Dietary polyphenols, a natural component in many kinds of foods such as fruits and vegetables, play essential roles in a wide range of plant functions. Importantly, the discovery of the functions of polyphenols including anti-oxidant, anti-carcinogenic and anti-inflammatory has been appealing to researchers' attentions. Dietary polyphenols have shown protective effects on chronic degenerative diseases (CDD) such as cardiovascular diseases, cancers, and neurodegenerative diseases by regulating gene expression. Dietary polyphenols also affect the composition and activity of gut microbiota, in reverse, gut microbiota influences the bioavailability and physiological activity of dietary polyphenols. However, not all kinds of dietary polyphenols are beneficial for human health. The potential deleterious effects of several dietary polyphenols have been reported by inducing DNA damage and gene mutants. This review summarizes the potential therapeutic effects of dietary polyphenols on chronic degeneration diseases, the polyphenols-gut microbiota interactions, and the potential dangers of individual dietary polyphenols on human health.
The past decades have witnessed a rapid increase in the use of molecularly targeted therapies. One class of agents includes the epidermal growth factor receptor inhibitors (EGFRIs), which afford patients longer progression-free survival (PFS) times, especially among non-small cell lung cancer (NSCLC) and metastatic colorectal carcinoma (mCRC). Certain adverse effects, particularly skin toxicity, are mainly manifested as rash, xerosis, pruritus, nails changes, hair changes and mucositis. Previous studies reported the adverse events occurred based on the cutaneous inflammation reaction. Treatment recommended glucocorticoids and antibiotics. It is suggested that skin toxicity is an important issue because it usually affects patients' quality of life (QoL) and still causes dose reduction or discontinuation of targeted therapies. For these reasons, more and more oncologists and dermatologists recognize the importance of recognition and management of skin toxicities with the expansion in availability of EGFRIs. In this review, we conducted a systematic review of recent data to examine the types and frequencies of dermatologic toxicities associated with anti-epidermal growth factor receptor (EGFR) therapies in NSCLC and mCRC. In addition, we would like to explore the management and treatment options currently used by clinicians based on the possible mechanism.
Neural networks have garnered attention over the past few years. A neural network is a typical model of machine learning that is used to identify visual patterns. Neural networks are used to solve a wide variety of problems, including image recognition problems and time series prediction problems. In addition, neural networks have been applied to medicine over the past few years. This paper classifies the ways in which neural networks have been applied to medicine based on the type of data used to train those networks. Applications of neural networks to medicine can be categorized two types: automated diagnosis and physician aids. Considering the number of patients per physician, neural networks could be used to diagnose diseases related to the vascular system, heart, brain, spinal column, head, neck, and tumors/cancer in three fields: vascular and interventional radiology, interventional cardiology, and neuroradiology. Lastly, this paper also considers areas of medicine where neural networks can be effectively applied in the future.
Since serious problematic cases regarding the technical safety of technically demanding operations were reported in Japan, the Ministry of Health, Labor and Welfare issued new regulations on June 10, 2016 requiring each hospital to check the status of informed consent, skill of surgery team and governance system of the surgical unit, when the highly difficult new medical technologies were introduced to a hospital. In order to firmly establish this new system for highly difficult new medical technologies, it is very important and informative to survey the current situation for guidelines and consensus regarding introduction of medical technology with special skills in Japan and overseas. Based on the survey of questionnaires, document retrieval, and expert interviews, we found that documentation related to the introduction process of highly difficult medical technologies is very rare, and the regulations were mainly issued by academic societies. Moreover, even if such documentation existed, the quality of the regulations is poor and not sufficient enough to perform surgical practice safely. Therefore, for medical practitioners, comprehensive and concrete regulations should be issued by the government or ministry to legally follow in regard to technically demanding operations. A new practice guideline was proposed by our special research group to regulate the introduction process of highly difficult new medical technologies in hospitals in Japan. This guideline, gained understanding from relevant academic societies, provided a comprehensive view on the interpretation of "high difficulty new medical technology" prescribed by the law and show the basic idea at a preliminary examination from the viewpoints of "Surgeon's requirement", "Guidance system", "Medical safety" , and "Informed consent". These efforts will contribute to the improvement of the quality of guidelines regarding "highly difficult new medical technology".
