ABSTRACT
Diabetic cardiomyopathy(DCM) is a chronic complication of diabetes mellitus that leads to cardiac damage in the later stages of the disease, and its pathogenesis is complex, involving metabolic disorders brought about by a variety of aberrant alterations such as endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis, defects in cardiomyocyte Ca~(2+) transporter, and myocardial fibrosis. Currently, there is a lack of specific diagnosis and treatment in the clinic. Autophagy is a highly conserved scavenging mechanism that removes proteins, damaged organelles or foreign contaminants and converts them into energy and amino acids to maintain the stability of the intracellular environment. Inhibition of autophagy can cause harmful metabolites to accumulate in the cell, while over-activation of autophagy can disrupt normal cellular structures and cause cell death. Prolonged high glucose levels disrupt cardiomyocyte autophagy levels and exacerbate the development of DCM. The protective or detrimental effects of autophagy on cells ring true with the traditional Chinese medicine theory of healthy Qi and pathogenic Qi. Autophagy in the physiological state of the removal of intracellular substances and the generation of substances beneficial to the survival of cells is the inhibition of pathogenic Qi to help the performance of healthy Qi, so the organism is healthy. In the early stages of the disease, when autophagy is impaired and incapable of removing waste substances, pathogenic Qi is prevalent; In the later stages of the disease, excessive activation of autophagy can destroy normal cells, leading to a weakening of healthy Qi. Traditional Chinese medicine has the advantage of targeting multiple sites and pathways. Studies in recent years have confirmed that traditional Chinese medicine monomers or formulas can target autophagy, promote the restoration of autophagy levels, maintain mitochondrial and endoplasmic reticulum homeostasis, and reduce oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis in order to prevent and control DCM. This study provides a review of the relationship between autophagy and DCM and the intervention of traditional Chinese medicine in autophagy for the treatment of DCM, with a view to providing new clinical ideas and methods for the treatment of DCM with traditional Chinese medicine.
Subject(s)
Autophagy , Diabetic Cardiomyopathies , Drugs, Chinese Herbal , Medicine, Chinese Traditional , Autophagy/drug effects , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/drug therapy , Diabetic Cardiomyopathies/physiopathology , Humans , Animals , Drugs, Chinese Herbal/pharmacology , Endoplasmic Reticulum Stress/drug effectsABSTRACT
Cell-penetrating peptides (CPPs) are attractive non-viral gene delivery vectors due to their high transfection capacity and safety. Previously, we have shown that cell-penetrating peptide RALA can be a promising gene delivery vector for chronic wound regeneration application. In this study, we engineered a novel peptide called RALA-E by introducing elastin-derived VGVAPG fragment into RALA, in order to target the elastin-binding protein on the cell surface and thus improve delivery efficacy of RALA. The transfection efficiency of RALA-E was evaluated by transfecting the HEK-293T and HeLa cell lines cells with RALA-E/pDNA complexes and the flow-cytometry results showed that RALA-E significantly increased the transfection efficiency by nearly 20% in both cell lines compared to RALA. Inhibition of pDNA transfection on HEK-293T cells via chlorpromazine, genistein and mßCD showed that the inhibition extent in transfection efficiency was much less for RALA-E group compared to RALA group. In addition, RALA-E/miR-146a complexes showed up to 90% uptake efficiency in macrophages, and can escape from the endosome and enter the nucleus to inhibit the expression of inflammation genes. Therefore, the developed RALA-E peptide has high potential as a safe and efficient vector for gene therapy application.
