Predicting In Vivo Anti-Hepatofibrotic Drug Efficacy Based on In Vitro High-Content Analysis

Background/Aims Many anti-fibrotic drugs with high in vitro efficacies fail to produce significant effects in vivo. The aim of this work is to use a statistical approach to design a numerical predictor that correlates better with in vivo outcomes. Methods High-content analysis (HCA) was performed with 49 drugs on hepatic stellate cells (HSCs) LX-2 stained with 10 fibrotic markers. ~0.3 billion feature values from all cells in >150,000 images were quantified to reflect the drug effects. A systematic literature search on the in vivo effects of all 49 drugs on hepatofibrotic rats yields 28 papers with histological scores. The in vivo and in vitro datasets were used to compute a single efficacy predictor (Epredict). Results We used in vivo data from one context (CCl4 rats with drug treatments) to optimize the computation of Epredict. This optimized relationship was independently validated using in vivo data from two different contexts (treatment of DMN rats and prevention of CCl4 induction). A linear in vitro-in vivo correlation was consistently observed in all the three contexts. We used Epredict values to cluster drugs according to efficacy; and found that high-efficacy drugs tended to target proliferation, apoptosis and contractility of HSCs. Conclusions The Epredict statistic, based on a prioritized combination of in vitro features, provides a better correlation between in vitro and in vivo drug response than any of the traditional in vitro markers considered.Institute of Bioengineering and Nanotechnology (Singapore)Singapore. Biomedical Research CouncilSingapore. Agency for Science, Technology and ResearchSingapore-MIT Alliance for Research and Technology Center (C-185-000-033-531)Janssen Cilag (R-185-000-182-592)Singapore-MIT Alliance Computational and Systems Biology Flagship Project (C-382-641-001-091)Mechanobiology Institute, Singapore (R-714-001-003-271

Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration via Estrogen Receptor Alpha in Female Mice

Temporomandibular joint degenerative disease (TMJ-DD) is a chronic form of TMJ disorder that specifically afflicts people over the age of 40 and targets women at a higher rate than men. Prevalence of TMJ-DD in this population suggests that estrogen loss plays a role in the disease pathogenesis. Thus, the goal of the present study was to determine the role of estrogen on chondrogenesis and homeostasis via estrogen receptor alpha (ERα) during growth and maturity of the joint. Young and mature WT and ERαKO female mice were subjected to ovariectomy procedures and then given placebo or estradiol treatment. The effect of estrogen via ERα on fibrocartilage morphology, matrix production, and protease activity was assessed. In the young mice, estrogen via ERα promoted mandibular condylar fibrocartilage chondrogenesis partly by inhibiting the canonical Wnt signaling pathway through upregulation of sclerostin (Sost). In the mature mice, protease activity was partly inhibited with estrogen treatment via the upregulation and activity of protease inhibitor 15 (Pi15) and alpha-2- macroglobulin (A2m). The results from this work provide a mechanistic understanding of estradiol on TMJ growth and homeostasis and can be utilized for development of therapeutic targets to promote regeneration and inhibit degeneration of the mandibular condylar fibrocartilage.National Institute of Dental & Craniofacial Research of the National Institutes of Health under Award Numbers R56DE020097 (SW) and F32DE026366 (JR

Current and Emerging Innovations in Minimally Invasive Caries and Endodontic Treatments

Deep carious lesions frequently lead to pulpal exposure and require subsequent root canal treatment in order to save the tooth. Unfortunately, this treatment is often unsuccessful in the long term with periapical disease as the result. New insights into the biological processes associated with pulpal healing and innovations in biocompatible capping agents have led to new treatment strategies, which can keep teeth vital and functional for longer. Dentine is a bioactive substance that releases growth factors when demineralised by carious processes, which has a positive effect on the regeneration of the pulp. Controlling caries in cavitated carious lesions should be attempted using methods which are aimed at biofilm removal and control. Only when cavitated carious dentine lesions are either non-cleansable, or can no longer be sealed, are restorative interventions indicated. Carious tissue is removed purely to create conditions suitable for long-lasting restoration. Bacterially contaminated or demineralised tissue close to the pulp does not need to be removed. To ascertain the state of the pulp, the symptoms observed are critical in determining the most appropriate treatment modality and often with only partial removal of inflamed pulp tissue, the remainder of the pulp can heal. The evidence and, therefore, these recommendations support minimally invasive carious lesion management in conjunction with less invasive endodontic treatment to preserve tooth tissue and maintain pulp viability and function in the long term.</p

A preliminary screening and characterization of suitable acids for sandstone matrix acidizing technique: a comprehensive review