Alternative splicing is a post- and co-transcriptional regulatory mechanism of gene expression. Pentatricopeptide repeat (PPR) family proteins were recently found to be involved in RNA editing in plants. The aim of this study was to investigate the tissue-specific expression and alternative splicing of PPR family genes and their effects on protein structure and functionality. Of the 27 PPR genes in Arabidopsis thaliana, we selected six PPR genes of the P subfamily that are likely alternatively spliced, which were confirmed by sequencing. Four of these genes show intron retention, and the two remaining genes have 3' alternative-splicing sites. Alternative-splicing events occurred in the coding regions of three genes and in the 3' UTRs of the three remaining genes. We also identified five previously unannotated alternatively spliced isoforms of these PPR genes, which were confirmed by PCR and sequencing. Among these, three contain 3' alternative-splicing sites, one contains a 5' alternative-splicing site, and the remaining gene contains a 3'-5' alternative-splicing site. The new isoforms of two genes affect protein structure, and three other alternative-splicing sites are located in 3' UTRs. These findings suggest that tissue-specific expression of different alternatively spliced transcripts occurs in Arabidopsis, even at different developmental stages.
Irisin is a myokine secreted from the cleavage of fibronectin type III domain-containing protein 5 (FNDC5) and has an effect on bone formation. There are limited studies about the structure of irisin and its functional unit. In order to clarify the candidate domain responsible for irisin action, we constructed several irisin variants and tested their influence on the proliferation and osteogenesis of MC3T3-E1 cells. On the one hand, His-tag was added to the N terminal or C terminal of irisin. On the other hand, the flexible region or salt bridge site were chosen as the candidate for point mutation. Alkaline phosphatase (ALP), Runt related transcription factor 2 (Runx2) and collagen type I alpha 1 (COL1α1) were chosen to test the differentiation efficiency. We found point mutation on flexible regions, Glu-57 and Ile-107, and adding His-tag on the C-terminal of irisin did affect its action. The osteogenic potential of irisin E57K, irisin I107F and irisinC-His decreased about 90.1%, 88.8% and 96.6% activity of recombinant-irisin (r-irisin) (P < 0.05), respectively. Point mutation on the salt bridge, Arg-75, partly decreased the effect of irisin (45 ± 11.3% of r-irisin) (P < 0.05). N-terminal His-tag showed almost no effect (93.5 ± 25.7% of r-irisin) (P = 0.658). This study suggested that the flexible region of residues 55-58 and 106-108, and C-terminal of irisin are vital for its activity. Disrupting the dimerization of irisin might result in a partly reduced effect on cell differentiation.
Obesity has become a severe public health problem worldwide. Crocin, a natural product, has been reported to have a number of pharmacological activities, including anti-inflammatory, anti-cancer, neuroprotective, antihypertensive, and cardioprotective action. The aims of the current study were to identify the beneficial effects of crocin on obesity, adipocyte differentiation, and lipolysis and to evaluate the possible role of AMPK. Results indicated that crocin significantly increased AMPK phosphorylation in differentiated adipocytes in vitro and in adipose tissue in db/db mice. Crocin reduced lipid accumulation in differentiated adipocytes. In addition, crocin inhibited the expression of mRNA of important adipogenesis-related regulators, including CEBPα, CEBPβ, PPARγ, aP2, FAS, and CD36, in both differentiated adipocytes and adipose tissue in db/db mice. Crocin increased the expression of mRNA of key lipolysis-associated factors, including PPARα, LPL, and HSL, in both differentiated adipocytes and adipose tissue in db/db mice. In adipocytes, knockdown of AMPK significantly suppressed the crocin-induced inhibition of adipocyte differentiation and increase in lipolysis. BML-275 is an inhibitor of AMPK. In adipose tissue in db/db mice, BML-275 suppressed crocin-induced inhibition of fat formation and alleviation of a metabolic disorder. The current results suggest that crocin alleviates obesity in db/db mice and that it inhibits adipocyte differentiation in preadipocytes. Crocin inhibits adipogenesis and promotes lipolysis via activation of AMPK. Therefore, crocin may have promise as an option for the clinical treatment for obesity and associated metabolic diseases.