ABSTRACT
Harnessing the inflammation and angiogenesis is extremely important in wound healing. In this study, we developed bioactive elastin-based hydrogels which can recruit and modulate the innate immune cells and accelerate angiogenesis in the wound site and subsequently improve wound regeneration. These hydrogels were formed by visible-light cross-linking of acryloyl-(polyethylene glycol)-N-hydroxysuccinimide ester modified elastin with methacrylated gelatin, in order to mimic dermal microenvironment. These hydrogels showed highly tunable mechanical properties, swelling ratios and enzymatic degradation profiles, with moduli within the range of human skin. To mimic the in vivo degradation of the elastin by elastase from neutrophils, in vitro co-culture of the hydrogels and neutrophils was conducted. The derived conditioned medium containing elastin derived peptides (EDP-conditioned medium) promoted the expression of both M1 and M2 markers in M1 macrophages in vitro. Additionally, the EDP-conditioned medium induced superior tube formation of endothelia cells in Matrigel. In mice wound model, these elastin-based hydrogels attracted abundant neutrophils and predominant M2 macrophages to the wound and supported their infiltration into the hydrogels. The outstanding immunomodulatory effect of the elastin-based hydrogels resulted in superior angiogenesis, collagen deposition and dermal regeneration. Hence, these elastin-based hydrogels can be a promising regenerative platform to accelerate wound repair.
ABSTRACT
Cell-penetrating peptides (CPPs), as non-viral gene delivery vectors, are considered with lower immunogenic response, and safer and higher gene capacity than viral systems. In our previous study, a CPP peptide called RALA (arginine rich) presented desirable transfection efficacy and owns a potential clinic use. It is believed that histidine could enhance the endosome escaping ability of CPPs, yet RALA peptide contains only one histidine in each chain. In order to develop novel superior CPPs, by using RALA as a model, we designed a series of peptides named HALA (increased histidine ratio). Both plasmid DNA (pDNA) and siRNA transfection results on three cell lines revealed that the transfection efficacy is better when histidine replacements were on the C-terminal instead of on the N-terminal, and two histidine replacements are superior to three. By investigating the mechanism of endocytosis of the pDNA nanocomplexes, we discovered that there were multiple pathways that led to the process and caveolae played the main role. During the screening, we discovered a novel peptide-HALA2 of high cellular transfection efficacy, which may act as an exciting gene delivery vector for gene therapy. Our findings also bring new insights on the development of novel robust CPPs.
ABSTRACT
Sea urchin Mesocentrotus nudus, Glyptocidaris crenularis, and Strongylocentrotus intermedius gonad protein isolates (mnGPIs, gcGPIs, and siGPIs) were extracted by isoelectric solubilization/precipitation (ISP) from the defatted gonads, and their functional properties were compared. Sodium dodecyl sulfate polyacrylamide gel electrophoresis results showed the similar protein pattern between each protein isolate and defatted gonad, indicating the high efficiency of ISP processing for protein recovery. Amino acid profileconfirmed that the mnGPIs and siGPIs could be potential sources of essential amino acid in nature. As regard to functional properties, mnGPIs showed higher water- and oil- holding capacities followed bysiGPIs and gcGPIs and all protein isolates presented great foaming property. As for emulsifying activity index (EAI), mnGPIs, gcGPIs, and siGPIs showed the minimum solubility and EAI at pH 5, 3, and 4, respectively, and behaved a pH-dependent manner. The gcGPIs revealed the highest EAI from pH 6 to 8 among the samples. In addition, circular dichroism showed increased content of ß-sheet at the expense of α-helix and ß-turn, suggesting the structure denaturation of the protein isolates. Indeed, no statistical difference was observed between secondary structure of mnGPIs and siGPIs. Moreover, ISP processing increased free sulfhydryl content of sea urchin protein isolates, but no difference was observed among the samples. Furthermore, siGPIs revealed the highest amount of total sulfhydryl and disulfide bonds, whereas both defatted gonads and protein isolates from G. crenularis presented the maximum surface hydrophobicity. These results suggest that gonad protein isolates from three species of sea urchin possess various functionalities and therefore can be potentially applied in food system. PRACTICAL APPLICATION: Sea urchin M. nudus, G. crenularis, and S. intermedius gonads are edible, whereas the functional properties of protein isolates from sea urchin gonad remain unknown. In this case, the extraction and comparison of three species of sea urchin gonad protein isolates will not only confirm functional properties but also screen food ingredients with suitable functions. In this study, functionalities of protein isolates derived from M. nudus, G. crenularis, and S. intermedius gonads would provide potential application in bakery food and meat products or as emulsifier candidates in food system.
