Main Target Research Articles

Exploring the Therapeutic Potential of Alkaloids in Alzheimer's Disease Management.

Alkaloids are important phytoconstituents obtained from various plant sources. The study's primary goal is to assess the anti-Alzheimer potential of alkaloids using a molecular docking study. Alzheimer's disease (AD) is considered a gradual decline in memory, reasoning, decision-making, orientation to one's physical surroundings, and language. The main target i.e. acetylcholinesterase proteins was selected for the molecular docking study. The structures of various alkaloids were drawn using Chem Draw Software, PDB was retrieved from the RCSB PDB database, and molecular docking study was performed on Molergo Virtual Docker. The potential alkaloids were identified with anti-Alzheimer potency. Reserpine, vinblastine, ergotamine, and tubocurarine were found to exhibit potential anti-Alzheimer potency.

Network Pharmacology-Based and Molecular Docking combined with GEO gene chips to Investigate the Potential Mechanism of Duhuo Jisheng Decoction against Rheumatoid Arthritis.

Background： Rheumatoid Arthritis (RA) is a chronic autoimmune disease with various symptoms in patients. Duhuo Jisheng Decoction (DHJSD) has been used to treat RA in China for a long history as a classic TCM formula. However, the underlying pharmacological mechanism still needs to be elucidated. Purpose： In the current study, we combined network pharmacology with molecular docking to investigate the potential mechanism of DHJSD treating RA. Methods: The active compounds and related targets of DHJSD were obtained from the TCMSP database. The RA targets were retrieved from the GEO database. The PPI network of overlapping targets was constructed, whereas the core genes were selected by CytoNCA for molecular docking. GO and KEGG enrichment analyses were used to further explore the biological process and pathways of overlapping targets. On this basis, molecular docking was carried out to verify the interrelations of the main compounds and core targets. Results： In this study, we found 81 active components corresponding to 225 targets of DHJSD. Moreover, 775 RA-related targets were obtained, of which 12 were shared between DHJSD targets and RA genes. From GO and KEGG analysis, there were 346 GO items and 18 signaling pathways. As the molecular docking showed, the binding of components was stable with the core gene. Conclusion： In conclusion, our works revealed the underlying mechanism of DHJSD for treating RA using network pharmacology and molecular docking, which provided a theoretical basis for further clinical application in the future.

Hierarchical Virtual Screening of SARS-CoV-2 Main Protease Potential Inhibitors: Similarity Search, Pharmacophore Modeling, and Molecular Docking Study

Background: The outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) resulted in a widespread pandemic. Various approaches involved the repositioning of antiviral remedies and other medications. Several therapies, including oral antiviral treatments, represent some approaches to adapting to the long existence of the COVID-19 pandemic. In silico studies provide valuable insights throughout drug discovery and development in compliance with global efforts to overcome the pandemic. The main protease is an essential target in the viral cycle. Computer-aided drug design accelerates the identification of potential treatments, including oral therapy. Aims: This work aims to identify potential SARS-CoV-2 main protease inhibitors using different aspects of in silico approaches. Methods: In this work, we conducted a hierarchical virtual screening of SARS-CoV-2 main protease inhibitors. A similarity search was conducted to screen molecules similar to the inhibitor PF-07321332. Concurrently, structure-based pharmacophores, besides ligand-based pharmacophores, were derived. A drug-likeness filter filtered the compounds retrieved from similarity search and pharmacophore modeling before being subjected to molecular docking. The candidate molecules that showed higher affinity to the main protease than the reference inhibitor were further filtered by absorption, distribution, metabolism, and excretion (ADME) parameters. Results: According to binding affinity and ADME analysis, four molecules (CHEMBL218022, PubChem163362029, PubChem166149100, and PubChem 162396459) were prioritized as promising hits. The compounds above were not reported before; no previous experimental studies and bioactive assays are available. Conclusion: Our time-saving approach represents a strategy for discovering novel SARS-CoV- 2 main protease inhibitors. The ultimate hits may be nominated as leads in discovering novel SARS-CoV-2 main protease inhibitors.

Huangqin-Huanglian Decoction Protects Liver against Non-alcoholic Fatty Liver Disease in High Fat-diet Mice.

Traditional Chinese medicine (TCM) has the advantage of low toxicity of natural ingredients, multiple targets and effects, and low medication costs. It has unique advantages for metabolic and chronic diseases. Huangqin-Huanglian decoction (HQHLD) is composed of Scutellariae Radix, Coptidis Rhizoma, Rehmanniae Radix, and Gentianae Radix Et Rhozima; it has great potential for the treatment of NAFLD with the modern pharmacological research and TCM theory, but there is still a relative lack of research on the potential targets and pharmacological effects of HQHLD. In this work, we have used network pharmacology to predict the targets and signaling pathways of HQHLD, and validated NAFLD-related targets using the HFD model in order to explore more therapeutic drugs and methods for NAFLD. We collected the HQHLD ingredients and NAFLD targets through TCMSP, ETCM, DisGeNET, HGMD, MalaCards, OMIM, and TTD, built ingredients-target networks by Cytoscape, and screened key ingredients in HQHLD. DAVID and Metascape databases were used for GO functional enrichment analysis and KEGG pathway enrichment analysis, respectively. Molecular docking of the key ingredients and key targets was performed by AutoDock. We verified the effect of HQHLD on high-fat diet (HFD) mice by measuring the weight, liver weight index, and the level of TG, TC, LDL-C, and HDLC. HE staining and oil-red staining were performed to detect the damage and fat accumulation in the liver. The changes in INSR, PPAR-α, PPAR-γ, TNF-α, and caspase3 were experimented with WB. With the network pharmacology analysis, we found quercetin, baicalein, sitosterol, wogonin, oroxylin-A, glycyrrhizin, hydroberberine, berberine, sesamin, and carotene to be the main ingredients in HQHLD. According to KEGG pathway analysis, INSR, AKT, JNK1, PPAR-α, PPAR-γ, and the other 16 targets are the main targets of HQHLD in the treatment of NAFLD. We took HFD mice as the in vivo model of NAFLD. Our results showed that HQHLD could reduce liver weight, and TG and LDL-C levels, and increase HDL-C level in serum. By HE and oil red staining, we found that HQHLD could protect the morphology of hepatocytes and reduce fat in the liver. We also found HQHLD to protect the liver by increasing the expression of INSR and PPAR-α, and reducing the expression of PPAR-γ, TNF-α, and caspase3 in the liver. In conclusion, our study has firstly studied the main ingredients and key targets of HQHDL in treating NAFLD by network pharmacology analysis, and preliminarily confirmed that HQHLD could alleviate NAFLD in a multi-target way by lowering fatty acids, and decreasing insulin resistance, inflammation, and apoptosis in the liver.

