Plant-derived lignans as potential antiviral agents: a systematic review.

Medicinal plants are one of the most important sources of antiviral agents and lead compounds. Lignans are a large class of natural compounds comprising two phenyl propane units. Many of them have demonstrated biological activities, and some of them have even been developed as therapeutic drugs. In this review, 630 lignans, including those obtained from medicinal plants and their chemical derivatives, were systematically reviewed for their antiviral activity and mechanism of action. The compounds discussed herein were published in articles between 1998 and 2020. The articles were identified using both database searches (e.g., Web of Science, Pub Med and Scifinder) using key words such as: antiviral activity, antiviral effects, lignans, HBV, HCV, HIV, HPV, HSV, JEV, SARS-CoV, RSV and influenza A virus, and directed searches of scholarly publisher's websites including ACS, Elsevier, Springer, Thieme, and Wiley. The compounds were classified on their structural characteristics as 1) arylnaphthalene lignans, 2) aryltetralin lignans, 3) dibenzylbutyrolactone lignans, 4) dibenzylbutane lignans, 5) tetrahydrofuranoid and tetrahydrofurofuranoid lignans, 6) benzofuran lignans, 7) neolignans, 8) dibenzocyclooctadiene lignans and homolignans, and 9) norlignans and other lignoids. Details on isolation and antiviral activities of the most active compounds within each class of lignan are discussed in detail, as are studies of synthetic lignans that provide structure-activity relationship information.

Blockage of TGF-β1-induced epithelial-to- mesenchymal transition by oxymatrine prevents renal interstitial fibrosis

Abstract Most chronic kidney disease inevitably progress to renal fibrosis. Tubular epithelial- to-mesenchymal transition (EMT) is recognized to play major roles in renal fibrosis. Oxymatrine (OM) is a major alkaloid component found in a Chinese herb Sophora roots and has many effects. The aim is to investigate the effect of OM on renal tubular EMT and elucidate its mechanism. Mice underwent unilateral ureteral obstruction (UUO) followed by intraperitoneal injection of OM (120 mg/kg) or control vehicle. Human kidney proximal tubular cell line (HK-2) was used and EMT was induced with 5 ng/mL of transforming growth factor-β1 (TGF-β1). In vivo, renal tubulointerstitial fibrosis was induced and E-cadherin was down-regulated, while the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), TGF-β1 and its type I receptor (TGF-βRI) were up-regulated in UUO mice. In contrast, OM significantly ameliorated renal fibrotic lesions and attenuated the expressions of FN, α-SMA, TGF-β1 and TGF-βRI, but increased E-cadherin in the obstructed kidneys. In vitro, OM abolished TGF-β1-mediated E-cadherin suppression and FN, α-SMA and TGF-βRI induction in HK-2 cells in a dose-dependent manner. These observations strongly suggest that the renal protective effects of OM could be mediated by prevention of EMT and manifested as suppression of TGF-β1 and TGF-βRI expressions.

Characterization and Oxidative Stability of Cold-pressed Sesame Oil Microcapsules Prepared by Complex Coacervation.

Although cold-pressed sesame oil (CPSO) possesses high nutritional value, its application in the food industry is limited due to its poor oxidative stability. The aim of this study was to enhance the oxidative stability of CPSO by complex coacervation microcapsule technology with gelatin and gum Arabic as wall materials. The characterization of CPSO microcapsules were evaluated by a particle image analyzer, a laser particle size distribution analyzer, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). The encapsulation efficiency (EE) reached 90.25%. The average particle size of the microcapsules was approximately 117.1 µm and many oil droplets were encapsulated by complex coacervation to form a multinuclear spherical microcapsule. The FTIR study confirmed that the process of complex coacervation was formed between gelatin and gum Arabic by electrostatic interactions. The TGA study suggested that the microcapsules had good heat resistance. The fatty acid composition, the content of sesamin, sesamolin and vitamin E in CPSO were determined before and after microencapsulation. It showed that the microencapsulation process had almost no effect on the fatty acid composition, sesamin and sesamolin, only Vitamin E was slightly lost during the microencapsulation process. The accelerated storage test showed that microencapsulation significantly increased the oxidative stability of CPSO.

DNA methylation and hydroxymethylation profiles reveal possible role of highly methylated TLR signaling on Fasciola gigantica excretory/secretory products (FgESPs) modulation of buffalo dendritic cells.