Subject(s)
Gonads/chemistry , Proteins/chemistry , Sea Urchins/chemistry , Animals , Sea Urchins/classification , Strongylocentrotus/chemistryABSTRACT
To investigate the variation in the condition factor of the sea urchin Strongylocentrotus nudus (S. nudus), gonads were collected in May (MAY), June (JUN), and July (JUL), at the beginning (AUG-b) and end of August (AUG-e). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) detection of the gonads revealed an obvious enhancement of the band at about 37 kDa from July, which was identified as transforming growth factor-beta-induced protein ig-h3 (TGFBI) by nanoLC-ESI-MS/MS. Gonadal proteins were identified by isobaric tagging for relative and absolute quantitation (iTRAQ), and regulation of the identified proteins in pairs of the collected groups was observed. A total of 174 differentially expressed proteins (DEPs) were identified. Seven of the DEPs showed significant correlations with both the gonad index (GI) and protein content. These correlations included 6-phosphogluconate dehydrogenase, decarboxylating isoform X2 (6PGD), CAD protein, myoferlin isoform X8, ribosomal protein L36 (RL36), isocitrate dehydrogenase [NADP], mitochondrial isoform X2 (IDH), multifunctional protein ADE2 isoform X3, sperm-activating peptides (SAPs) and aldehyde dehydrogenase, and mitochondrial (ALDH). However, TGFBI had no correlation with gonad index (GI) or protein content. 6PGD, IDH, multifunctional protein ADE2 isoform X3, and ALDH were shown to interact with each other and might play key roles in changing the condition factor of S. nudus gonads.
Subject(s)
Proteome/metabolism , Sea Urchins/metabolism , Strongylocentrotus/metabolism , Animals , Extracellular Matrix Proteins/metabolism , Gonads/metabolism , Seasons , Transforming Growth Factor beta/metabolismABSTRACT
The complete mitochondrial genome of Solegnathus hardwickii was determined to be 16,519 bp long circular molecule with a typical gene arrangement of vertebrate mitochondrial. The complete mitochondrial genomes were obtained by conventional and long PCR. Tree constructed using maximum likelihood based on protein-coding genes and ribosomal RNAs showed close relationship of S. hardwickii with Hippocampus spp.
ABSTRACT
OBJECTIVE: To evaluate the long-term clinical effect of Tangyiping Granules (, TYP) on patients with impaired glucose tolerance (IGT) to achieve normal glucose tolerance (NGT) and hence preventing them from conversion to diabetes mellitus (DM). METHODS: In total, 127 participants with IGT were randomly assigned to the control (63 cases, 3 lost to follow-up) and treatment groups (64 cases, 4 lost to follow-up) according to the random number table. The control group received lifestyle intervention alone, while the patients in the treatment group took orally 10 g of TYP twice daily in addition to lifestyle intervention for 12 weeks. The rates of patients achieving NGT or experiencing conversion to DM as main outcome measure were observed at 3, 12, and 24 months after TYP treatment. The secondary outcome measures included fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-h insulin (2hINS), homeostatic model assessment of insulin resistance (HOMA-IR), blood lipid and patients' complains of Chinese medicine (CM) symptoms before and after treatment. RESULTS: A higher proportion of the treatment group achieved NGT compared with the control group after 3-, 12- and 