Inhibitory Effect
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2021 ◽  
Hiroko Munakata ◽  
Risa Ishikawa ◽  
Toshiaki Saitoh ◽  
Toshie Kambe ◽  
Terumasa Chiba ◽  

Abstract 1,2,3,4-Tetrahydroisoquinoline (TIQ) is endogenously present in human brain, and some of its derivatives are thought to contribute to the induction of Parkinson’s disease (PD)-like symptoms in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ (1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQ derivatives (loading an N-propyl, N-propenyl, N-propargyl, or N-butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like symptoms in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me-N-propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQ and 1-Me-N-propyl-TIQ did not. Induction of thiobarbituric acid reactive substances (TBARS) by MPTP in the substantia nigra was significantly suppressed by not only 1-Me-N-propargyl-TIQ and 1-Me-N-butynyl-TIQ, but also by 1-Me-N-propyl-TIQ; in contrast, 1-Me-N-propenyl-TIQ had no effect. These results suggest that although loading an N-propargyl group on 1-MeTIQ clearly enhanced neuroprotective effects, other N-functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N-functional group may contribute to the observed differences in effect.

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5651
Tzung-Hsun Tsai ◽  
Chi-I Chang ◽  
Ya-Ling Hung ◽  
Wen-Cheng Huang ◽  
Hsiang Chang ◽  

Porphyromonas gingivalis has been identified as one of the major periodontal pathogens. Activity-directed fractionation and purification processes were employed to identify bioactive compounds from bitter melon leaf. Ethanolic extract of bitter melon leaf was separated into five subfractions by open column chromatography. Subfraction-5-3 significantly inhibited P. gingivalis-induced interleukin (IL)-8 and IL-6 productions in human monocytic THP-1 cells and then was subjected to separation and purification by using different chromatographic methods. Consequently, 5β,19-epoxycucurbita-6,23(E),25(26)-triene-3β,19(R)-diol (charantadiol A) was identified and isolated from the subfraction-5-3. Charantadiol A effectively reduced P. gingivalis-induced IL-6 and IL-8 productions and triggered receptors expressed on myeloid cells (TREM)-1 mRNA level of THP-1 cells. In a separate study, charantadiol A significantly suppressed P. gingivalis-stimulated IL-6 and tumor necrosis factor-α mRNA levels in gingival tissues of mice, confirming the inhibitory effect against P. gingivalis-induced periodontal inflammation. Thus, charantadiol A is a potential anti-inflammatory agent for modulating P. gingivalis-induced inflammation.

Yunjie Zhu ◽  
Yanan Shao ◽  
Min Wei ◽  
Kefu Yu ◽  
Yuanyuan Zhang ◽  

Abstract Sulfate radical (•SO4−)-based advanced oxidation processes are widely used for wastewater treatment. This study explored the potential use of UV/persulfate (UV/PS) system for the degradation of 17β-estradiol (E2). The pH of the reaction system can affect the degradation rate of E2 by UV/PS and the optimum pH was 7.0; Br− and Cl− in water can promote the degradation rate, HCO3− has an inhibitory effect on the reaction, SO42− and cations (Na+, Mg2+, K+) have no effect on the degradation rate. The degradation of E2 by UV/PS was a mineralization process, with the mineralization rate reaching 90.97% at 8 h. E2 in the UV/PS system was mainly degraded by hydroxylation, deoxygenation, and hydrogenation. E2 reaction sites were mainly located on benzene rings, mainly carbonylation on quinary rings, and bond breakage between C10 and C5 resulted in the removal of benzene rings and carboxyl at C2 and C3 sites. In the presence of halogen ions, halogenated disinfection by-products were not formed in the degradation process of E2 by UV/PS. E2 in the UV/PS system could inhibit the formation of bromate. The results of this study suggest that UV/PS is a safe and reliable method to degrade E2.

