A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.

Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.

Paraesophageal hernia repair: a curative consideration for chronic anemia?

INTRODUCTION: Chronic anemia is a common, coinciding or presenting diagnosis in patients with paraesophageal hernia (PEH). Presence of endoscopically identified ulcerations frequently prompts surgical consultation in the otherwise asymptomatic patient with anemia. Rates of anemia resolution following paraesophageal hernia repair (PEHR) often exceed the prevalence of such lesions in the study population. A defined algorithm remains elusive. This study aims to characterize resolution of anemia after PEHR with respect to endoscopic diagnosis. MATERIALS AND METHODS: Retrospective review of a prospectively maintained database of patients with PEH and anemia undergoing PEHR from 2007 to 2018 was performed. Anemia was determined by preoperative labs: Hgb < 12 mg/dl in females, Hgb < 13 mg/dl in males, or patients with ongoing iron supplementation. Improvement of post-operative anemia was assessed by post-operative hemoglobin values and continued necessity of iron supplementation. RESULTS: Among 56 identified patients, 45 were female (80.4%). Forty patients (71.4%) were anemic by hemoglobin value, 16 patients (28.6%) required iron supplementation. Mean age was 65.1 years, with mean BMI of 27.7 kg/m2. One case was a Type IV PEH and the rest Type III. 32 (64.0%) had potential source of anemia: 16 (32.0%) Cameron lesions, 6 (12.0%) gastric ulcers, 12 (24.0%) gastritis. 10 (20.0%) had esophagitis and 4 (8%) Barrett's esophagus. 18 (36%) PEH patients had normal preoperative EGD. Median follow-up was 160 days. Anemia resolution occurred in 46.4% of patients. Of the 16 patients with pre-procedure Cameron lesions, 10 (63%) had resolution of anemia. Patients with esophagitis did not achieve resolution. 72.2% (13/18) of patients with no lesions on EGD had anemia resolution (p = 0.03). CONCLUSION: Patients with PEH and identifiable ulcerations showed 50% resolution of anemia after hernia repair. Patients without identifiable lesions on endoscopy demonstrated statistically significant resolution of anemia in 72.2% of cases. Anemia associated with PEH adds an indication for surgical repair with curative intent.

Systematic review of ultrasound visual biofeedback in intervention for speech sound disorders.

BACKGROUND: As cost and access barriers to ultrasound technology have decreased, interest in using ultrasound visual biofeedback (U-VBF) as a tool for remediating speech sound disorders (SSD) has increased. A growing body of research has investigated U-VBF in intervention for developmental SSD; however, diversity in study design, participant characteristics, clinical methods and outcomes complicate the interpretation of this literature. Thus, there is a need for a synthesis and review of the evidence base for using U-VBF in intervention for SSD. AIMS: To synthesise and evaluate the research evidence for U-VBF in intervention for developmental SSD. METHODS: A systematic review was conducted. Eight electronic databases were searched for peer-reviewed articles published before 2018. Details about study design, participants, intervention procedures, service delivery, intervention intensity and outcomes were extracted from each study that met the inclusion criteria. The included studies were rated using both a critical appraisal tool and for their reporting of intervention detail. MAIN CONTRIBUTIONS: Twenty-eight papers, comprising 29 studies, met the inclusion criteria. The most common research design was single-case experimental design (44.8% of studies). The studies included between one and 13 participants (mean = 4.1) who had a mean age of approximately 11 years (range = 4;0-27 years). Within the research evidence, U-VBF intervention was typically provided as part of, or as an adjunct to, other articulatory-based therapy approaches. A range of lingual sounds were targeted in intervention, with 80.6% of participants across all reviewed studies receiving intervention targeting rhotics. Outcomes following therapy were generally positive with the majority of studies reporting that U-VBF facilitated acquisition of targets, with effect sizes ranging from no effect to a large effect. Difficulties with generalisation were observed for some participants. Most studies (79.3%) were categorised as efficacy rather than effectiveness studies and represented lower levels of evidence. Overall, the reviewed studies scored more highly on measures of external validity than internal validity. CONCLUSIONS: The evidence base for U-VBF is developing; however, most studies used small sample sizes and lower strength designs. Current evidence indicates that U-VBF may be an effective adjunct to intervention for some individuals whose speech errors persist despite previous intervention. The results of this systematic review underscore the need for more high-quality and large-scale research exploring the use of this intervention in both controlled and community contexts.