24-month follow-up (75.00% vs. 43.33%, 58.33% vs. 35.00%, 46.67% vs. 26.67%, respectively, P<0.05). The IGT to DM conversion rate of the treatment group was significantly lower than that of the control group at the end of 24-month follow-up (16.67% vs. 31.67%, P<0.05). Before treatment, FPG, 2hPG, HbA1c, FINS, 2hINS, HOMA-IR, triglyceride (TG), total cholesterol, low- and high-density lipoprotein cholesterol levels had no statistical difference between the two groups (P>0.05). After treatment, the 2hPG, HbA1c, HOMA-IR, and TG levels of the treatment group decreased significantly compared with those of the control group (P<0.05). CM symptoms such as exhaustion, irritability, chest tightness and breathless, spontaneous sweating, constipation, and dark thick and greasy tongue were significantly improved in the treatment group as compared with the control group (P<0.05). No severe adverse events occurred. CONCLUSION: TYP administered at the IGT stage with a disciplined lifestyle delayed IGT developing into type 2 DM.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Glucose Intolerance/drug therapy , Blood Glucose/metabolism , Blood Platelets/drug effects , Blood Platelets/metabolism , Case-Control Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Drugs, Chinese Herbal/pharmacology , Erythrocytes/drug effects , Erythrocytes/metabolism , Female , Glucose Intolerance/blood , Humans , Insulin/blood , Kidney/drug effects , Kidney/physiopathology , Leukocytes/drug effects , Leukocytes/metabolism , Lipids/blood , Liver/drug effects , Liver/physiopathology , Male , Middle Aged , Time FactorsABSTRACT
PURPOSE: Tumor boundary delineation using F-FDG PET/CT is a promising tool for radiotherapy applications, but no consensus has been established regarding the optimal delineation method. Time-phase variability of F-FDG PET/CT imaging frequently affects metabolically active volumes and treatment planning for nasopharyngeal carcinoma (NPC). This study aimed to evaluate the time-phase robustness of 8 methods commonly used for tumor volume delineation in NPC. PATIENTS AND METHODS: Twenty patients with biopsy-proven NPC were included and underwent multiple time-phase F-FDG PET/CT imaging. Gross tumor volumes (GTVs), absolute SUV, gradient-based watershed segmentation (GTV-GWT), and anatomic biologic contouring (GTV-ABC) values were determined. The volume of overlap between GTV-CT and the 8 PET-based GTVs was enclosed and the overlap fraction (OF-CT) calculated. Color matrix was used to semiquantify the time-phase differences. Gross tumor volume values obtained with different methods were recorded and compared using paired t test. Time-phase differences of GTVs and SUVmax were compared among groups by analysis of variance with Tukey honest significance tests. The coefficients of variation were computed to assess intrapatient time-phase variability. Similarity coefficient was calculated to evaluate similarity. RESULTS: Differences were observed between GTVs obtained at different time points using various delineation procedures. Nonsignificantly higher percentages were obtained for GTV-GWT (88.17%) and GTV-ABC (86.98%) compared with other methods, showing their robustness. GTV-40% (0.81-0.88) and GTV-ABC (0.82-0.88) indicated higher similarity with GTV-MRI than the other methods. CONCLUSIONS: PET/CT-based GTV-ABC between 35 and 55 minutes should be the first choice for NPC treatment planning.
