Antibiotic-resistant (AR) bacterial wound infections (WIs) impose major burdens on healthcare systems, exacerbated by ineffective therapies and stalled antibiotic development. Phage therapy and phage-derived enzymes have gained traction as potent alternatives, leveraging targeted bactericidal mechanisms to combat AR pathogens. In this review, we summarised the antimicrobial mechanisms of both phage therapy and phage-derived enzymes as antimicrobial therapy, and outlined recent advances in their use for in vitro , in vivo and clinical applications for WI management. In addition, we also highlights recent advancements in their development, driven by genetic engineering, chemical modifications, and artificial intelligence. Finally, we identified the potential barriers and challenges they may encounter in clinical practice and the corresponding strategies to address these issues. The entire review gives us a comprehensive understanding of the latest advances in phages and their derivative enzyme therapies for treating WIs, in the hope that research in this field will continue to improve and innovate, accelerating the transition from the laboratory to application at the bedside and ultimately improving the efficacy of treatment for AR bacterial WIs.
Humans ; Phage Therapy/methods* ; Wound Infection/drug therapy* ; Bacteriophages/enzymology* ; Enzyme Therapy/methods* ; Animals ; Bacterial Infections/therapy*

Lysosomal storage disorders (LSDs) are a group of single-gene inherited metabolic diseases caused by defects in lysosomal enzymes or function-related proteins. Enzyme replacement therapy is the main treatment method in clinical practice, but it has a poor effect in patients with neurological symptoms. With the rapid development of multi-omics, sequencing technology, and bioengineering, gene therapy has been applied in patients with LSDs. As one of the vectors of gene therapy, adeno-associated virus (AAV) has good prospects in the treatment of genetic and metabolic diseases. More and more studies have shown that AAV-mediated gene therapy is effective in LSDs. This article reviews the application of AAV-mediated gene therapy in LSDs.
Humans ; Dependovirus/genetics* ; Genetic Therapy/methods* ; Lysosomal Storage Diseases/therapy* ; Enzyme Replacement Therapy ; Proteins/genetics*

OBJECTIVES: Ovarian hormones have been shown to regulate body weight, intra-abdominal fat accumulation and plasma level of cytokines. The aim of this study was to investigate the effect of estrogen replacement therapy on visceral adipose tissue, plasma level of apelin, lipid profiles, and glucose in ovariectomized (OVX) rats. METHODS: Thirty female Wistar rats were divided into OVX (n = 20) and sham (n = 10) groups. OVX rats were subdivided into estrogen replacement therapy (OVX+est; n = 10) receiving 17 β-estradiol valerates (30 µg/kg, s.c., 5 day/week, for eight weeks), and vehicle control group receiving sesame oil same as experiment group (OVX+ses oil; n = 10). After the treatments, all groups were sacrificed and blood samples were collected, visceral fats were taken from the abdominal cavity and weighed immediately. Apelin were measured using enzyme-linked immunosorbent assay kits. Lipid profiles and glucose were measured using the enzymatic colorimetric method. Data were analyzed with one-way analysis of variance and (P < 0.05) determined as the statistical significance level. RESULTS: After eight weeks, body weight, body mass index (BMI), visceral fat, apelin and lipid profiles (P < 0.01) were increased significantly in OVX rats compared to sham group. Treatment with estrogen leads to significant reduction in body weight and BMI (P < 0.05), there was no significant change in serum apelin level in OVX+est rats compared to OVX+ses. CONCLUSIONS: These results suggest that estradiol replacement therapy successfully attenuated some of the metabolic syndrome components, and apelin does not probably stand as a mediator of these physiological functions.
Abdominal Cavity ; Animals ; Blood Glucose* ; Body Mass Index ; Body Weight ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Estradiol ; Estrogen Replacement Therapy* ; Estrogens* ; Female ; Glucose ; Humans ; Intra-Abdominal Fat* ; Methods ; Plasma ; Rats* ; Rats, Wistar ; Sesame Oil ; Valerates