Cost-effectiveness of rivaroxaban versus warfarin for treatment of nonvalvular atrial fibrillation in patients with worsening renal function.

BACKGROUND: Nonvalvular atrial fibrillation (NVAF) is highly prevalent and increases the risks of cardiovascular events. In a recent subgroup analysis, treatment response was shown to vary for patients exhibiting worsening renal function (WRF) on-treatment. It is important to understand the cost-effectiveness of novel oral anticoagulant (NOAC) use in this population. METHODS: A cost-effectiveness analysis (CEA) was conducted using a Markov model to determine whether NOAC rivaroxaban treatment is cost-effective relative to warfarin in NVAF patients with on-treatment WRF. Input parameters were sourced from clinical literature including a multicenter clinical trial and subgroup analysis. We studied elderly US male patients at increased risk for stroke (CHADS2 score ≥ 2) undergoing treatment for NVAF and exhibiting WRF. Main outcome measures included total healthcare costs in 2017 US dollars (societal perspective), total quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net monetary benefits (INMB) per-patient. RESULTS: The remaining lifetime use of rivaroxaban is associated with 5.69 QALYs at a cost of $66,075 per patient, while warfarin produced 5.22 QALYs with costs of $78,504 per patient. At a willingness-to-pay (WTP) of $150,000 per QALY, incremental net monetary benefits (INMB) per patient are $83,590. In our population, treatment with warfarin was dominated by rivaroxaban in 99.4% of 10,000 simulations. CONCLUSIONS: Rivaroxaban is likely a dominant treatment over warfarin in elderly US male NVAF patients exhibiting WRF, providing increased QALYs at a decreased overall cost. Application of these findings may require healthcare providers to predict which patients are likely to exhibit WRF.

Research and Development of Proteins and Peptides with Therapeutic Potential from Yam Tubers.

We discuss the diverse biological activities, therapeutic potential, and clinical applications of peptides and proteins isolated from various yams species including Dioscorea opposita Thunb (Chinese yam), D alata, D japonica (Japanese yam), D pseudojaponica, D batatas (Korea yam), and D cayenensis. Yam peptides and proteins have many pharmacological activities including immunomodulatory, antioxidant, estrogen-stimulating, osteogenic, angiotensin I-converting enzyme inhibiting, carbonic anhydrase and trypsin inhibiting, chitinase, anti-insect, anti-dust mite, lectin, and anti-proliferative activities. Yam peptides and proteins have therapeutic potential for treating cardiovascular diseases, inflammatory diseases, cancers, aging disorders, menopause, and osteoporosis.

TRIF-dependent Toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-ß (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells. The aggravated steatosis in Trif-/- mice was due to the increased hepatocyte transcription of the gene encoding stearoyl-coenzyme A (CoA) desaturase 1 (SCD1), the rate-limiting enzyme for lipogenesis. Activation of the TRIF pathway by polyinosinic:polycytidylic acid [poly(I:C)] suppressed the increase in SCD1 abundance induced by palmitic acid or an HFD and subsequently prevented lipid accumulation in hepatocytes. Interferon regulatory factor 3 (IRF3), a transcriptional regulator downstream of TRIF, acted as a transcriptional suppressor by directly binding to the Scd1 promoter. These results suggest an unconventional metabolic function for TLR/TRIF signaling that should be taken into consideration when seeking to pharmacologically inhibit this pathway.