BACKGROUND: Excretory/secretory products (ESPs) released by parasites influence the development and functions of host dendritic cells (DCs). However, little is known about changes of DNA (hydroxy)methylation on DC development during Fasciola gigantica infection. The present study aimed to investigate whether F. gigantica ESPs (FgESPs) affects the development and functions of buffalo DCs through altering the DNA (hydroxy)methylation of DCs. METHODS: Buffalo DCs were prepared from peripheral blood mononuclear cells (PBMCs) and characterized using scanning and transmission electron microscopy (SEM/TEM) and quantitative reverse transcriptional PCR (qRT-RCR). DCs were treated with 200 µg/ml of FgESPs in vitro, following DNA extraction. The DNA methylome and hydroxymethylome were profiled based on (hydroxy)methylated DNA immunoprecipitation sequencing [(h)MeDIP-Seq] and bioinformatics analyses. qRT-RCR was also performed to assess the gene transcription levels of interest. RESULTS: FgESPs markedly suppressed DC maturation evidenced by morphological changes and downregulated gene expression of CD1a and MHC II. Totals of 5432 and 360 genes with significant changes in the 5-methylcytosine (5-mC) and the 5-hydroxymethylcytosine (5-hmC) levels, respectively, were identified in buffalo DCs in response to FgESPs challenge. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these differentially expressed genes were highly enriched in pathways associated with immune response. Some cancer-related pathways were also indicated. There were 111 genes demonstrating changes in both 5-mC and 5-hmC levels, 12 of which were interconnected and enriched in 12 pathways. The transcription of hypermethylated genes TLR2, TLR4 and IL-12B were downregulated or in a decreasing trend, while the mRNA level of high-hydroxymethylated TNF gene was upregulated in buffalo DCs post-exposure to FgESPs in vitro. CONCLUSIONS: To our knowledge, the present study provides for the first time a unique genome-wide profile of DNA (hydroxy)methylation for DCs that interact with FgESPs, and suggests a possible mechanism of FgESPs in suppressing DC maturation and functions that are involved in TLR signaling.

Effect of Total Flavones from Cuscuta Chinensis on Anti-Abortion via the MAPK Signaling Pathway.

For centuries, the Chinese herb Cuscuta chinensis has been applied clinically for abortion prevention in traditional Chinese medicine (TCM). Total flavones extracted from Cuscuta chinensis (TFCC) are one of the active components in the herb and also display anti-abortion effect similar to the unprocessed material. However, how TFCC exerts the anti-abortion effect remains largely unknown. In this study, we aim at characterizing the anti-abortion effects of TFCC and its underlying molecular mechanism in vitro and in vivo using human primary decidua cells and a mifepristone-induced abortion model in rat, respectively. The damage to the decidua caused by mifepristone in vivo was reversed by TFCC treatment in a dosage-dependent manner. High dosage of TFCC significantly upregulated the expression of estrogen receptor (ER), progesterone receptor (PR), and prolactin receptor (PRLR) in decidua tissue but downregulated the expression of p-ERK. Furthermore, we detected higher level of p-ERK and p-p38 in primary decidua cells from spontaneous abortion while treatment by TFCC downregulated their expression. Our results suggest TFCC mediates its anti-abortion effect by interfering with MAPK signaling pathway.

Histological component quantification for the evaluation of endometrial receptivity in women with natural cycles undergoing in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: Our aim was to evaluate the value of the volumetric fraction of vascular endothelial cells (EnVF) for determining endometrial receptivity in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). MATERIALS AND METHODS: The records of women undergoing IVF/ICSI between 2006 and 2010 were retrospectively reviewed. An endometrial biopsy was performed in the cycle prior to IVF/ICSI. EnVF was calculated from endometrial biopsy staining. RESULTS: Twenty-seven patients who did not become pregnant, 8 who had a miscarriage, and 21 with a clinical pregnancy were included. The three groups were similar with respect to infertility and IVF characteristics. An EnVF ≤3.85 was associated with not becoming pregnant, an EnVF >5.29 with miscarriage, and a level between 3.86 and 5.29 was associated with clinical pregnancy (p = 0.001). CONCLUSIONS: EnVF examined in the prior cycle may be a marker of endometrial receptivity and predict the chance of pregnancy in women undergoing IVF/ICSI.

Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial.