Matrix acidizing is a broadly developed technique in sandstone stimulation to improve the permeability and porosity of a bottom-hole well. The most popular acid used is mud acid (HF–HCl). It is a mixture of hydrofluoric acid and hydrochloric acid. However, one of the conventional problems in sandstone acidizing is that mud acid faces significant issues at high temperature such as rapid rate of reaction, resulting in early acid consumption. This downside has given a negative impact to sandstone acidizing as it will result in not only permeability reduction, but can even extend to acid treatment failure. So, the aim of this study is to provide a preliminary screening and comparison of different acids based on the literature to optimize the acid selection, and targeting various temperatures of sandstone environment. This paper has comprehensively reviewed the experimental works using different acids to understand the chemical reactions and transport properties of acid in sandstone environment. The results obtained indicated that fluoroboric acid (HBF4) could be useful in enhancing the sandstone acidizing process, although more studies are still required to consolidate this conclusion. HBF4 is well known as a low damaging acid for sandstone acidizing due to its slow hydrolytic reaction to produce HF. This would allow deeper penetration of the acid into the sandstone formation at a slower rate, resulting in higher porosity and permeability enhancement. Nevertheless, little is known about the effective temperature working range for a successful treatment. Considering the pros and cons of different acids, particularly those which are associated with HF and HBF4, it is recommended to perform a comprehensive analysis to determine the optimum temperature range and effective working window for sandstone acidizing before treatment operation. Prior to sandstone acid stimulation, it is essential to predict the feasibility of acid selected by integrating the effects of temperature, acid concentration and injection rate. Therefore, this manuscript has thrown light into the research significance of further studies

Anti-trypanosomatid drug discovery:an ongoing challenge and a continuing need

The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.</p

Palmitic Acid-Induced Toxicity Reduction Due to Production of Triacylglycerol in Cardiac Muscle Cells by Linoleic Acid

BACKGROUND AND OBJECTIVE: Lipotoxicity-induced cardiovascular diseases are increasing significantly in human populations. The effect of linoleic acid in reducing lipotoxicity of cardiac muscle cells was investigated in this study. METHODS: In this empirical study, ventricular muscle cells from the hearts of five adult rats were cultured in 24-well plates. They were randomly treated in four groups including one control group (0.5 mM bovine serum albumin (BSA)) and three treatment groups treated with palmitic acid (0.5 mM), linoleic acid (0.25 mM) and a combination of linoleic acid and palmitic acid (0.25 mM + 0.5 mM). Wells in each row of plates were dedicated to one group. Level of cellular triacylglycerol, cellular diacylglycerol, DNA Fragmentation and survival rate was evaluated 24 and 48 hours after culturing. Each two wells belonging to each group were used to evaluate every factor and all the steps were repeated three times. FINDINGS: Compared with palmitic acid treatment alone, adding linoleic acid to palmitic acid decreased the level of DNA Fragmentation by 4.65% and 6.15% (p0.05). It also increased the level of cellular triacylglycerol by 40% and 44% (p<0.03) and increased cellular survival by 6.25% and 10.52% (p<0.01), respectively 24 and 48 hours after cultivation. CONCLUSION: Results of the study revealed that linoleic acid reduces the palmitic acid-induced toxicity by producing triacylglycero

Performance of Phosphate Solubilizing Bacteria with Various Phosphorus Levels on Wheat in Pot Culture

A pot experiment was conducted to investigate the effect of different phosphate solubilizing bacteria (PSB) with various levels of inorganic phosphorus (P) on the growth and yield of wheat with three soil at the Microbiology laboratory, Soil Science Division, Bangladesh Institute of Nuclear Agriculture (BINA), Mymensingh. Four levels of P fertilizer (P0 : Without P, P24 : 24 mg P kg-1 soil, P36 : 36 mg P kg-1 soil and P48 : 48 mg P kg-1 soil) were assigned as main factors and six PSB inoculants with an uninoculant (I0, MR1, IL1, IW1, IC2, RC1and MW1) were assigned as sub factors in a factorial CRD. The soil used for the experiment belong to three Agroecological Zones (AEZs) such as AEZ 9 from the BAU farm, Mymensingh, AEZ 28 from the BADC farm, Madhupur, Tangail and AEZ 11 from the BINA substation farm, Ishurdi, Pabna. Eight kilogram soils were taken in each of the plastic pot. PSB were applied as broth inoculants with the wheat seeds (var. Shatabdi) before sowing. Irrespective of the PSB inoculants, 36 mg P kg-1 soil gave the highest grain and straw yield of wheat pot-1 with Mymensingh and Mdhupur soil while 48 mg P kg-1 soil showed the highest wheat yield pot-1 with Ishurdi soil. Among the PSB inoculants, MR1 showed the maximum grain and straw yields of wheat pot-1 followed by MW1. The PSB inoculant MR1 with 36 mg P kg-1 soil had better performance in terms of total P uptake and grain and straw yields of wheat.DOI: http://dx.doi.org/10.3329/jesnr.v6i1.22069 J. Environ. Sci. &amp; Natural Resources, 6(1): 221-226 2013</jats:p