Computational and bioinformatics tools for understanding disease mechanisms

Computational methods have significantly transformed biomedical research,offering a comprehensive exploration of disease mechanisms and molecular protein functions.This article reviews a spectrum of computational tools and network analysis databases that play a crucial role in identifying potential interactions and signaling networks contributing to the onset of disease states.The utilization of protein/gene interaction and genetic variation databases,coupled with pathway analysis can facilitate the identification of potential drug targets.By bridging the gap between molecular-level information and disease understanding,this review contributes insights into the impactful utilization of computational methods,paving the way for targeted interventions and therapeutic advancements in biomedical research.

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Effect of Dietary Resistant Starch on Prevention and Treatment of Obesity-related Diseases and Its Possible Mechanisms

Overweight or obesity has become a serious public health problem in the world, scientists are concentrating their efforts on exploring novel ways to treat obesity. Nowadays, the availabilities of bariatric surgery and pharmacotherapy have enhanced obesity treatment, but it should has support from diet, physical exercise and lifestyle modification, especially the functional food. Resistant starch, an indigestible starch, has been studied for years for its beneficial effects on regulating blood glucose level and lipid metabolism. The aim of this review is to summarize the effect of resistant starch on weight loss and the possible mechanisms. According to numerous previous studies it could be concluded that resistant starch can reduce fat accumulation, enhance insulin sensitivity, regulate blood glucose level and lipid metabolism. Recent investigations have focused on the possible associations between resistant starch and incretins as well as gut microbiota. Resistant starch seems to be a promising dietary fiber for the prevention or treatment of obesity and its related diseases.

Okadaic acid: a tool to study regulatory mechanisms for neurodegeneration and regeneration in Alzheimer's disease

Okadaic acid： Okadaic acid （OKA）, a polyether （C38 fatty acid） toxin, is a potent and selective inhibitor of protein phosphatase, PP1 and protein phosphatase 2A （PP2A）. It is mainly extracted from a black sponge Hallichondria okadaii and has been suggested to play a potent probe for studying the various molecular, cellular, biochemical and mechanism of neurotoxicity. It is known as a selective and potent in- hibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. It has been reported that Alzheimer＇s disease （AD） is a complex multi- factorial neurodegenerative disorder and hyperphosphor- ylated tau protein is a major pathological hallmark of AD. The reduced activity of phosphatases like, PP2A has been implicated in the brain of AD patients. OKA also induced inhibition of protein phosphatases cause neurofibrillary tangles （NFTs） like pathological changes and tau hyperphos- phorylation seen in AD pathology. Our and others reports inferred that OKA induces neurodegeneration along with tau hyperphosphorylation, GSK3β activation, oxidative stress, neuroinflammation and neurotoxicity which are char- acteristic of AD pathology （Figure 1）.

The brain compensatory mechanisms and Alzheimer's disease progression:a new protective strategy

Compensatory/adaptive mechanisms in the brain are hy- pothesized to be involved in its protection from the Alz- heimer＇s disease （AD） progression. These mechanisms are activated by malfunctioning of various brain systems： anti- oxidant, neurotrophic, neurotransmitter, immune, and oth- ers. Detailed analysis of compensatory^adaptive capabilities of these systems might be a start point for further discovery and development of perspective approaches for early diag- nostics and treatment of AD and associated neurodegenera- tive disorders.

Hydrogen sulfide responsive nanoplatforms: Novel gas responsive drug delivery carriers for biomedical applications

Hydrogen sulfide(H_(2)S)is a toxic,essential gas used in various biological and physical processes and has been the subject of many targeted studies on its role as a new gas transmitter.These studies have mainly focused on the production and pharmacological side effects caused by H_(2)S.Therefore,effective strategies to remove H_(2)S has become a key research topic.Furthermore,the development of novel nanoplatforms has provided new tools for the targeted removal of H_(2)S.This paper was performed to review the association between H_(2)S anddisease,relatedH_(2)S inhibitory drugs,aswell as H_(2)S responsive nanoplatforms(HRNs).This review first analyzed the role of H_(2)S in multiple tissues and conditions.Second,common drugs used to eliminate H_(2)S,as well as their potential for combination with anticancer agents,were summarized.Not only the existing studies on HRNs,but also the inhibition H_(2)S combined with different therapeutic methods were both sorted out in this review.Furthermore,this review provided in-depth analysis of the potential of HRNs about treatment or detection in detail.Finally,potential challenges of HRNs were proposed.This study demonstrates the excellent potential of HRNs for biomedical applications.