BACKGROUND: Increasing the biological effective dose (BED) of radiotherapy for non-small cell lung cancer (NSCLC) can increase local control rates and improve overall survival. Compared with conventional fractionated radiotherapy, accelerated hypofractionated radiotherapy can yield higher BED, shorten the total treatment time, and theoretically obtain better efficacy. However, currently, there is no optimal hypofractionated radiotherapy regimen. Based on phase I trial results, we performed this phase II trial to further evaluate the safety and preliminary efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy(3-DCRT) combined with concurrent chemotherapy for patients with unresectable stage III NSCLC. METHODS: Patients with previously untreated unresectable stage III NSCLC received 3-DCRT with a total dose of 69 Gy, delivered at 3 Gy per fraction, once daily, five fractions per week, completed within 4.6 weeks. At the same time, platinum doublet chemotherapy was applied. RESULTS: After 12 patients were enrolled in the group, the trial was terminated early. There were five cases of grade III radiation esophagitis, of which four cases completed the radiation doses of 51 Gy, 51 Gy, 54 Gy, and 66 Gy, and one case had 16 days of radiation interruption. The incidence of grade III acute esophagitis in patients receiving an irradiation dose per fraction ≥2.7 Gy on the esophagus was 83.3% (5/6). The incidence of symptomatic grade III radiation pneumonitis among the seven patients who completed 69 Gy according to the plan was 28.6% (2/7). The median local control (LC) and overall survival (OS) were not achieved; the 1-year LC rate was 59.3%, and the 1-year OS rate was 78.6%. CONCLUSION: For unresectable stage III NSCLC, the accelerated hypofractionated radiotherapy with a total dose of 69 Gy (3 Gy/f) combined with concurrent chemotherapy might result in severe radiation esophagitis and pneumonitis to severely affect the completion of the radiotherapy. Therefore, we considered that this regimen was infeasible. During the hypofractionated radiotherapy with concurrent chemotherapy, the irradiation dose per fraction to esophagus should be lower than 2.7 Gy. Further studies should be performed using esophageal tolerance as a metric in dose escalation protocols. TRIAL REGISTRATION: NCT02720614, the date of registration: March 23, 2016.

A phase I clinical trial of dose escalation of lobaplatin in combination with fixed-dose docetaxel for the treatment of human solid tumours that had progressed following chemotherapy.

In this study, the maximum tolerated dose (MTD) of lobaplatin (LBP) when it was combined with docetaxel (TXT) for the treatment of solid tumours that had progressed following chemotherapy was determined, and toxicities to this regimen were evaluated. A modified Fibonacci method was used for the dose escalation of LBP. The patients received TXT (at a fixed dose of 60 mg/m2) on day one (d1) and LBP (at an initial tested dose of 30 mg/m2) on day two (d2) of a treatment cycle that was repeated every 21 days. Each dose group consisted of at least three cases. In the absence of dose-limiting toxicity (DLT), we proceeded to the next dose group, with a dose increment of 5 mg/m2 between groups, until DLT occurred. The dose immediately below the dose that produced DLT was regarded as the MTD. The 17 patients examined in this study completed a total of 58 cycles of chemotherapy, and a total of three dose-escalation groups (30 mg/m2 LBP, 35 mg/m2 LBP, and 40 mg/m2 LBP) were established. The main adverse event that was observed was myelosuppression. DLT occurred in four patients, including three patients in the 40 mg/m2 LBP group and one patient in the 35 mg/m2 LBP group. In total, three out of the four patients in the 40 mg/m2 LBP group exhibited DLT. We determined that the treatment administered to the 35 mg/m2 LBP group represented the MTD. Thus, our phase I trial revealed that the MTD for the tested LBP combination regimen was 35 mg/m2 LBP and 60 mg/m2 TXT. This regimen resulted in mild adverse reactions and favourable patient tolerance. Therefore, we recommend the use of these dosages in phase II clinical trials.

Phase II clinical trial of whole-brain irradiation plus three-dimensional conformal boost with concurrent topotecan for brain metastases from lung cancer.

BACKGROUND: Patients with brain metastases from lung cancer have poor prognoses and short survival time, and they are often excluded from clinical trials. Whole-cranial irradiation is considered to be the standard treatment, but its efficacy is not satisfactory. The purpose of this phase II clinical trial was to evaluate the preliminary efficacy and safety of the treatment of whole-brain irradiation plus three-dimensional conformal boost combined with concurrent topotecan for the patients with brain metastases from lung cancer. METHODS: Patients with brain metastasis from lung cancer received concurrent chemotherapy and radiotherapy: conventional fractionated whole-brain irradiation, 2 fields/time, 1 fraction/day, 2 Gy/fraction, 5 times/week, and DT 40 Gy/20 fractions; for the patients with ≤ 3 lesions with diameter ≥ 2 cm, a three-dimensional (3-D) conformal localised boost was given to increase the dosage to 56-60 Gy; and during radiotherapy, concurrent chemotherapy with topotecan was given (the chemoradiotherapy group, CRT). The patients with brain metastasis from lung cancer during the same period who received radiotherapy only were selected as the controls (the radiotherapy-alone group, RT). RESULTS: From March 2009 to March 2012, both 38 patients were enrolled into two groups. The median progression-free survival(PFS) time , the 1- and 2-year PFS rates of CRT group and RT group were 6 months, 42.8%, 21.6% and 3 months, 11.6%, 8.7% (χ2 = 6.02, p = 0.014), respectively. The 1- and 2-year intracranial lesion control rates of CRT and RT were 75.9% , 65.2% and 41.6% , 31.2% (χ2 = 3.892, p = 0.049), respectively. The 1- and 2-year overall survival rates (OS) of CRT and RT were 50.8% , 37.9% and 40.4% , 16.5% (χ2 = 1.811, p = 0.178), respectively. The major side effects were myelosuppression and digestive toxicities, but no differences were observed between the two groups. CONCLUSION: Compared with radiotherapy alone, whole-brain irradiation plus 3-D conformal boost irradiation and concurrent topotecan chemotherapy significantly improved the PFS rate and the intracranial lesion control rate of patients with brain metastases from lung cancer, and no significant increases in side effects were observed. Based on these results, this treatment method is recommended for phase III clinical trial.