Steroidogenic effect of Erxian decoction for relieving menopause via the p-Akt/PKB pathway in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Erxian decoction (EXD), an empirical Chinese medicine formula, is effectively used in the clinical treatment of menopause-related symptoms in China. Previous data from our group show that EXD has steroidogenic effect on natural menopausal Sprague-Dawley-rats (SD-rats) as an animal model of menopause. However, the mechanistic studies on steroidogenic effects of EXD are still inadequate. Hence, the mechanisms of steroidogenic effects of EXD were studied in vitro and in vivo in this study. MATERIALS AND METHODS: Menopause causes a decline of endocrine function and a series of symptoms. In this study, 16-20-month-old female SD rats with a low serum estradiol level were employed. Their endocrine functions after treatment with EXD (4.1g/kg) were assessed by determination of their serum estradiol level. Proteins involved in the steroidogenic pathway including StAR, 17ßHSD, 3ßHSD, aromatase, and activation of phosphorylated Protein Kinase B (p-Akt/PKB), as well as estradiol receptor proteins (ERα & ERß) after EXD treatment were analyzed. Kinase inhibition assay was conducted to confirm the mechanism of steroidogenic effects of EXD in vitro. MCF-7 and BT-483 cells were used to investigate whether EXD stimulated breast cancer cell proliferation. RESULTS: Results revealed a significantly ameliorated serum estradiol level, and a significantly increased expression of ovarian aromatase and PKB in the EXD-treated rats. EXD attenuated 17ß-estradiol stimulated proliferation of breast cancer cells. CONCLUSIONS: The results obtained from immunoblotting and measurements of serum estradiol level of the present investigation revealed that EXD may relieve the menopausal syndrome through an upregulation of ovarian aromatase and p-PKB expression without stimulating the growth of breast cancer cells.

Network pharmacological identification of active compounds and potential actions of Erxian decoction in alleviating menopause-related symptoms.

BACKGROUND: Erxian decoction (EXD) is used to treat menopause-related symptoms in Chinese medicine. This study aims to identify the bioactive compounds and potential actions of EXD by network pharmacological analysis. METHODS: Two databases, the Traditional Chinese Medicine Systems Pharmacology database and TCM Database@Taiwan, were used to retrieve literature of phytochemicals of EXD. STITCH 4.0 and the Comparative Toxicogenomics Database were used to search for compound-protein and compound-gene interactions, respectively. DAVID Bioinformatics Resources 6.7 and Cytoscape 3.01 with Jepetto plugin software were used to perform a network pharmacological analysis of EXD. RESULTS: A total of 721 compounds were identified in EXD, of which 155 exhibited 2,656 compound-protein interactions with 1,963 associated proteins determined by STITCH4.0 database, and of which 210 had 14,893 compound-gene interactions with 8,536 associated genes determined by Comparative Toxicogenomics Database. Sixty three compounds of EXD followed the Lipinski's Rule with OB ≥30% and DL index ≥0.18, of which 20 related to 34 significant pathway- or 12 gene- associated with menopause. CONCLUSIONS: Twenty compounds were identified by network pharmacology as potential effective ingredients of EXD for relieving menopause with acceptable oral bioavailability and druggability.

A Novel, Stable, Estradiol-Stimulating, Osteogenic Yam Protein with Potential for the Treatment of Menopausal Syndrome.

A novel protein, designated as DOI, isolated from the Chinese yam (Dioscorea opposita Thunb.) could be the first protein drug for the treatment of menopausal syndrome and an alternative to hormone replacement therapy (HRT), which is known to have undesirable side effects. DOI is an acid- and thermo-stable protein with a distinctive N-terminal sequence Gly-Ile-Gly-Lys-Ile-Thr-Thr-Tyr-Trp-Gly-Gln-Tyr-Ser-Asp-Glu-Pro-Ser-Leu-Thr-Glu. DOI was found to stimulate estradiol biosynthesis in rat ovarian granulosa cells; induce estradiol and progesterone secretion in 16- to 18-month-old female Sprague Dawley rats by upregulating expressions of follicle-stimulating hormone receptor and ovarian aromatase; counteract the progression of osteoporosis and augment bone mineral density; and improve cognitive functioning by upregulating protein expressions of brain-derived neurotrophic factor and TrkB receptors in the prefrontal cortex. Furthermore, DOI did not stimulate the proliferation of breast cancer and ovarian cancer cells, which suggest it could be a more efficacious and safer alternative to HRT.