Streptozotocin induced Alzheimer's disease like changes and the underlying neural degeneration and regeneration mechanism

Alzheimer’s disease（AD）is a neurodegenerative disorder which is remarkably characterized by pathological hallmarks that include neurofibrillary tangles,neuronal loss extracellular senile plaques containing aggregated amyloid beta（Aβ）,and neurofibrillary tangles composed of the hyperphosphorylated form of the microtubule protein tau.It is the most common form of dementia which is characterized by severe neurodegenerative changes such as loss of neurons and synapses in brain（Kamat et al.,2014）.

Computational and theoretical modeling of intermediate filament networks:Structure,mechanics and disease

Intermediate filaments, in addition to microtubules and actin microfilaments, are one of the three major components of the cytoskeleton in eukaryotic cells. It was discovered during the recent decades that in most cells, intermediate filament proteins play key roles to reinforce cells subjected to large-deformation, and that they participate in signal transduction, and it was proposed that their nanome- chanical properties are critical to perform those functions. However, it is still poorly understood how the nanoscopic structure, as well as the combination of chemical composition, molecular structure and interfacial properties of these protein molecules contribute to the biomechanical properties of filaments and filament networks. Here we review recent progress in computational and theoretical studies of the intermediate filaments network at various levels in the protein＇s structure. A multiple scale method is discussed, used to couple molecular modeling with atomistic detail to larger-scale material properties of the networked material. It is shown that a finer-trains-coarser method- ology as discussed here provides a useful tool in understanding the biomechanical property and disease mechanism of intermediate filaments, coupling experiment and simulation. It further allows us to improve the understanding of associated disease mechanisms and lays the foundation for engineering the mechanical properties of biomaterials.

Melastatin-related transient receptor potential 2 channel in Aβ_(42)-induced neuroinflammation: implications to Alzheimer's disease mechanism and development of therapeutics

Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.

Tetrahydrohyperforin(IDN5706) targets the endoplasmic reticulum for autophagy activation： potential mechanism for Alzheimer＇s disease therapy

Alzheimer’s disease（AD）is the most common form of dementia worldwide among the older population.To date,there is no therapy to stop the destruction of brain cells and all the available treatments only compensate for the loss of synaptic transmission,thus resulting in marginal benefits to patients.

Gut microbiota axis:potential target of phytochemicals from plant-based foods

Food-microbiota-host interactions provide an overarching framework for understanding the function of the gut microbiota axis.Diet is a major modulator of gut microbiota.Plant-based foods are rich in phytochemicals;therefore,it is essential to assess such foods and elucidate the mechanisms underlying their action.In this review,we summarize the role of gut microbiota in the communication between the gut and the brain,liver,lung,kidney,and joints,as well as the role of the gut microbiota axis in diseases involving these organs.In addition,we assess the effects of phytochemicals from plant-based foods on the gut microbiota axis via different pathways.

Protect Sick Prisoners' Rights Through Regulation and Innovation——Chengdu launches coordinating mechanism for sick prisoners with major diseases

In May 2011, the Prison Management Bureau of Sichuan Province in Southwest China held a conference in its capital city Chengdu to discuss the management of severely sick prisoners. Coordinating Management on Major Diseases of Sick Prisoners in Sichuan （Trial） was issued then, marking the start of an overall deployment.

Why do we study animal toxins?

Venom （toxins） is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance and the coevolutionary patterns with other organisms are greatly helpful in understanding many fundamental biological questions, i.e., the environmental adaptation and survival competition, the evolution shaped development and balance of venoms, and the sophisticated correlations among venom, immunity, body power, intelligence, their genetic basis, inherent association, as well as the cost-benefit and trade-offs of biological economy. Lethal animal envenomation can be found worldwide However, from foe to friend, toxin studies have led lots of important discoveries and exciting avenues in deciphering and fighting human diseases, including the works awarded the Nobel Prize and lots of key clinic therapeutics. According to our survey, so far, only less than 0.1% of the toxins of the venomous animals in China have been explored. We emphasize on the similarities shared by venom and immune systems, as well as the studies of toxin knowledge-based physiological toxin-like proteins/peptides （TLPs）. We propose the natural pairing hypothesis. Evolution links toxins with humans. Our mission is to find out the right natural pairings and interactions of our body elements with toxins, and with endogenous toxin-like molecules. Although, in nature, toxins may endanger human lives, but from a philosophical point of view, knowing them well is an effective way to better understand ourselves. So, this is why we study toxins.

