Ching-Shu Lai

Widespread exposure to endocrine disruptors is associated with metabolic dysfunction and reproductive toxicity. Tetrahydrocurcumin (THC) has attracted attention as it offers protection against obesity and metabolic disorders due to its potent antioxidative and diverse biological properties but its influence and underlying mechanism of action on adipose tissue function and DEHP-induced testicular injury remain unknown. Our results showed that THC (100 mg kg⁻¹ day⁻¹) administration for 27 weeks enlarged adipocytes while attenuating macrophage infiltration and IL-6 expression in the adipose tissue of male C57BL/6J mice exposed to 5 mg kg⁻¹ day⁻¹ of DEHP. Moreover, THC ameliorated DEHP-induced deregulation of adiponectin but not leptin. DEHP caused testicular histological damage, spermatogenesis impairment, apoptosis, inflammation, and AGE, which were improved by THC. THC treatment elevated Nrf2/HO-1 and decreased Glut1 in interstitial Leydig cells, which may contribute to its beneficial effects on the testis. Our results further demonstrated that THC also ameliorated circulating adiponectin and testicular adipoR1-AMPK signaling, partially accounting for the improvement of DEHP-caused testicular dysfunction. The finding of this study revealed that THC is a promising candidate for improving adipose and testicular dysfunction caused by DEHP.

Associations exist between fine particulate matter (PM_2.5) exposure and impaired kidney function. However, the specific mechanisms and components causing renal damage remain unclear. PM_2.5 was collected from an industrial and a rural area. Mice were categorized according to exposure, and biochemical, western blotting, histological, and immunohistochemical analyses were performed to evaluate the impact of PM_2.5 constituents on their kidneys. The impact of different PM_2.5 components on inflammatory responses was assessed by exposing the murine macrophage cell line (RAW 264.7); a chelating resin, which removed heavy metals from the water extract, allowed for evaluating the inflammatory effects caused by various PM_2.5 constituents. The major metallic elements at the industrial site were Fe, Mg, Zn, and Ca, whereas those at site Rural were Ca, K, and Mg. PM_2.5 water extracts from both sites induced inflammatory cytokine upregulation in the lungs and kidneys, and inflammatory cell infiltration, antioxidant activity downregulation, and elevated levels of kidney injury molecule 1 in the kidneys. Compared to industrial-site PM_2.5, rural-site PM_2.5 significantly upregulated inflammatory cytokine infiltration in the lungs, increased inflammatory cell levels in the kidneys, and significantly increased kidney Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells. Exposure to PM_2.5 water extract increased the mRNA levels of tumor necrosis factor-α and interleukin-6, and nitrite production in RAW264.7 macrophages. The inflammatory response and nitrite production induced by the industrial-site PM_2.5 water extract were significantly suppressed after treatment with a chelating resin, whereas that in the rural area were suppressed by the Toll-like receptor 4 (TLR4) antagonist. At equivalent dosages, renal toxicity induced by the rural-site PM_2.5 water-soluble components might exceed that from industrial areas. Metal components may be crucial factors in PM_2.5-induced cellular inflammatory responses in industrial areas, while TLR4-mediated inflammatory pathways were a major factor responsible for this response in the rural area.

Cancer is a complicated disease with many puzzles of tumorigenesis remaining unsolved; however, there is strong evidence regarding the link between oxidative stress and cancer. The malignant transformation of cells requires the integration of many factors, and reactive oxygen species (ROS) are dynamically implicated in each step of tumorigenesis. Moreover, ROS are involved in tumorigenesis not only within cancer cells, but also in the interplay between malignant and nonmalignant cells. Therefore, targeting oxidative stress could be a potential strategy for the prevention and treatment of human malignancies. Numerous dietary natural compounds have long been recognized as attractive candidates for nutraceuticals and pharmaceuticals because of their antioxidative properties. Natural dietary compounds exert their anticancer potential through ROS scavenging, metal chelation, inhibition of ROS production, and upregulation of antioxidants, which block oxidative damage, abnormal proliferation, inflammatory response, malignant progression, and metabolic reprogramming. Although the clinical efficacy and oral bioavailability are still being challenged, natural dietary compounds offer attractive promise for cancer treatment. Some dietary natural compounds, namely resveratrol, curcumin, tetrahydrocurcumin, and (−)-epigallocatechin-3-gallate which exhibit anticancer potential through their antioxidative effects, and the underlying molecular mechanisms of their actions, are summarized and discussed in this chapter.

Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (p < 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic β-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.

