&beta; release have not gained much attention. We aimed to study the effects of alpinetin (AP) on IL-1&beta; production in human macrophage upon exposure to ZIKV. Our study demonstrated that ZIKV stimulated IL-1&beta; release in the culture supernatant of ZIKV-infected cells, and AP could effectively reduce the level of this cytokine. AP exhibited no virucidal activities against ZIKV nor caused alteration in viral production. Instead, AP greatly inhibited intracellular IL-1&beta; synthesis. Surprisingly, this compound did not inhibit ZIKV-induced activation of NF-&kappa;B and its nuclear translocation. However, AP could significantly inhibit ZIKV-induced p38 MAPK activation without affecting the phosphorylation status of ERK1/2 and JNK. These observations suggest the possibility that AP may reduce IL-1&beta; production, in part, through suppressing p38 MAPK signaling. Our current study sheds light on the possibility of using AP as an alternative agent for treating complications caused by ZIKV infection-induced IL-1&beta; secretion

Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity

Neuronal insulin resistance is a significant feature of Alzheimer&rsquo;s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer&rsquo;s formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3&beta;). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer&rsquo;s proteins like A&beta; in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition