Beneficial health effects of lupeol triterpene: a review of preclinical studies

Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol and triterpene, is widely found in edible fruits, and vegetables. Extensive research over the last three decades has revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies suggest that lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in vivo models, lupeol has also been tested for its therapeutic efficiency against conditions including wound healing, diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells. Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as cytokines IL-2, IL4, IL5, ILβ, proteases, α-glucosidase, cFLIP, Bcl-2 and NFκB. This minireview discusses in detail the preclinical studies conducted with lupeol and provides an insight into its mechanisms of action.     

Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies

Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.     

Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature

Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin’s potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin’s role in management of posterior segment disorders. However, given metformin’s proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.     

In vivo imaging in experimental preclinical tumor research--a review.

The multiparametric molecular cell and tissue analysis in vitro and in vivo is characterized by rapid progress in the field of image generation technologies, sensor biotechnology, and computational modeling. Fascinating new potentials in unraveling the detailed functions of single cells, organs, and whole organisms are presently emerging and permit the close monitoring i.e. tumor development or basic cell development processes with an unprecedented multiplicity of promising investigative possibilities. To answer basic questions of in vivo tumor development and progression fluorescence based imaging techniques provide new insights into molecular pathways and targets. Genetic reporter systems (eGFP, DsRED) are available and high sensitive detection systems are on hand. These techniques could be used for in vitro assays and quantified e.g. by microscopy and CCD based readouts. The introduction of novel fluorescent dyes emitting in the near infrared range (NIR) combined with the development of sensitive detector systems and monochromatic powerful NIR-lasers for the first time permits the quantification and imaging of fluorescence and/or bioluminescence in deeper tissues. Laser based techniques particularly in the NIR-range (like two-photon microscopy) offer superb signal to noise ratios, and thus the potential to detect molecular targets in vivo. In combination with flat panel volumetric computed tomography (fpVCT), questions dealing e.g. with tumor size, tumor growth, and angiogenesis/vascularization could be answered noninvasively using the same animal. The resolution of down to 150 microm/each direction can be achieved using fpVCT. It is demonstrated by many groups that submillimeter resolutions can be achieved in small animal imaging at high sensitivity and molecular specificity. Since the resolution in preclinical small animal imaging is down to approximately 10 microm by the use of microCT and to subcellular resolutions using ( approximately 1 microm) microscope based systems, the advances of different techniques can now be combined to "multimodal" preclinical imaging and the possibilities for in vivo intravital cytometry now become within one's reach.     

Next-generation optimized biotherapeutics — A review and preclinical study

Biotherapeutics have been clinically used since the 1990s. Recently, next-generation optimized biotherapeutics, which are expected to act on the same molecular target as their predecessors with further properties by antibody–drug conjugation, radiolabeling, PEGylation and glycoconjugation, are on the market. This article reviews recent next-generation optimized biotherapeutics. Moreover, since trials of protein engineering for biotherapeutics have been conducted, these preclinical approaches are also described. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody.     

A highly multiplexed quantitative phosphosite assay for biology and preclinical studies

Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug treatment in cells and tissues but are presently lacking. Here, we present SigPath, a targeted mass spectrometry (MS) assay that measures 284 phosphosites in 200 phosphoproteins of biological interest. SigPath probes a broad swath of signaling biology with high throughput and quantitative precision. We applied the assay to investigate changes in phospho‐signaling in drug‐treated cancer cell lines, breast cancer preclinical models, and human medulloblastoma tumors. In addition to validating previous findings, SigPath detected and quantified a large number of differentially regulated phosphosites newly associated with disease models and human tumors at baseline or with drug perturbation. Our results highlight the potential of SigPath to monitor phosphoproteomic signaling events and to nominate mechanistic hypotheses regarding oncogenesis, response, and resistance to therapy.     

Behavioral pharmacology of designer cathinones: A review of the preclinical literature

“Bath salts” is one street name for a family of synthetic cathinones that display pharmacological effects resembling cocaine and commonly abused amphetamines. Despite extensive legislation aimed at the criminalization of bath salts, several designer cathinones are gaining a foothold in the illicit drug scene; for example, in the United Kingdom, mephedrone (4-methylmethcathinone, MEPH) is highly popular among drug abusers whereas, in the United States, MDPV (methylenedioxypyrovalerone) and methylone are highly prevalent. To date, knowledge about the hazards of designer cathinones is based mostly on hospital reports and anecdotal evidence derived from online surveys. Despite the paucity of preclinical studies directed toward designer cathinones, a number of invaluable findings arising from those studies are enabling scientists to develop their neuropharmacological profiles. Despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce different behavioral effects, including unique effects on locomotor activity, learning, anxiety, thermoregulation, and abuse liability. The present review will discuss the behavioral effects of MEPH, MDPV, and methylone and compare those effects to established psychostimulant drugs. The rise in the use of designer cathinones in the United States and abroad justifies further investigations into these compounds, both for a greater understanding of the danger that “bath salts” pose to the public, and to provide insight into replacement cathinones as they emerge onto the market.     

