Trends in the incidence of urothelial carcinoma in Taiwan after the ban on aristolochic acid-containing Chinese herbal preparations, 2001-2018: a national population-based cohort study.

PURPOSE: Urothelial carcinoma (UC) of the bladder (BUC) and the upper urinary tract (UTUC) are the two most common UCs. The incidence of UTUC in Taiwan is the highest worldwide. Aristolochic acid (AA) was identified as the main cause of UTUC in Taiwan. To explore trends in the incidence of UC in Taiwan after the ban on Chinese herbal preparations containing AA in 2003. METHODS: We used data from the Taiwanese National Health Insurance Research Database-linked Taiwanese National Cancer Registry for 2001-2018. UC was defined in accordance with the International Classification of Disease for Oncology. The age-standardized incidence was calculated on the basis of the World Health Organization standard population. Trends in the incidence were calculated as the annual percent change (APC) by using the Joinpoint regression program. RESULTS: Over the investigated period, the incidence of UC decreased at an average annual percent change (AAPC) of - 1.19% (95% CI - 1.47 ~ - 0.91, P < 0.001). However, the incidence in UTUC significantly increased, with the AAPC being 1.47% (95% CI 1.03 ~ 1.90, P < 0.001). In contrast, the incidence of BUC significantly decreased, with the overall AAPC being - 1.92% (95% CI - 2.3 ~ - 1.54, P < 0. 001). From 2001 to 2018, the overall incidence of UCs and BUC decreased in Taiwan, but the incidence of UTUC significantly increased. CONCLUSION: We suggest to apply the same review standards of new drug development process to herbal preparations and incorporate them into the adverse drug reaction or poison surveillance system. Most importantly, raise public awareness of the potential toxicity of phytotherapy.

Oxidative stress-mediated intrinsic apoptosis in human promyelocytic leukemia HL-60 cells induced by organic arsenicals.

Arsenic trioxide has shown the excellent therapeutic efficiency for acute promyelocytic leukemia. Nowadays, more and more research focuses on the design of the arsenic drugs, especially organic arsenicals, and on the mechanism of the inducing cell death. Here we have synthesized some organic arsenicals with Schiff base structure, which showed a better antitumor activity for three different kinds of cancer cell lines, namely HL-60, SGC 7901 and MCF-7. Compound 2a (2-(((4-(oxoarsanyl)phenyl)imino)methyl)phenol) and 2b (2-methoxy-4-(((4-(oxoarsanyl)phenyl)imino)methyl)phenol) were chosen for further mechanism study due to their best inhibitory activities for HL-60 cells, of which the half inhibitory concentration (IC50) were 0.77 µM and 0.51 µM, respectively. It was illustrated that 2a or 2b primarily induced the elevation of reactive oxygen species, decrease of glutathione level, collapse of mitochondrial membrane potential, release of cytochrome c, activation of Caspase-3 and apoptosis, whereas all of the phenomena can be eliminated by the addition of antioxidants. Therefore, we concluded that compound 2a and 2b can induce the oxidative stress-mediated intrinsic apoptosis in HL-60 cells. Both the simplicity of structure with Schiff base group and the better anticancer efficiency demonstrate that organic arsenicals are worthy of further exploration as a class of potent antitumor drugs.

Rat Liver Mitochondrial Dysfunction Induced by an Organic Arsenical Compound 4-(2-Nitrobenzaliminyl) Phenyl Arsenoxide.

Arsenic is successfully used in cancer chemotherapy and several cancer treatments on account of its apoptogenic effects. However, it is environmentally hazardous with potential for toxicity when distributed in the soil, water, and food, and long exposure to water contaminated with Arsenic may induce cancers. Some research studies have reported that liver is the storage site and an important target organ for Arsenic toxicity. In the present work, a new kind of organic arsenic compound, 4-(2-nitrobenzaliminyl) phenyl arsenoxide (NPA), was synthesized, and its potential involvement of mitochondria was explored. The results presented that the toxicology of NPA, at least in part, mediated mitochondrial function and may thoroughly destroy mitochondrial membrane physiological functions. NPA induced mitochondrial permeability transition pore (mtPTP) opening that induces mitochondrial biochemical abnormalities as evidenced by mitochondrial swelling, mitochondrial membrane potential breakdown, membrane fluidity alterations, and the strikingly remarkable protection of CsA. Meanwhile, both the decreased respiration rate of state 4 and the increased inner membrane H(+) permeabilization revealed that the inner membrane function regarding important energy production chain was destroyed. The toxicity of NPA is due to its interaction with mitochondrial membrane thiol protein. This conclusion is based on the protective effects of RR, DTT, and MBM(+).