The transmission mechanism theory of disease dynamics:Its aims,assumptions and limitations

Most of the progress in the development of single scale mathematical and computational models for the study of infectious disease dynamics which now span over a century is build on a body of knowledge that has been developed to address particular single scale descriptions of infectious disease dynamics based on understanding disease transmission process.Although this single scale understanding of infectious disease dynamics is now founded on a body of knowledge with a long history,dating back to over a century now,that knowledge has not yet been formalized into a scientific theory.In this article,we formalize this accumulated body of knowledge into a scientific theory called the transmission mechanism theory of disease dynamics which states that at every scale of organization of an infectious disease system,disease dynamics is determined by transmission as the main dynamic disease process.Therefore,the transmission mechanism theory of disease dynamics can be seen as formalizing knowledge that has been inherent in the study of infectious disease dynamics using single scale mathematical and computational models for over a century now.The objective of this article is to summarize this existing knowledge about single scale modelling of infectious dynamics by means of a scientific theory called the transmission mechanism theory of disease dynamics and highlight its aims,assumptions and limitations.

Effects of extrinsic positive end-expiratory pressure on work of breathing in patients with chronic obstructive pulmonary disease

Objective To investigate the effects of extrinsic positive end-expiratory pressure (PEEPe) on work of breathing in patients with chronic obstructive pulmonary disease (COPD) and their corresponding mechanism.Methods Ten ventilated patients with COPD were included in the study. A Bicore CP-100 pulmonary monitor (Bicore Monitoring System, USA) was used for monitoring respiratory mechanics. First, dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn) was measured when PEEPe was zero, which was called PEEPi,dynz. Then the PEEPe was set randomly at 0%, 40%, 60%, 80% and 100% of PEEPi,dynz respectively. Pulmonary mechanics and other parameters (heart rate, blood pressure and blood gas analysis) were measured 30 minutes after the level of PEEPe was changed.Results Work of breathing patient (WOBp), pressure time product, difference of esophageal pressure and PEEPi,dyn decreased significantly when PEEPe was applied, and continued decreasing as PEEPe was increased. Work of breathing ventilator increased significantly when PEEPe was increased to 80% and 100% of PEEPi,dynz. Significantly positive linear correlation was found between the changes in WOBp and in PEEPi,dyn.Conclusions WOBp decreases gradually as PEEPe is increased. WOBp decreases by narrowing the difference between the alveolus pressure and the central airway pressure at the end of expiration when PEEPe is applied.

Effects of extrinsic positive end-expiratory pressure on cardiopulmonary function in patients with chronic obstructive pulmonary disease

Objective To choose one optimal extrinsic positive end-expiratory pressure (PEEPe) for ventilated patients with chronic obstructive pulmonary disease (COPD) and to compare two methods for choosing the optimal level of PEEPe.Methods Ten ventilated patients with COPD were included in the study. First, static intrinsic positive end-expiratory pressure (PEEPi,st) was measured when PEEPe was zero, and the PEEPi,st was called PEEPi,stz. PEEPe at 0%, 40%, 50%, 60%, 70%, 80%, 90% and 100% of PEEPi,stz, respectively, were applied randomly. Respiratory mechanics, hemodynamics, and oxygen dynamics were recorded 30 minutes after the level of PEEPe was changed.Results When PEEPe was not higher than 80% of PEEPi,stz, no measurement changed significantly. When PEEPe was increased to 90% and 100% of PEEPi,stz, PEEPi,st, peak inspiratory pressure, plateau pressure, pulmonary capillary wedge pressure and central venous pressure increased significantly, P<0.01. Cardiac output and left ventricular work index decreased significantly, P<0.01. Oxygen delivery decreased significantly, P<0.05. When PEEPe was increased to 100% of PEEPi,stz, the right ventricular work index decreased significantly, P<0.05.Conclusion Eighty percent of PEEPi,stz was the upper limit of PEEPe. The results of the two methods used to set the level of PEEPe were identical.