Beta多样性研究进展

Beta多样性度量时空尺度上物种组成的变化, 是生物多样性的重要组成部分, 与许多生态学和进化生物学问题密切相关, 并且其信息可用于保护区选址和布局规划, 因此在最近10年间成为生物多样性研究的热点问题之一。多年来, 学者们利用各种度量方式和分析方法, 在不同地理区域, 对许多生物类群beta多样性的时空格局和形成机制进行了大量研究。本文主要从beta多样性的度量方法、时空格局、形成机制及其在生物多样性保护中的应用等几个方面, 总结了最近10多年来相关研究的进展。Whittaker(1960)最初提出beta多样性概念时就缺乏严格的定义, 随着概念的不断演化, 度量方法也同样呈现出多样化, 而度量手段的多样化非常不利于不同研究之间的比较。目前应用最普遍的度量方法是采用相似性指数, 如Jaccard和Sørensen指数。最近几年, 新的度量方法还在不断出现, 其中一些方法非常值得注意。Beta多样性具有时空尺度和分类尺度依赖性, 一般随分析粒度(grain)的增加而降低。虽然有些研究表明beta多样性随纬度增加而降低, 但学者们并没有达成共识。山区和生物地理区的交界处beta多样性都比较高, 因而需要在这些地区增加保护区的面积或者数量以囊括物种变化梯度。对时间尺度上beta多样性的研究表明, 气候变化确实导致了物种组成在时间上的变化, 并且物种在不同大陆和地区间的迁移导致了生物同质化。扩散过程和生态位过程共同决定了beta多样性, 只是这两个过程的相对重要性依尺度、地理区域和物种类群的不同而有所差异。综上所述, 我们认为未来beta多样性研究的热点问题是：(1)不同生物类群的进化历史和生物学特征对beta多样性的影响; (2)不同的时空尺度对beta多样性及其维持机制的影响; (3)人类活动对beta多样性的影响。     

家域研究进展

家域是动物行为学和保护生物学的重要概念之一,它在动物对资源环境的适应与选择,种群密度及社会关系等生态学过程研究中有着重要的作用.对家域的内涵、特征、估算方法(包括取样方法,样本含量,位点数据自相关,模型评价等)等方面进行阐述,总结了家域估算模型的发展过程及发展方向,评述了3种主要家域估算模型的优势与不足,并结合最新的理论和应用,对未来的研究方向提出建议.     

APP mouse models for Alzheimer's disease preclinical studies

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.     

Use of CRISPR/Cas9 gene editing to improve chimeric antigen-receptor T cell therapy: A systematic review and meta-analysis of preclinical studies

BackgroundChimeric antigen-receptor T (CAR-T) cells represent great promise in cancer treatment. CRISPR/Cas9 gene editing in preclinical studies has enabled the development of enhanced CAR-T products with improved function and reduced toxicity.MethodsA systematic review of preclinical animal studies was conducted to determine the efficacy and safety of this approach.Results3753 records were identified (to September 9, 2020), with 11 studies using CRISPR/Cas9 gene editing in combination with CAR-T therapy against human cells in animal models of acute leukemia (four studies), glioma (two studies), melanoma (two studies), and other cancers (three studies). Compared with unedited controls, gene-edited CAR-T cells reduced tumor volume in treated animals and improved survival. No adverse side effects were reported. Use of allogeneic “third-party” CAR-T cells appears feasible. Improved efficacy was achieved through both knock-in and knockout gene editing of various targets implicated in immune function. Targeting multiple genes also appears feasible. Significant heterogeneity in study design and outcome reporting was observed, and potential bias was identified in all studies.Conclusion: CRISPR/Cas9 gene editing enables manufacturing of CAR-T cells with improved anti-cancer effects. Future studies should reduce unintentional bias and heterogeneity of study designs and strive to augment long-term persistence of edited cells.Protocol registration: PROSPERO; registration number CRD42020220313 registered November 30, 2020     