Nd(III)-induced rice mitochondrial dysfunction investigated by spectroscopic and microscopic methods.

The production capacity and yield of neodymium (Nd) in China have ranked the first in the world. Because of its unique biophysical and biochemical properties, Nd compounds have entered into the agricultural environment greatly to promote plant growth. Mitochondria play a crucial role in respiration and metabolism during the growth of plants. However, little is known about the mechanism by which Nd act at the mitochondrial level in plant cells. In this study, rice mitochondrial swelling, collapsed transmembrane potential and decreased membrane fluidity were examined to be important factors for mitochondria permeability transition pore (mPTP) opening induced by Nd(III). The protection of cyclosporin A (CsA) and dithiothreitol (DTT) could confirm that Nd(III) could trigger mPTP opening. Additionally, mitochondrial membrane breakdown observed by TEM and the release of cytochrome c (Cyt c) could also elucidate the mPTP opening from another point of view. At last, the study showed that Nd(III) could restrain the mitochondrial membrane lipid peroxide, so it might interact with anionic lipid too. This detection will be conductive to the safe application of Nd compounds in agriculture and food industry.

Antibacterial evaluation of novel organoarsenic compounds by the microcalorimetric method.

Antibacterial activities of novel organoarsenic compounds As(III)-containing Schiff bases on Escherichia coli (CCTCCAB91112) were investigated by microcalorimetry in this study. The experimental result showed that the arsenic(III)-containing Schiff bases at micromolar concentration exhibit strong inhibition on the E. coli. Specifically, the growth rate constant k decreased, and the generation time t G and the inhibitory ratio I (percentage) increased with the increased dose of the arsenicals as inhibitors. All of the arsenicals display the feature of considerable lag phase inhibition on the cell growth. The compound 4-(4-bromobenzaliminyl)phenylarsenoxide makes the lag phase of E. coli cell growth cycles to reach 650 min at 5 µmol/L. The compounds with donating electron groups at aromatic ring B have lower IC50 to present higher antibacterial activity. The compound 4-(4-hydroxyl-3-methoxylbenzaliminyl)phenylarsenoxide has the lowest IC50 (1.82 µmol/L) to show the strongest antibacterial activity among them.

Ce(III)-induced rice mitochondrial permeability transition investigated by spectroscopic and microscopic studies.

Cerium has been widely used as fertilizer and feed additives in agriculture, but it might finally impair human health by food chain accumulation with its dosage increased in environmental and crops samples. To resolve the conflict, we investigated the effects of Ce(III) on isolated rice mitochondrial permeability transition (MPT) by examining mitochondrial swelling, transmembrane potential, membrane fluidity with spectroscopy, and observing the mitochondrial ultrastructure, meanwhile, the interaction site(s) and mechanism between Ce(III) and mitochondria were also studied. The results showed that the low level of Ce(III) had little effect on rice MPT, however, the higher level of Ce(III) could induce rice MPT, and the thiol (-SH) groups of membrane proteins (defined as "S" site) matched by Ce(III)-triggered rice MPT pore opening.

Microcalorimetric studies of the effect of cerium (Ш) on isolated rice mitochondria fed by pyruvate.

Mitochondria were isolated from the hybrid rice Xiangzaoxian 31, then the effects of low and high concentrations of Ce (Ш) on metabolism of mitochondria fed by pyruvate were investigated respectively, by microcalorimetry and oxygen electrode method The thermogenic curve of mitochondria without Ce (Ш) could be divided into three parts: activity recovery phase, stationary phase and decline phase. And the thermokinetic parameters have been calculated through the metabolic thermogenic curves. With addition of different concentrations of Ce (Ш), the results demonstrated that low levels of cerium ion stimulated the metabolic activity of energized mitochondria and the inhibition was discovered with high concentrations of Ce (Ш). At the same time, it is shown that the effect in respiration correspond to the effect on mitochondrial metabolism on addition of different concentrations of Ce (Ш). Moreover, the addition of low and high concentrations of Ce (Ш) had no obvious effect on the total heat output (Q). The concentration-dependent effect of Ce (Ш) on metabolism of mitochondria is similar to plant growth response to rare earth elements (Hormesis effect).