Yufan Zhang ◽  
Junfei Huang ◽  
Danlan Fu ◽  
Zhen Liu ◽  
Hailin Wang ◽  

Dermal papillae are a target of androgen action in patients with androgenic alopecia, where androgen acts on the epidermis of hair follicles in a paracrine manner. To mimic the complexity of the dermal papilla microenvironment, a better culture model of human dermal papilla cells (DPCs) is needed. Therefore, we evaluated the inhibitory effect of dihydrotestosterone (DHT)-treated two-dimensional (2D)- and 3D-cultured DPCs on hair follicle growth. 2D- and 3D-cultured DPC proliferation was inhibited after co-culturing with outer root sheath (ORS) cells under DHT treatment. Moreover, gene expression levels of β-catenin and neural cell adhesion molecules were significantly decreased and those of cleaved caspase-3 significantly increased in 2D- and 3D-cultured DPCs with increasing DHT concentrations. ORS cell proliferation also significantly increased after co-culturing in the control-3D model compared with the control-2D model. Ki67 downregulation and cleaved caspase-3 upregulation in DHT-treated 2D and 3D groups significantly inhibited ORS cell proliferation. Sequencing showed an increase in the expression of genes related to extracellular matrix synthesis in the 3D model group. Additionally, the top 10 hub genes were identified, and the expression of nine chemokine-related genes in DHT-treated DPCs was found to be significantly increased. We also identified the interactions between transcription factor (TF) genes and microRNAs (miRNAs) with hub genes and the TF–miRNA coregulatory network. Overall, the findings indicate that 3D-cultured DPCs are more representative of in vivo conditions than 2D-cultured DPCs and contribute to our understanding of the molecular mechanisms underlying androgen-induced alopecia.

2021 ◽  
Vol 22 (18) ◽  
pp. 10029
Yueh-Ming Shyu ◽  
Lawrence Yu-Min Liu ◽  
Yung-Jen Chuang

Melanoma is the most lethal form of skin cancer, which is intrinsically resistant to conventional chemotherapy. Combination therapy has been developed to overcome this challenge and show synergistic anticancer effects on melanoma. Notably, the histone deacetylase inhibitor, valproic acid (VPA), has been indicated as a potential sensitizer of chemotherapy drugs on various metastatic cancers, including advanced melanoma. In this study, we explored whether VPA could serve as an effective sensitizer of chemotherapy drug etoposide (ETO) on B16-F10 and SK-MEL-2-Luc melanoma cell lines in response to drug-induced DNA damages. Our results demonstrated that the VPA-ETO simultaneous combined treatment and ETO pretreated sequential combined treatment generated higher inhibitory effectivities than the individual treatment of each drug. We found the VPA-ETO simultaneous combined treatment contributed to the synergistic inhibitory effect by the augmented DNA double-strand breaks, accompanied by a compromised homologous recombination activity. In comparison, the ETO pretreated sequential combined treatment led to synergistic inhibitory effect via enhanced apoptosis. Surprisingly, the enhanced homologous recombination activity and G2/M phase arrest resulted in the antagonistic effect in both cells under VPA pretreated sequential combined treatment. In summary, our findings suggested that sequential order and effective dose of drug administration in VPA-ETO combination therapy could induce different cellular responses in melanoma cells. Such understanding might help potentiate the effectiveness of melanoma treatment and highlight the importance of sequential order and effective dose in combination therapy.