景观边界研究概况

景观边界指在特定时空尺度下 ,相对均质的景观之间所存在的异质景观[6 9] 。过去 ,生态学家的注意力往往集中在景观边界两侧的同质区域来研究生态系统的结构和过程 ,忽视生态系统间的异质区域 ,它们在地图上往往被忽视或缩成一条线。但是 ,景观边界是一个客观存在的空间实体 ,有自己特定的结构和功能。由于景观边界包含有不同类型和不同尺度上的均质景观和异质景观 ,因而它具有等级结构[13] ,同时景观边界都有长度和宽度 ,在此范围内 ,相邻景观单元的小斑块交叉出现 ,因此景观边界是相邻景观单元相互转化的发生区。从景观的演替过程可以看出…     

A review of epidemiologic studies of vasectomy

A number of epidemiologic studies of vasectomy have been published in recent years. These studies have been methodologically diverse and have involved several groups of investigators in several countries. The studies are consistent in finding no long-term effects of vasectomy on the risk of cardiovascular disease, cancer, impotence, prostatic disease, or disease related to immune function and dysfunction. Continued follow-up of vasectomized men to evaluate further the possibility of adverse effects of vasectomy is recommended. At this time, epidemiologic studies of vasectomy in man are strongly reassuring. Vasectomy decreases prostatic secretory function. In a study conducted by Sidney, no association was found between vasectomy and benign prostatic hypertrophy or prostatic cancer. Massey et al. found that the incidence of impotence was 1.9/1000 man-years of observation in men with vasectomy and 1.7/1000 man-years in non-vasectomized men, a difference that was not statistically significant. 3 studies examining the risk of malignant and nonmalignant neoplasms in vasectomized and nonvasectomized men revealed that vasectomy was not associated with an increased risk of malignant or nonmalignant neoplasms.     

植物大年结实研究概述

大年结实指一个指物种群在不同年份同时产生具有很大变化的种子产量,这种生殖特征普遍存在于多年生植物中,是植物有性生殖过程中的一个重要进化对策。植物种子产量的周期性变化和种群内不同个体结实的同步程度是植物大年结实的两个重要特征。本文对大年结实的有关假说以及各自依据和缺陷进行了分析,讨论了植物种群内不同个体生殖同步性的程度和时间尺度的延续和空间尺度的异质性。     

昆虫趋光性研究的回顾

利用昆虫的趋光性开展农林卫生害虫诱杀,一直是害虫绿色防控的组成部分。本文综述了昆虫的多种趋光性行为,昆虫趋光性机制—罗盘理论、马赫带效应理论和开放空间理论,对在物理、生物环境条件、光和光源属性条件下昆虫趋光的生态适应性,以及对昆虫抵达光源的位置和移动轨迹进行了讨论。     

Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice

Preclinical studies of enzyme-replacement therapy for Fabry disease (deficient alpha-galactosidase A [alpha-Gal A] activity) were performed in alpha-Gal A-deficient mice. The pharmacokinetics and biodistributions were determined for four recombinant human alpha-Gal A glycoforms, which differed in sialic acid and mannose-6-phosphate content. The plasma half-lives of the glycoforms were approximately 2-5 min, with the more sialylated glycoforms circulating longer. After intravenous doses of 1 or 10 mg/kg body weight were administered, each glycoform was primarily recovered in the liver, with detectable activity in other tissues but not in the brain. Normal or greater activity levels were reconstituted in various tissues after repeated doses (10 mg/kg every other day for eight doses) of the highly sialylated AGA-1 glycoform; 4 d later, enzyme activity was retained in the liver and spleen at levels that were, respectively, 30% and 10% of that recovered 1 h postinjection. Importantly, the globotriaosylceramide (GL-3) substrate was depleted in various tissues and plasma in a dose-dependent manner. A single or repeated doses (every 48 h for eight doses) of AGA-1 at 0.3-10.0 mg/kg cleared hepatic GL-3, whereas higher doses were required for depletion of GL-3 in other tissues. After a single dose of 3 mg/kg, hepatic GL-3 was cleared for > or =4 wk, whereas cardiac and splenic GL-3 reaccumulated at 3 wk to approximately 30% and approximately 10% of pretreatment levels, respectively. Ultrastructural studies demonstrated reduced GL-3 storage posttreatment. These preclinical animal studies demonstrate the dose-dependent clearance of tissue and plasma GL-3 by administered alpha-Gal A, thereby providing the in vivo rationale-and the critical pharmacokinetic and pharmacodynamic data-for the design of enzyme-replacement trials in patients with Fabry disease.