Secondary hypertension occurs in a significant proportion of adult patients (~10%). In young patients, renal causes (glomerulonephritis) and coarctation of the aorta should be considered. In older patients, primary aldosteronism, obstructive sleep apnoea and renal artery stenosis are more prevalent than previously thought. Primary aldosteronism can be screened by taking morning aldosterone and renin levels, and should be considered in patients with severe, resistant or hypokalaemia-associated hypertension. Symptoms of obstructive sleep apnoea should be sought. Worsening of renal function after starting an angiotensin-converting enzyme inhibitor suggests the possibility of renal artery stenosis. Recognition, diagnosis and treatment of secondary causes of hypertension lead to good clinical outcomes and the possible reversal of end-organ damage, in addition to blood pressure control. As most patients with hypertension are managed at the primary care level, it is important for primary care physicians to recognise these conditions and refer patients appropriately.
Aldosterone ; blood ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Aortic Coarctation ; complications ; diagnosis ; Blood Pressure ; Glomerulonephritis ; complications ; diagnosis ; Humans ; Hyperaldosteronism ; diagnosis ; Hypertension ; complications ; diagnosis ; therapy ; Primary Health Care ; methods ; Referral and Consultation ; Renal Artery Obstruction ; drug therapy ; Renin ; blood ; Sleep Apnea, Obstructive ; complications

BACKGROUND/AIMS: We investigated the time of onset of antituberculous drug-induced hepatotoxicity (ADIH) and related characteristics. METHODS: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. RESULTS: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of 39.6 +/- 43.7 days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The < or = 30-day group was characterized by higher peak alanine aminotransferase (ALT) level and a high proportion of patients with maintenance of first-line antituberculous drugs compared to the > 30-day group. In subgroup analysis, the < or = 7-day group was characterized by higher baseline aspartate aminotransferase and ALT, high proportion of patients with maintenance of first-line antituberculous drugs, and high proportion of patients with extrapulmonary tuberculosis compared to patients with ADIH that developed beyond 7 days. In multivariate analysis, serum ALT > 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. CONCLUSIONS: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first-line drug regimen.
Adult ; Aged ; Alanine Transaminase/blood ; Antitubercular Agents/*adverse effects ; Aspartate Aminotransferases/blood ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/*diagnosis/etiology ; Chi-Square Distribution ; Clinical Enzyme Tests ; Coinfection ; Drug Monitoring/*methods ; Drug Therapy, Combination ; Early Diagnosis ; Female ; Hepatitis/complications/diagnosis ; Humans ; *Liver Function Tests ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Predictive Value of Tests ; Retrospective Studies ; Risk Factors ; Time Factors

BACKGROUND/AIMS: Angiotensin II type 1 receptor blockers (ARBs) have not been adequately evaluated in patients without left ventricular (LV) dysfunction or heart failure after acute myocardial infarction (AMI). METHODS: Between November 2005 and January 2008, 6,781 patients who were not receiving angiotensin-converting enzyme inhibitors (ACEIs) or ARBs were selected from the Korean AMI Registry. The primary endpoints were 12-month major adverse cardiac events (MACEs) including death and recurrent AMI. RESULTS: Seventy percent of the patients were Killip class 1 and had a LV ejection fraction > or = 40%. The prescription rate of ARBs was 12.2%. For each patient, a propensity score, indicating the likelihood of using ARBs during hospitalization or at discharge, was calculated using a non-parsimonious multivariable logistic regression model, and was used to match the patients 1:4, yielding 715 ARB users versus 2,860 ACEI users. The effect of ARBs on in-hospital mortality and 12-month MACE occurrence was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality(1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to0.756; p = 0.006) and 12-month MACE occurrence (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051). CONCLUSIONS: Our results suggest that ARBs are not inferior to, and may actually be better than ACEIs in Korean patients with AMI.
Angiotensin II Type 1 Receptor Blockers/adverse effects/*therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/adverse effects/*therapeutic use ; Chi-Square Distribution ; Hospital Mortality ; Humans ; Kaplan-Meier Estimate ; Logistic Models ; Multivariate Analysis ; Myocardial Infarction/diagnosis/*drug therapy/mortality/physiopathology ; Proportional Hazards Models ; Prospective Studies ; Recurrence ; Registries ; Republic of Korea ; Risk Factors ; Secondary Prevention/*methods ; Stroke Volume ; Time Factors ; Treatment Outcome ; Ventricular Function, Left

PURPOSE: Angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) are associated with a decreased incidence of new-onset diabetes mellitus (NODM). The aim of this study was to compare the protective effect of ACEI versus ARBs on NODM in an Asian population. MATERIALS AND METHODS: We investigated a total of 2817 patients who did not have diabetes mellitus from January 2004 to September 2009. To adjust for potential confounders, a propensity score matched (PSM) analysis was performed using a logistic regression model. The primary end-point was the cumulative incidence of NODM, which was defined as having a fasting blood glucose > or =126 mg/dL or HbA1c > or =6.5%. Multivariable cox-regression analysis was performed to determine the impact of ACEI versus ARB on the incidence of NODM. RESULTS: Mean follow-up duration was 1839+/-1019 days in all groups before baseline adjustment and 1864+/-1034 days in the PSM group. After PSM (C-statistics=0.731), a total 1024 patients (ACEI group, n=512 and ARB group, n=512) were enrolled for analysis and baseline characteristics were well balanced. After PSM, the cumulative incidence of NODM at 3 years was lower in the ACEI group than the ARB group (2.1% vs. 5.0%, p=0.012). In multivariate analysis, ACEI vs. ARB was an independent predictor of the lower incidence for NODM (odd ratio 0.37, confidence interval 0.17-0.79, p=0.010). CONCLUSION: In the present study, compared with ARB, chronic ACEI administration appeared to be associated with a lower incidence of NODM in a series of Asian cardiovascular patients.
Adult ; Aged ; Angiotensin Receptor Antagonists/*therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/*therapeutic use ; Asian Continental Ancestry Group/*statistics & numerical data ; Blood Glucose/analysis ; Diabetes Mellitus/*diagnosis/*epidemiology ; Dose-Response Relationship, Drug ; Drug Monitoring/methods ; Female ; Follow-Up Studies ; Humans ; Hypertension/*drug therapy ; Incidence ; Kaplan-Meier Estimate ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Propensity Score ; Republic of Korea/epidemiology ; Risk Factors

OBJECTIVETo explore the effect of short peptides specifically binding to highly metastatic human ovarian cancer HO8910PM cells and their effect on the biological behavior of ovarian cancer cells.

METHODSThe phage-displayed peptide library was used to isolate the peptides binding and internalizing into the HO8910PM cells. Positive phage clones were characterized with DNA sequencing and bioinformatics analysis. The positive phage clones specifically bound to HO8910 cells were validated with immunofluorescence detection and enzyme-linked immunosorbent assay (ELISA). Furthermore, selected peptides were investigated for their cancer-related functions, including cell adhesion, spreading, motility, and invasion in vitro and in nude mice in vivo. The apoptotic index was detected by TUNEL assay, and VEGF expression by immunohistochemistry.

RESULTSAfter 4 rounds of screening, apparent enrichment of phages was observed on the HO8910PM cells. ELISA assay showed that among the randomly selected 20 phage clones, 12 can specifically bind to HO8910PM cells. Immunofluorescence assay also showed that the selected positive phage clones can specifically bind to HO8910PM cells. The adherence test showed that the adherence rates of HO8910PM-peptide20, HO8910PM-peptide16 and HO8910PM cells were 49.0%, 96.8% and 100.0%, respectively. There was a significant difference between the cell adherence rates of HO8910PM-peptide20 and HO8910PM cells (P < 0.05). The peptide20 read as "THRVHLH" was a positive peptide and showed preferential binding to targeted cells. The peptide20 effectively inhibited tumor growth and metastasis in the nude mice, and the positive rates of VEGF protein in the tumor tissue of experimental, negative control and blank mice were 21.2%, 81.4% and 85.7%, respectively, showing that the positive rate of VEGF protein in the experimental group was significantly lower than that in the negative control and blank groups (P < 0.01), and the apoptotic index (AI) of the experimental group was (18.21 ± 2.49)%, significantly higher than the (3.76 ± 1.77)% in the negative control group and the (4.78 ± 1.57)% in the blank group (P < 0.01).

CONCLUSIONSA novel short peptide able to specifically bind to highly metastatic human ovarian cancer cells is successfully screened. It can effectively inhibit the growth, invasion and metastasis of ovarian cancer cells, and provides an ideal vector in targeted drug therapy for ovarian cancer.

Animals ; Base Sequence ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Enzyme-Linked Immunosorbent Assay ; Female ; Genetic Vectors ; Humans ; Immunohistochemistry ; Mice ; Mice, Nude ; Molecular Targeted Therapy ; methods ; Neoplasms, Glandular and Epithelial ; metabolism ; Ovarian Neoplasms ; metabolism ; Peptide Library ; Peptides ; metabolism

Identification and validation of a new target is one of the most important steps for new antituberculosis (TB) drug discovery. Researches have shown that Mycobacterium tuberculosis (Mtb) encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets. In this paper, the phylogenetic analysis, the structural features, and the enzymatic functions of Mtb CYPs, as well as the mechanism of interactions with selective inhibitors such as azole antifungal agents for the CYPs have been reviewed and summarized. The druggability of the CYPs has also been analyzed for their further utility as targets in high throughput screening and rational design of more selective inhibitors.
Antitubercular Agents ; chemistry ; pharmacology ; Azoles ; chemistry ; pharmacology ; Cytochrome P-450 Enzyme Inhibitors ; chemistry ; pharmacology ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Drug Delivery Systems ; methods ; Drug Discovery ; Humans ; Mycobacterium tuberculosis ; drug effects ; enzymology ; genetics ; Phylogeny ; Tuberculosis ; drug therapy ; microbiology

Phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB, Akt) pathway plays a major role in proliferation and survival of many types of cells. The inhibitory effect of LY294002, widely applied as an inhibitor of PI3K, in combination with gemcitabine on proliferation of PANC-1 cells was investigated. The expression of PI3K, phosphorylated Akt (p-Akt) and multidrug-resistance like protein (MRP) in normal pancreas tissues, chronic pancreatitis tissues and pancreatic carcinoma tissues was detected. The effects of LY294002 combined with gemcitabine on proliferation of PANC-1 cells and protein levels of p-Akt and MRP were detected. The results showed that the positive expression rate of PI3K, p-Akt and MRP in pancreatic carcinoma tissues was significantly higher than that in normal pancreas tissues and chronic pancreatitis tissues (P<0.01 and P<0.05 respectively). LY294002 could effectively enhance the inhibitory effect of gemcitabine on proliferation of PANC-1 cells. Furthermore, Western blotting revealed that LY294002 combined with gemcitabine reduced the protein levels of p-Akt and MRP, which contributed to the inhibition of proliferation. It is concluded that LY294002 in combination with gemcitabine may represent an alternative therapy for pancreatic carcinoma.
Adult ; Antimetabolites, Antineoplastic ; administration & dosage ; Cell Proliferation ; drug effects ; Chromones ; administration & dosage ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; methods ; Enzyme Inhibitors ; administration & dosage ; Female ; Humans ; Male ; Middle Aged ; Morpholines ; administration & dosage ; Pancreatic Neoplasms ; drug therapy ; pathology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Treatment Outcome ; Tumor Cells, Cultured