2021 ◽  
Shikui Sun ◽  
Yue Liang ◽  
Ke Li ◽  
Yizhen Wang ◽  
Huimin Li ◽  

Abstract Ovarian cancer is the leading cause of death from malignancies of the female reproductive system. In recent years, there has been little development regarding the treatment of ovarian cancer. Wild-type tumor protein p53 (P53) can inhibit the development of tumor, however, mutations in P53 have been shown in most cases of ovarian cancer. The mutated gene encoded P53 transforms from a tumor suppressor gene to an oncogene, losing its original anti-tumor function. Studies have shown that the zinc metallochaperone NSC319726 can promote the correct folding of P53 in cancer cells and restore its physiological function, however, the function of NSC319726 in ovarian cancer has not been elaborated. So we investigated the role of NSC319726 on biological functions of ovarian cancer and preliminarily determined the specific molecular mechanism. The results showed that NSC319726 could inhibit proliferation, migration and invasion of ovarian cancer cells and promote their apoptosis. Mechanically, NSC319726 regains the tumor-suppressed function of P53, further activates the downstream cyclin-dependent kinase CDK inhibited protein P21, thereby blocking the cell cycle and inhibiting cells proliferation. Therefore, NSC319726 has the potential to act as a novel drug for treating ovarian cancer.

Pharmacology ◽  
2021 ◽  
pp. 1-7
Norio Ogata ◽  
Hideaki Tagishi

<b><i>Introduction:</i></b> Anisakiasis is a common disease in countries such as Japan, where raw or undercooked marine fish are frequently consumed. The disease is caused by accidental ingestion of a live larva of <i>Anisakis</i> in raw or undercooked marine fish. In typical cases, it causes abrupt gastrointestinal symptoms, such as epigastric pain, nausea, and vomiting. According to a published report, the disease was alleviated by oral ingestion of an over-the-counter drug containing wood creosote. <b><i>Methods:</i></b> We performed an in vitro experiment to elucidate whether wood creosote can inhibit the motor activity of <i>Anisakis</i> larvae, using infrared locomotion tracking and agarose gel penetration techniques. <b><i>Results:</i></b> Our results clearly demonstrate that wood creosote inhibits the motor activity of <i>Anisakis</i> larvae. The concentration of wood creosote used in our experiment is similar to that found in stomach juice when a usual oral dose is taken of the medicine containing wood creosote. <b><i>Discussion/Conclusion:</i></b> Our results suggest the potential usefulness of the medicine containing wood creosote in the treatment of acute <i>Anisakis</i> infection of the gastrointestinal tract.

2021 ◽  
Vol 12 ◽  
Yanan Duan ◽  
Ran Chen ◽  
Rong Zhang ◽  
Weitao Jiang ◽  
Xuesen Chen ◽  

Apple replant disease (ARD) is a common problem in major apple planting areas, and biological factors play a leading role in its etiology. Here, we isolated the bacterial strain QSB-6 from the rhizosphere soil of healthy apple trees in a replanted orchard using the serial dilution method. Strain QSB-6 was provisionally identified as Bacillus amyloliquefaciens based on its morphology, physiological and biochemical characteristics, carbon source utilization, and chemical sensitivity. Maximum likelihood analysis based on four gene sequences [16S ribosomal RNA gene (16S rDNA), DNA gyrase subunit A (gyrA), DNA gyrase subunit B (gyrB), and RNA polymerase subunit B (rpoB)] from QSB-6 and other strains indicated that it had 100% homology with B. amyloliquefaciens, thereby confirming its identification. Flat standoff tests showed that strain QSB-6 had a strong inhibitory effect on Fusarium proliferatum, Fusarium solani, Fusarium verticillioides, Fusarium oxysporum, Alternaria alternata, Aspergillus flavus, Phoma sp., Valsa mali, Rhizoctonia solani, Penicillium brasilianum, and Albifimbria verrucaria, and it had broad-spectrum antibacterial characteristics. Extracellular metabolites from strain QSB-6 showed a strong inhibitory effect on Fusarium hyphal growth and spore germination, causing irregular swelling, atrophy, rupture, and cytoplasmic leakage of fungal hyphae. Analysis of its metabolites showed that 1,2-benzenedicarboxylic acid and benzeneacetic acid, 3- hydroxy-, methyl ester had good inhibitory effects on Fusarium, and increased the length of primary roots and the number of lateral roots of Arabidopsis thaliana plantlet. Pot experiments demonstrated that a QSB-6 bacterial fertilizer treatment (T2) significantly improved the growth of Malus hupehensis Rehd. seedlings. It increased root length, surface area, tips, and forks, respiration rate, protective enzyme activities, and the number of soil bacteria while reducing the number of soil fungi. Fermentation broth from strain QSB-6 effectively prevented root damage from Fusarium. terminal restriction fragment length polymorphism (T-RFLP) and quantitative PCR (qPCR) assays showed that the T2 treatment significantly reduced the abundance of Fusarium in the soil and altered the soil fungal community structure. In summary, B. amyloliquefaciens QSB-6 has a good inhibitory effect on Fusarium in the soil and can significantly promote plant root growth. It has great potential as a biological control agent against ARD.