iBIG:An Integrative Network Tool for Supporting Human Disease Mechanism Studies

Understanding the mechanism of complex human diseases is a major scientitic challenge. Towards this end, we developed a web-based network tool named iBIG （stands for integrative BioloGy）, which incorporates a variety of information on gene interaction and regulation. The generated network can be annotated with various types of information and visualized directly online. In addition to the gene networks based on physical and pathway interactions, networks at a functional level can also be constructed. Furthermore, a supplementary R package is provided to process microarray data and generate a list of important genes to be used as input for iBIG. To demonstrate its usefulness, we collected 54 microarrays on common human diseases including cancer, neurolog- ical disorders, infectious diseases and other common diseases. We processed the microarray data with our R package and constructed a network of functional modules perturbed in common human diseases. Networks at the functional level in combination with gene networks may provide new insight into the mechanism of human diseases, iBIG is freely available at http：//lei.big.ac.cn/ibig.

CLINICAL OUTCOMES OF 22 PEDIATRIC PATIENTS WITH CONGENITAL HEART DISEASE MANAGED WITH MECHANICAL CIRCULATORY SUPPORT AFTER CARDIAC SURGERY

Objective To investigate the clinical outcomes of children with congenital heart disease （CHD） requiring extracorporeal membrane oxygenation （ECMO） and left ventricular assist device （LVAD） support after cardiac surgery. Methods A total of 22 patients with CHD who required postcardiotomy mechanical circulatory support between March 2004 and March 2011 （85 months ） were analyzed retrospectively. Median age of the patients was 420 d （ 15 d - 4 years） and median weight was 3.4 kg （ 2 - 14. 5 kg ）. Eight patients were put on ECMO, while 14 patients were placed on LVAD. Results Thirteen （59%） patients died and 9 （41% ） survived to discharge. In survivals, the duration of LVAD and the duration of ECMO were both shorter than those of nonsurvivals （P 〈 O. 05）. The main complication was bleeding. Conclusion The earlier treatment and application of more advanced cardiac support devices for CHD patients are key factors for reducing complications.

Attractor landscape analysis of the cardiac signaling network reveals mechanism-based therapeutic strategies for heart failure

Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure （HF）, a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the development of effective treatments due to its complexity. To identify effective therapeutic strategies for HF at a system level, we develop a large-scale comprehensive mathematical model of the cardiac signaling network by integrating all available experimental evidence. Attractor landscape analysis of the network model identifies distinct sets of control nodes that effectively suppress apoptosis and hypertrophy of cardiomyocytes under ischemic or pressure overload-induced HF, the two major types of HF. Intriguingly, our system-level analysis suggests that intervention of these control nodes may increase the efficacy of clinical drugs for HF and, of most importance, different combinations of control nodes are suggested as potentially effective candidate drug targets depending on the types of HF. Our study provides a systematic way of developing mechanism-based therapeutic strategies for HF.

In vitro Metabolomic Approaches to Investigating the Potential Biological Effects of Phenolic Compounds:An Update

Dietary phenolic compounds （PCs） have been receiving intercst lor their presumcd roles ill disease prevention. However, there is a lack of studies on the underlying molecular mechanisnls. In this regard, in vitro metabolomic approaches are suitable for the investigation o1 the molecular changes in response to PC exposure. Up to date, the biological effects of PCs have only been cxalnined for PCs from rosemary （Rosmarinus officinalis）, olive oil, and reSVCl-atrol using cell-based mctabolomic approach, although transcriptomic and/or proteomic studies have also been conducted in the same in vi[ro cell experiment in some cases. Our integral analysis of the reviewed studies suggest that PCs may be involved not only in basic cellular processes or macro-and micro-nutrient meta- bolism, but also in specific metabolic pathways that have been thoroughly investigated. These modulated pathways could have a clinical impact on neurodegenerativc diseases, type 2 diabetes, cancer, and cardiovascular diseases. In conclusion, the in vitro metabolomic approaches provide additional information of the molecular mechanisms involved in disease risk reduction of dietary PCs. In order to elucidate the mechanisms of action of PCs, more metabolomic cell-based studies are nccdcd and testing the physiological conjugated forms of PCs in these cell systems could be of special interest.