Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.     

Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures,NAC doses,and routes of administration

Conclusion. These studies extend previous work on N-acetyl-l-cysteine (NAC) and noise, showing protection with NAC against a high-kurtosis noise, showing protection with NAC at low doses, as well as protection by oral gavage. The studies further reveal the potential for the use of NAC in a clinical population exposed to noise. Objective. To extend previous work on NAC protection from noise, the current study examined the effectiveness of NAC against a high-kurtosis noise that combined continuous and impact noise, tested the effectiveness of NAC at varying doses, and tested NAC when administered by gavage. Materials and methods. Chinchillas were tested for auditory brainstem responses (ABRs) at five frequencies before and at three time points after one of three noise exposures: high-kurtosis (2 h, 108 dB L_eq), impulse (75 pairs of 155 dB pSPL impulses), or continuous (4 kHz octave band, 105 dB SPL for 6 h). Animals were treated with NAC or saline vehicle before and after noise. Results. The NAC was protective against the high-kurtosis noise both at low doses and when given orally by gavage.     

Cell Death by Polyvinylpyrrolidine-Coated Silver Nanoparticles is Mediated by ROS-Dependent Signaling

Silver nanoparticles (AgNPs) are widely used nanoparticles and they are mainly used in antibacterial and personal care products. In this study, we evaluated the effect of AgNPs on cell death induction in the murine dendritic cell line DC2.4. DC2.4 cells exposed to AgNPs showed a marked decrease in cell viability and an induction of lactate dehydrogenase (LDH) leakage in a time- and dose-dependent manner. In addition, AgNPs promoted reactive oxygen species (ROS)-dependent apoptosis and AgNP-induced ROS triggered a decrease in mitochondrial membrane potential. The activation of the intracellular signal transduction pathway was also observed in cells cultured with AgNPs. Taken together, our data demonstrate that AgNPs are able to induce a cytotoxic effect in DCs through ROS generation. This study provides important information about the safety of AgNPs that may help in guiding the development of nanotechnology applications.     

Pomegranate Extract Attenuates Gentamicin-Induced Nephrotoxicity in Rats by Reducing Oxidative Stress

Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe Gram-negative infections. Reactive oxygen species are important mediators of GEN-induced nephrotoxicity. Because of the strong antioxidant properties of pomegranate extract (PE), we evaluated the protective effect of PE against GEN-induced nephrotoxicity. Thirty-two adult male rats were randomly divided into four equal groups: (1) controls; (2) treated with GEN for 14 consecutive days (100 mg/kg/day); (3) treated with GEN plus distilled water; and (4) treated with GEN plus PE (100 μL). After 15 days, the rats were killed and their kidneys were taken, and blood analysis was performed. Tubular necrosis and interstitial fibrosis scores were determined histopathologically; and biochemically, nitric oxide (NO), malondialdehyde (MDA), and reduced glutathione (GSH) levels in kidneys were determined. Urea, creatinine, Na⁺, and K⁺ levels were investigated in the blood analysis. Statistical analyses were made by the chi-square test and analysis of variance. Serum urea and creatinine levels were significantly higher in rats treated with GEN alone than rats in the control and the GEN + PE-treated groups. The GSH level in renal tissue of only GEN-treated rats was significantly lower than those in the control group, and administration of PE to GEN-treated rats significantly increased the level of GSH. The group that was given GEN and PE had significantly lower MDA levels in kidney cortex tissue than those given GEN alone. There was no significant difference of NO levels between the groups. In rats treated with GEN + PE, despite the presence of mild tubular degeneration and tubular necrosis is less severe, and glomeruli maintained a better morphology when compared with the GEN-treated group. We think that PE prevents kidney damage by decreasing oxidative stress in kidney.     

Mechanisms of liver involvement in systemic disease

The liver may be injured during the course of many systemic diseases. The mechanisms of injury can be broadly divided into four pathways: vascular, toxic, immune, and hormonal. Vascular obstruction may be an early event but is also the late common pathway from all mechanisms. Despite the large number of possible initiating factors, the end results are few, including death of hepatocytes or cholangiocytes, leading to the stereotyped syndromes of acute liver failure, non-cirrhotic portal hypertension, or cirrhosis. This small number of outcomes is a reflection of the few anatomic patterns that can be generated by microvascular obstruction. Vascular obstruction may occur by thrombosis, inflammation, or congestive injury. The innate immunity pathway is activated by endotoxin and other agents, leading to inflammatory infiltration, release of cytokines and reactive oxygen species, and necrosis. The adaptive immune pathway involves the generation of antibodies and antigen-specific cell-mediated attack on hepatic cells. Hormonal effects are principally involved when overnutrition leads to hyperinsulinemia followed by hepatocellular necrosis.     

Isolation and characterisation of mineral-oxidising “Acidibacillus” spp. from mine sites and geothermal environments in different global locations

Eight strains of acidophilic bacteria, isolated from mine-impacted and geothermal sites from different parts of the world, were shown to form a distinct clade (proposed genus “Acidibacillus”) within the phylum Firmicutes, well separated from the acidophilic genera Sulfobacillus and Alicyclobacillus. Two of the strains (both isolated from sites in Yellowstone National Park, USA) were moderate thermophiles that oxidised both ferrous iron and elemental sulphur, while the other six were mesophiles that also oxidised ferrous iron, but not sulphur. All eight isolates reduced ferric iron to varying degrees. The two groups shared <95% similarity of their 16S rRNA genes and were therefore considered to be distinct species: “Acidibacillus sulfuroxidans” (moderately thermophilic isolates) and “Acidibacillus ferrooxidans” (mesophilic isolates). Both species were obligate heterotrophs; none of the eight strains grew in the absence of organic carbon. “Acidibacillus” spp. were generally highly tolerant of elevated concentrations of cationic transition metals, though “A. sulfuroxidans” strains were more sensitive to some (e.g. nickel and zinc) than those of “A. ferrooxidans”. Initial annotation of the genomes of two strains of “A. ferrooxidans” revealed the presence of genes (cbbL) involved in the RuBisCO pathway for CO₂ assimilation and iron oxidation (rus), though with relatively low sequence identities.     

辽吉两省部分鹿场鹿茸皮肤病的临床特征与真菌分离初探

目的 研究探讨生茸期梅花鹿、马鹿在鹿茸快速生长期常发生以“白皮茸”、“痂皮茸”为主要症状的皮肤病。方法 研究对吉林、辽宁8个梅花鹿、马鹿养殖场的20份患病鹿进行了临床观察、血细胞计数、病理观察、病原分离及ITS分子鉴定。结果 发现本病仅侵染鹿茸皮肤表层、主要病变为结痂处真皮组织坏死、炎性细胞浸润; 血液中淋巴细胞、白细胞和中性粒细胞数变化不明显。对茸皮患处分离菌的鉴定结果表明68株分离株中44株属于半知菌亚门(64.7%), 24株属于酵母亚门(35.3%), 其中, 半知菌亚门的毛癣菌属、表皮癣菌属以及酵母亚门的念珠菌等可能为本病的条件致病菌。结论 鹿茸“白皮茸”、“痂皮茸”病均符合真菌皮肤病的发病特征,为该类疾病的预防及治疗提供了一定的参考。