Subject(s)
Nasopharyngeal Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography , Radiotherapy Planning, Computer-Assisted/methods , Aged , Carcinoma , Female , Fluorodeoxyglucose F18 , Humans , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/pathology , Radiopharmaceuticals , Tumor BurdenABSTRACT
BACKGROUND: This analysis was conducted to evaluate the efficacy and safety of cisplatin based chemotherapy for treating patients with cutaneous squamous cell carcinoma. METHODS: Clinical studies evaluating the efficacy and safety of cisplatin based regimens on response and safety for patients with cutaneous squamous cell carcinoma were identified using a predefined search strategy. Pooled response rates (RR) of treatment were calculated. RESULTS: In cisplatin based regimens, 4 clinical studies which including 50 patients with advanced cutaneous squamous cell carcinoma were considered eligible for inclusion. Regimens included cisplatin, doxorubicin, or vindesine. Pooled analysis suggested that, in all patients, the pooled RR was 60% (30/50) in cisplatin based regimens. Nausea and vomiting were the main side effects. No grade III or IV renal or liver toxicity were observed. No treatment related death occurred with the cisplatin based treatments. CONCLUSION: Evidence based analysis suggests that cisplatin based regimens are associated with a good response rate and acceptable toxicity for treating patients with cutaneous squamous cell carcinoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Drug Resistance, Neoplasm/drug effects , Neoplasm Recurrence, Local/drug therapy , Salvage Therapy , Skin Neoplasms/drug therapy , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Cisplatin/administration & dosage , Doxorubicin/administration & dosage , Humans , Meta-Analysis as Topic , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Survival Rate , Vindesine/administration & dosageABSTRACT
Small ubiquitin-like modifier (SUMO) proteins regulate many important eukaryotic cellular processes through reversible covalent conjugation to target proteins. In addition to its many well-known biological consequences, like subcellular translocation of protein, subnuclear structure formation, and modulation of transcriptional activity, we show here that SUMO-2 also plays a role in mRNA translation. SUMO-2 promoted formation of the active eukaryotic initiation factor 4F (eIF4F) complex by enhancing interaction between Eukaryotic Initiation Factor 4E (eIF4E) and Eukaryotic Initiation Factor 4G (eIF4G), and induced translation of a subset of proteins, such as cyclinD1 and c-myc, which essential for cell proliferation and apoptosis. As expected, overexpression of SUMO-2 can partially cancel out the disrupting effect of 4EGI-1, a small molecule inhibitor of eIF4E/eIF4G interaction, on formation of the eIF4F complex, translation of the cap-dependent protein, cell proliferation and apoptosis. On the other hand, SUMO-2 knockdown via shRNA partially impaired cap-dependent translation and cell proliferation and promoted apoptosis. These results collectively suggest that SUMO-2 conjugation plays a crucial regulatory role in protein synthesis. Thus, this report might contribute to the basic understanding of mammalian protein translation and sheds some new light on the role of SUMO in this process.
Subject(s)
Eukaryotic Initiation Factor-4E/metabolism , Eukaryotic Initiation Factor-4G/metabolism , Protein Biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Small Ubiquitin-Related Modifier Proteins/metabolism , Apoptosis/genetics , Cell Proliferation , Cyclin D1/genetics , Cyclin D1/metabolism , Gene Expression Regulation , Genes, Reporter , HCT116 Cells , Humans , Hydrazones/pharmacology , Multiprotein Complexes/metabolism , Protein Binding/drug effects , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA Caps , Small Ubiquitin-Related Modifier Proteins/genetics , Thiazoles/pharmacologyABSTRACT
Isolated superficial inguinal metastases without any extended intra-abdominal spread is a rare event in patients with ovarian carcinoma. Here we report an isolated superficial inguinal metastasis in a patient with primary ovarian cancer. A 54-year-old Chinese patient with primary ovarian cancer, had an isolated painless enlarged right groin swelling (3×2cm) as the only manifestation, preoperative pathology confirmed metastatic adenocarcinoma. Gynecologic examination, transvaginal ultrasonography of the abdominopelvic cavity revealed a 5-cm mixed, right adnexal mass. At exploratory laparotomy, there was little intra-abdominal tumor dissemination but 100 ml of faint yellow peritoneal fluid and a 5-cm right ovarian tumor with intact capsule. Staging operation was performed and postoperative pathology confirmed adenocarcinoma located within right ovarian, with no evidence of involvement of other sites. Then the patient received adjuvant chemotherapy for Stage IVB. Five years later, the patient is currently still alive without evidence of recurrent disease. This case indicate that ovarian carcinoma isn't a disease localized only within the intra-peritoneal cavity, isolated superficial inguinal lymph node metastasis might occur in rare cases via potential lymphatic and (or) hematogenous route under special conditions. We propose the need to investigate the possible mechanisms, risk factors, metastatic patterns, the biology and natural history of such patients in a large-scale and multicenter analysis. Furthermore, efforts should be made for earlier and differential diagnosis and finally prolong survival time for such patients.