2021 ◽  
Vol 12 ◽  
Lulu Zhang ◽  
Bo Wen ◽  
Mei Bao ◽  
Yungchi Cheng ◽  
Tariq Mahmood ◽  

Methicillin-resistant Staphylococcus aureus (MRSA) is a drug-resistant pathogen threatening human health and safety. Biofilms are an important cause of its drug resistance and pathogenicity. Inhibition and elimination of biofilms is an important strategy for the treatment of MRSA infection. Andrographolide sulfonate (AS) is an active component of the traditional herbal medicine Andrographis paniculata. This study aims to explore the inhibitory effect and corresponding mechanisms of AS on MRSA and its biofilms. Three doses of AS (6.25, 12.5, and 25 mg/ml) were introduced to MRSA with biofilms. In vitro antibacterial testing and morphological observation were used to confirm the inhibitory effect of AS on MRSA with biofilms. Real-time PCR and metabonomics were used to explore the underlying mechanisms of the effect by studying the expression of biofilm-related genes and endogenous metabolites. AS displayed significant anti-MRSA activity, and its minimum inhibitory concentration was 50 μg/ml. Also, AS inhibited biofilms and improved biofilm permeability. The mechanisms are mediated by the inhibition of the expression of genes, such as quorum sensing system regulatory genes (agrD and sarA), microbial surface components–recognizing adhesion matrix genes (clfA and fnbB), intercellular adhesion genes (icaA, icaD, and PIA), and a gene related to cellular eDNA release (cidA), and the downregulation of five biofilm-related metabolites, including anthranilic acid, D-lactic acid, kynurenine, L-homocitrulline, and sebacic acid. This study provided valuable evidence for the activity of AS against MRSA and its biofilms and extended the methods to combat MRSA infection.

2021 ◽  
Vol 11 (1) ◽  
Yiqing Guo ◽  
Hua Zheng ◽  
Jie Yin ◽  
Huaming Wang

AbstractRecent evidence revealed an inhibitory effect of circ-ITCH on the progression of papillary thyroid cancer via affecting the circ-ITCH/miR-22-3p/CBL axis. Rs4911154, an SNP located in circ-ITHC, was previously reported to be significantly associated with an increased risk of hepatocellular carcinoma. Ultrasound testing was used to evaluate the doubling time of thyroid nodules. 202 patients diagnosed with thyroid nodule disorders were divided into three groups according to their genotypes at rs4911154. We found that the A allele was correlated with a shortening doubling time of thyroid nodules. Moreover, the A allele contributed to reduced expression of circ-ITCH/CBL and increased expression of miR-22-3p. Besides, decreased tissue apoptosis was linked to the A allele. Luciferase assays indicated that miR-22-3p could effectively suppress the luciferase activities of CBL and circ-ITCH. Furthermore, manual up-regulation of miR-22-3p effectively suppressed the expression of CBL, while CBL siRNA apparently abolished circ-ITCH induced CBL upregulation, reduced proliferation and increased apoptosis of K1 and TPC-1 cells. A signaling pathway of circ-ITCH/miR-22-3p/CBL axis was established to explain the effect of SNP of circ-ITCH in thyroid tumor malignancy. Compared with the G allele, the A allele in rs4911154 contributed to the malignancy of thyroid nodules with decreased doubling time and down-regulated CBL expression.

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