Dose escalation of accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in unresectable stage III non-small-cell lung cancer: a phase I trial.

BACKGROUND: Accelerated hypofractionated radiotherapy can shorten total treatment time and overcome the accelerated repopulation of tumour cells during radiotherapy. This therapeutic approach has demonstrated good efficacy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). However, the optimal fractionation scheme remains uncertain. The purpose of this phase I trial was to explore the maximum tolerated dose (MTD) of accelerated hypofractionated three-dimensional conformal radiotherapy (3-DCRT) (at 3 Gy/fraction) administered in combination with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for unresectable stage III NSCLC. METHODS: Previously untreated cases of unresectable stage III NSCLC received accelerated hypofractionated 3-DCRT, delivered at 3 Gy per fraction, once daily, with five fractions per week. The starting dose was 66 Gy and an increment of 3 Gy was utilized. Higher doses continued to be tested in patient groups until the emergence of dose-limiting toxicity (DLT). The MTD was regarded as the dose that was one step below the dose at which DLT occurred. Patients received at least one cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. RESULTS: A total of 13 patients were enrolled and progressed through three dose escalation groups: 66 Gy, 69 Gy, and 72 Gy. No treatment-related deaths occurred. The major adverse events included radiation oesophagitis, radiation pneumonitis, and neutropenia. Nausea, fatigue, and anorexia were commonly observed, although the magnitude of these events was typically relatively minor. Among the entire group, four instances of DLT were observed, including two cases of grade 3 radiation oesophagitis, one case of grade 3 radiation pneumonitis, and one case of grade 4 neutropenia. All of these cases of DLT occurred in the 72 Gy group. Therefore, 72 Gy was designated as the DLT dose level, and the lower dose of 69 Gy was regarded as the MTD. CONCLUSIONS: For unresectable stage III NSCLC 69 Gy (at 3 Gy/fraction) was the MTD of accelerated hypofractionated 3-DCRT administered in combination with concurrent NVB and CBP chemotherapy. The toxicity of this chemoradiotherapy regimen could be tolerated. A phase II trial is recommended to further evaluate the efficacy and safety of this regimen.

Phase II trial of capecitabine combined with docetaxel in previously treated patients with non-small cell lung cancer: A randomized controlled study.

Docetaxel alone has been confirmed to be beneficial to patients with advanced previously treated non-small cell lung cancer (NSCLC). However, the duration and survival time is short. The study of two-agent combination regimens has important clinical significance. We conducted this randomized controlled phase II trial to comparatively evaluate the efficacy and side effects of capecitabine combined with docetaxel in previously treated patients with NSCLC. Patients with previously treated NSCLC who failed first-line chemotherapy were randomized into two groups; one received capecitabine combined with docetaxel (XT group) and the other received docetaxel alone (T group). Patients in the XT group received chemotherapy as follows: capecitabine 625 mg/m(2), p.o. bid, days 5-18; and docetaxel 30 mg/m(2), days 1 and 8, while patients in the T group received docetaxel 35 mg/m(2) on days 1 and 8. The primary endpoint was time to progression (TTP), and secondary endpoints were overall survival (OS), response rate (RR) and disease control rate (DCR). Forty-eight patients were recruited (23 in the XT group and 25 in the T group). TTP, median survival time (MST) and 1-year OS rate in the XT group and the T group were 7 months, 12 months, 47.6% and 3 months, 12 months, 39.6%, respectively. The TTP in the XT group was significantly longer compared to that in the T group (χ(2)=4.763, p=0.029). The RR and DCR in the XT group and T group were 13.0% (3/23), 78.3% (18/23) and 12.0% (3/25), 76% (19/25), respectively. The difference was not significant (p>0.05). The major side effects observed in the two groups were neutropenia, fatigue and nausea, and toxicities were mild to modest. No severe cases of hand-foot syndrome were observed in the XT group. In conclusion, compared with docetaxel alone, capecitabine combined with docetaxel for patients with previously treated NSCLC achieved a significantly longer TTP and this regimen was well tolerated. The relatively high median TTP, 1-year OS rate and DCR encourage further evaluation of this regimen in a randomized phase III trial.