Danzhi Jiangtang Capsule (DJC), a traditional Chinese medicinal formula, has been used clinically in treating diabetes and diabetic nephropathy (DN). We previously demonstrated that DJC is capable of improving renal function in patients and rats with DN, but the mechanisms underlying these therapeutic benefits of DJC are not quite clear yet. In this study, STZ-induced diabetic rats were orally administered DJC for 8 weeks. Fasting blood glucose, renal function indicators in the serum, renal index, and the expression of proteins related to JAK-STAT signaling pathway were evaluated at the end of the experiment. The kidneys were sliced for pathological histology. Antioxidant status was assessed by measuring SOD, LPO and MDA in serum. The expression levels of COX2, iNOS, SOCS and the phosphorylation status of JAK2, STAT1, and STAT3 in renal tissues were evaluated by Western blot analyses. IL-6, TNF-α, and MCP-1 expression levels in renal tissues were determined using double-antibody sandwich ELISA. Diabetic renal dysfunction and its associated pathologies were ameliorated by DJC treatment. DJC significantly reversed the high expression of COX2 and iNOS in renal tissues. Furthermore, DJC inhibited the JAK2-STAT1/STAT3-SOCS3 signaling pathway, resulting in decreased concentrations of IL-6, TNF-α, and MCP-1. Moreover, the oxidant status in the kidney was substantially ameliorated by DJC treatment. In conclusion, the ability of DJC to ameliorate diabetic renal dysfunction and the associated pathologies of this disease might be due to its antioxidant capacity and suppression of the JAK2-STAT1/STAT3 cascade.
Mitochondrial damage is involved in the pathogenesis of osteoarthritis. Metformin, one of the most common prescriptions for patients with type 2 diabetes, can reportedly activate Sirtuin 3 (SIRT3) expression which protects mitochondria from oxidative stress. In this study, we investigated the inhibitory property of metformin on mitochondrial damage by focusing on the interleukin-1 beta (IL-1β)-stimulated osteoarthritis model by using primary murine chondrocytes. Our results demonstrated that SIRT3 was downregulated in chondrocytes under IL-1β stimulation, where its expression was positively correlated with mitochondrial damage and reactive oxygen species (ROS) production. Metformin treatment upregulated SIRT3 expression and mitigated loss of cell viability and decreased the generation of mitochondria-induced ROS in chondrocytes stimulated with IL-1β. Metformin also attenuated IL-1β-induced expressions of catabolic genes such as matrix metalloproteinase-3 (MMP3) and MMP13 and enhanced the anabolic indicator Collagen Ⅱ. These effects were mediated by phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1 (PINK1)/Parkin-dependent mitophagy and the autophagic elimination of damaged mitochondria. Further, the SIRT3 inhibitor 3-TYP effectively inhibited the initiation of mitophagy, as decreased expression of PINK1 and Parkin, decreased the LC3II/LC3I, enhanced the expression of MMP3 and MMP13, and decreased the expression of Collagen Ⅱ. Overall, our findings provide evidence that metformin suppresses IL-1β-induced oxidative and osteoarthritis-like inflammatory changes by enhancing the SIRT3/PINK1/Parkin signaling pathway, thereby indicating metformin's potential in prevention and treatment of osteoarthritic joint disease.
To assess the predictive value of integrating multiple of the median (MOM) with the risk cut-off value for serological screening of Down syndrome. In this retrospective study, women with singleton pregnancies who underwent triple serological screening for Down syndrome were followed, and their screening results and pregnancy outcomes were recorded. The range of MoM value of each indicator was calculated, different protocols integrating various MoM values with the risk cut-off value were compared. A total of 120,269 women with singleton pregnancy were screened and included in the analysis, of those 52 fetuses were confirmed as trisomy-21 by amniocentesis chromosomal karyotyping. Using a risk cut-off value of 1:380, 8,809 samples tested positive and the screen positive rate was 7.32% (8,809/120,269). The normal reference ranges (5-95%) of the MoM value of AFP, β-hCG, and uE3 were 0.60-1.72, 0.43-2.21 and 0.60-1.58, respectively. The detection rate of each screening protocol integrating different MoM percentile values was between 75% and 79%, the positive rate was between 7% and 18%, and the false positive rate was between 7% and 18%. Protocol-6 which combined the screening risk cut-off value and β-hCG MoM ≥ 97.5% percentile is an optimal protocol with a relatively high detection rate (78.8%) and low false positive rate (8.2%). Integrating MoM values of serological indicators can appropriately increase detection rate when interpreting the results of Down syndrome screening.