Type II collagen is an important component of cartilage; however, little is known about its effect on skin wound healing. In this study, type II collagen was extracted from the cartilage of Acipenser baerii and its effect on in vitro and in vivo wound healing was compared to type I collagen derived from tilapia skin. Sturgeon cartilage collagen (SCC) was composed of α1 chains and with a thermal denaturation (T_d) at 22.5 and melting temperature (T_m) at 72.5 °C. Coating SCC potentiated proliferation, migration, and invasion of human dermal fibroblast adult (HDFa) cells. Furthermore, SCC upregulated the gene expression of extracellular matrix (ECM) components (col Iα1, col IIIα1, elastin, and Has2) and epithelial-mesenchymal transition (EMT) molecules (N-cadherin, Snail, and MMP-1) in HDFa. Pretreatment with Akt and mitogen-activated protein kinase (MAPK) inhibitors significantly attenuated the HDFa invasion caused by SCC. In mice, the application of SCC on dorsal wounds effectively facilitated wound healing as evidenced by 40–59% wound contraction, whereas the untreated wounds were 18%. We observed that SCC reduced inflammation, promoted granulation, tissue formation, and ECM deposition, as well as re-epithelialization in skin wounds. In addition, SCC markedly upregulated the production of growth factors in the dermis, and dermal and subcutaneous white adipose tissue; in contrast, the administration of tilapia skin collagen (TSC) characterized by typical type I collagen was mainly expressed in the epidermis. Collectively, these findings indicate SCC accelerated wound healing by targeting fibroblast in vitro and in vivo.

In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.

Adipocyte–macrophage interaction in obesity can cause adipose tissue inflammation and contribute to insulin resistance. Here, we investigated the effect of SlimTrym®—a formulated product containing citrus polymethoxyflavones (PMFs), green tea extract, and lychee polyphenols—on 3T3-L1 adipocyte differentiation and obesity-induced inflammation. SlimTrym® inhibited mitotic clonal expansion (MCE) of 3T3-L1 adipocytes by inducing G1 cell cycle arrest via upregulation of p21 and p53. SlimTrym® attenuated adipogenic differentiation by downregulating adipogenic factors, such as CCAAT-enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), and upregulating AMP-activated protein kinase (AMPK). Pretreatment with compound C significantly reduced SlimTrym®-mediated suppression of lipid accumulation. SlimTrym® reduced the expression of pro-inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1β and IL-6, in co-cultured 3T3-L1 adipocytes and RAW264.7 macrophages. C57BL/6 mice administered with SlimTrym® for 16 weeks showed markedly reduced high-fat diet (HFD)-induced infiltration of monocytes/macrophages in adipose tissue; however, the level of M2 macrophage markers (CD163 and IL-10) was increased. Taken together, these findings indicate that SlimTrym® exerts both anti-adipogenic and anti-inflammatory effects, and can potentially treat obesity and adipose tissue inflammation.

Diet-induced obesity is strongly associated with non-alcoholic fatty liver disease (NAFLD) and insulin resistance. We aimed to investigate in vivo therapeutic value of THC intervention in high fat diet (HFD)-induced obesity and hepatic steatosis. C57BL/6 mice were fed a HFD for 10 weeks and then received 20 or 100 mg/kg THC with continuation on a HFD for another 10 weeks. Mice fed a HFD for 20 weeks experienced obesity, hepatic steatosis, hyperlipidemia, and insulin resistance. Tetrahydrocurcumin (THC) intervention for 10 weeks significantly reduced adiposity (epididymal fat weight, 6.6 ± 0.4 g for HFD alone group, 5.3 ± 0.8 g and 5.6 ± 0.7 g for HFD+20 mg/kg THC and HFD+100 mg/kg THC group, respectively; p<0.05) via downregulation of adipogenic factors. Inflammatory macrophage infiltration and polarization were decreased by THC in mouse epididymal adipose tissues. In the liver, THC markedly alleviated steatosis by approximately 28~37% (p<0.05) via the downregulation of lipogenesis, activation of AMP-activated protein kinase (AMPK), and increase of fatty acid oxidation. Elevated blood glucose and insulin resistance were also improved by THC, which might be caused by the regulation of the hepatic insulin signaling cascade, gene transcription involved in glucose metabolism, and the reduced macrophage infiltration in the liver and adipose tissue. Our results demonstrated the beneficial effect of THC-mediated intervention against obesity and NAFLD as well as other metabolic syndromes, revealing a novel therapeutic use of THC in obese populations.