Subject(s)
Cystadenocarcinoma/secondary , Lymph Nodes/pathology , Ovarian Neoplasms/pathology , Biopsy, Fine-Needle , CA-125 Antigen/analysis , Chemotherapy, Adjuvant , Cystadenocarcinoma/chemistry , Cystadenocarcinoma/surgery , Female , Humans , Hysterectomy , Immunohistochemistry , Lymph Node Excision , Lymph Nodes/chemistry , Lymph Nodes/surgery , Lymphatic Metastasis , Membrane Proteins/analysis , Neoplasm Staging , Ovarian Neoplasms/chemistry , Ovarian Neoplasms/surgery , Ovariectomy , Salpingectomy , Time Factors , Treatment Outcome , Ultrasonography, Doppler, ColorABSTRACT
In this paper, VHESH, which was a novel set of amino acid descriptors including hydrophobic, electronic, steric, and hydrogen bond contribution properties, were proposed to characterize the structures of the decapeptides binding the human amphiphysin-1 Src homology 3 (SH3) domains, and QSAR model was constructed by partial least square (PLS) with genetic algorithm-variable selection. It was found that diversified properties of the residues between P(2) and P(-3) (including P(2) and P(-3)) of the decapeptide (P(4)P(3)P(2)P(1)P(0)P(-1)P(-2)P(-3)P(-4)P(-5)) may contribute remarkable effect to the interactions between the SH3 domain and decapeptides. Particularly, hydrogen bond and steric properties of P(2) and electronic properties, steric properties of P(-3) may provide relatively large positive contributions to the interactions. Based on the GA-PLS model, a series of decapeptides, with relatively high binding affinities were designed. These results showed that VHESH descriptors can well represent the decapeptides. Furthermore, the model obtained, which showed low computational complexity, correlated VHESH descriptors with the binding affinities as well as that VHESH may also be applied in QSAR studies of peptides.
Subject(s)
Amino Acids/chemistry , Nerve Tissue Proteins/chemistry , src Homology Domains/drug effects , Amino Acid Sequence , Humans , Hydrogen Bonding , Ligands , Oligopeptides , Protein Conformation , Quantitative Structure-Activity RelationshipABSTRACT
BACKGROUND: The quality of life has been greatly influenced and the cost of medical expenses is very high in patients with irritable bowel syndrome (IBS). The etiology and pathogenesis of IBS are still unclear, and the prevention and treatment of this disease still lack of effective methods. OBJECTIVE: To explore and analyze the effects of Tiaohe Ganpi Hexin Decoction (TGHD), a compound traditional Chinese herbal medicine for regulating the liver and spleen, on IBS patients with diarrhea. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: All 40 IBS patients came from the First Hospital of Jinan University, Guangzhou Red Cross Hospital, and the First Affiliated Hospital of Guangzhou University of Chinese Medicine, and were randomly divided into two groups. Patients in the treatment group (n=20) were given TGHD, while those in the control group (n=20) were prescribed oral pinaverium with a four-week treatment period. MAIN OUTCOME MEASURES: Traditional Chinese medicine (TCM) syndrome score, total obviously effective rate, disappearance rate of symptoms, and clinical symptom score in the two groups were evaluated before and after four-week treatment. RESULTS: After the treatment, TCM syndrome scores in both groups were decreased (P<0.01), and the TCM syndrome score in the treatment group was significantly lower than that in the control group (P<0.01). There was a significant difference in the total obviously effective rate between the two groups (P<0.01), and the total obviously effective rates in the treatment and control groups were 85%(17/20) and 45%(9/20) respectively. The disappearance rates of abdominal pain, abdominal distention, poor stool output, stool frequency, stool character and mucous stool in the treatment group were higher than those in the control group (P<0.05). The symptom scores of abdominal pain, abdominal distention, poor stool output, stool frequency, stool character and mucous stool in the treatment group were lower than those in the control group (P<0.05). CONCLUSION: TGHD can significantly improve the clinical symptoms in IBS patients with diarrhea.