Surgical treatment for intra-abdominal/retroperitoneal desmoid-type fibromatosis (IA/RPDF) is still controversial. Studies regarding en bloc resection in IA/RPDF with adjacent organ involvement are scanty. This study aims to evaluate the safety and effectiveness of en bloc resection in IA/RPDF with adjacent organ involvement. This retrospective clinical study included 21 patients who were diagnosed with IA/RPDF and underwent tumor resection at a single center between March 2013 and June 2018. All patients included in the study underwent surgery with curative intent, and IA/RPDF with adhesive organs was removed en bloc. The safety of surgical treatment was verified by the analysis of intraoperative bleeding, postoperative morbidity and perioperative mortality. The efficacy of surgical treatment was evaluated based on the status of tumor infiltration of adjacent organs and patient follow-up results. Complete macroscopic (R0 or R1) resection was achieved in all cases. A median of 2 (range, 1-7) organs were resected. The median operating time was 300 (90-650) minutes. The median intraoperative bleeding was 300 (20-4,500) milliliters. For postoperative pathological diagnosis at our center, tumor infiltrated at least one organ in each patient. Infiltration was noted in 45 resected organs (45/57, 78.9%). Grade III-V postoperative morbidity developed in one patient (4.8%). During the follow-up, one patient developed local recurrence. No DF-related death was noted during the follow-up. The 3-year disease-free survival rate was 94.1% (95% confidence interval: 83.6-100%). Therefore, en bloc resection of the tumor and involved adjacent organs is a safe and effective treatment modality for IA/RPDF.
A novel protocol to reuse agarose following agarose gel electrophoresis was established in this study. By repeated freeze-and-thaw of the agarose gel, ethidium bromide and other buffer components in the gel were safely removed from the gel without generation of any toxic fume. The agarose recovered using this method can be used for further electrophoretic experiments without any issues.
FliL is an inner membrane protein, occupying a position between the rotor and the stator of the bacterial flagellar motor. Its proximity to, and interactions with, the MS (membrane and supramembranous) ring, the switch complex and the stator proteins MotA/B suggests a role in recruitment and/or stabilization of the stator around the rotor, although the precise role of FliL in the flagellum remains to be established. In this study, recombinant C-terminal domain of Helicobacter pylori FliL (amino-acid residues 81-183) has been expressed in Escherichia coli and purified to > 98% homogeneity. Purified recombinant protein behaved as a monomer in solution. Crystals were obtained by the hanging-drop vapour-diffusion method using ammonium phosphate monobasic as a precipitant. These crystals belong to space group P1, with unit-cell parameters a = 62.5, b = 82.6, c = 97.8 Å, α = 67.7, ꞵ = 83.4, γ = 72.8°. A complete data set has been collected to 2.8 Å resolution using synchrotron radiation. This is an important step towards elucidation of the function of FliL in the bacterial flagellar motor.
In Japan, national official surveillance for influenza has been performed at about 5,000 sentinel hospitals/clinics by the National Official Sentinel Surveillance of Infectious Diseases (NOSSID). Meanwhile, all electronic medical claims nationwide in the National Database of Electronic Medical Claims (NDBEMC) were recently disclosed by the Ministry of Health, Labour and Welfare of Japan. We compared the regional variation of influenza incidence among prefectures between the NOSSID and NDBEMC. The data were extracted from NOSSID and the NDBEMC for the 2010/2011 through 2013/2014 seasons. We compared the data of both datasets season by season by using Spearman's rank correlation in each season. Spearman's rank correlation values for the four seasons were 0.7823, 0.3907, 0.4961 and 0.4543, and their p-values were less than 0.00005, 0.0066, 0.0004 and 0.0013, respectively. Statistically, regional variation of influenza incidence in NOSSID is not imprecise, but its correlation with the NDBEMC dataset is not so high. It is important to note this fact when interpreting regional variation in NOSSID.
Benign portal vein stenosis is a rare complication following pancreaticoduodenectomy. Because a direct surgical approach to the portal vein is difficult due to severe adhesions following pancreaticoduodenectomy, portal vein stent placement is considered a good treatment option. Herein, we report 3 cases of severe portal vein stenosis following pancreaticoduodenectomy that were treated with portal venous stent placement in a hybrid operating room, combining a conventional operating room with an angiography suite. High-resolution images on digital subtraction angiography provide better contrast and support accurate stent placement compared to using a mobile C-arm.