The polarization of the boundary layer around weakly magnetized neutron stars in X-ray binaries

Context. X-ray binaries hosting a compact object have been among the main targets of the Imaging X-ray Polarimetry Explorer (IXPE) since its launch, due to their high brightness in the 2–8 keV energy band. The spectropolarimetric analysis performed so far has proved to be of great importance in providing constraints on the accretion geometry of these systems. However, the data statistics is not enough to unambiguously disentangle the contribution of the single components to the net observed polarimetric signal. Aims. In this work, we aim to present a model for computing the polarization degree and polarization angle of the boundary layer around weakly magnetized neutron stars in low-mass X-ray binaries in the soft state. The main motivation is to provide strong theoretical support to data interpretation of observations performed by IXPE or future satellites for X-ray polarimetry. Methods. The results were obtained by modeling the boundary layer as an equatorial belt around the compact object and locally approximating it as a plane-parallel scattering atmosphere, for which the associated radiative transfer equation for polarized radiation in the Thomson limit was solved. The polarimetric quantities were then transformed from the comoving frame to the observer frame using the numerical methods formerly developed for X-ray pulsars. Results. For typical values of the optical depth and electron temperature of the boundary layer of these systems in a soft state, the polarization degree was less then 0.5%, while the polarization angle was rotated by ≲5° with respect to the neutron star spin axis due to special and general relativistic effects for fast rotation, the amount progressively decreasing for lower spin frequencies. The derived quantities can be used to remove degeneracy when multicomponent spectropolarimetry is performed.

Cyclin D1 (G870A) polymorphism and breast cancer risk in an Iranian population

Background and Objective: Cyclins are the key regulator of the cell cycle and their over-expression has been seen in many cancers including breast cancer. Cyclin D1 is an oncoprotein encoded by CCND1 gene located on chromosome 11 (11q) which regulates cell cycle in shifting from G1 to S phase. It’s the main target for steroids and mitogenic growth hormones in breast epithelial cells. This study aimed to evaluate the relationship between Cyclin D1 G870A polymorphism and breast cancer risk in a population in the north of Iran.
 Methods: Whole blood samples collected from 82 patients with breast cancer and 66 healthy women. DNA was extracted and genotyping was performed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) technique.
 Results: Genotypic prevalence of AA, AG, GG genotypes among patients were 40.2%, 35.3% and 24.4% and in controls were 30%, 47%, 23%, respectively. There was no significant difference in CCND1 G870A genotype polymorphism between patients and control group (p=0.32). Also, allelic prevalence of A and G alleles in breast cancer patients were 58% and 42%, in controls were 54% and 46%, respectively. The present study showed that there is no significant association between CCND1 G870A polymorphism with the risk of breast cancer.
 Conclusion: The results of this study revealed that there is no significant association between CCND1 G870A genetic polymorphism and the risk of breast cancer in the population of the north of Iran. More studies with larger samples of cases and controls would be beneficial.

Sustainability and Resilience Assessment Methods: A Literature Review to Support the Decarbonization Target for the Construction Sector

It is a well-known issue that the 2050 target of carbon emissions neutrality will be reached only with the co-operation of all the interested sectors, and the construction sector could be one of the main contributors to this change. With the built environment globally responsible for about 40% of annual global energy-related CO2 emissions, the construction sector offers an important opportunity to drive transformative change and presents the most challenging mitigation potential among all industrial sectors, which also brings opportunities for adopting sustainability practices and increasing resilience. This paper presents a systematic literature review of those two pivotal concepts to reach the decarbonization goal: sustainability and resilience. Starting from an extensive literature review (2536 scientific documents) based on the PRISMA statement, the definitions and assessment methodologies of those concepts for the construction sector have been studied. The methodological approach followed for their analysis has been conducted on a first selection of 42 documents, further reduced to 12 by using clear inclusion criteria to identify the integrated assessment procedures. The main goal of this study is to clarify the correlation between sustainability and resilience concepts for constructions and their integrated assessment, in line with the latest regulations and market needs. The results show that, currently, sustainability and resilience are mainly evaluated in a distinct way to obtain building energy performance certificates, as well as to quantify the building market value and its complementary contribution to the ‘energy efficiency first’ principle and energy-saving targets towards the emergent issue of climate change. Few works focus on the integrated assessment of both concepts considering the construction industries’ point of view about materials and/or systems for buildings. The novelty of this study is the critical review of the current sustainability and resilience integrated assessment methods used for the construction value chain, declined for four main target groups. Researchers, policymakers, industries, and professionals could gain dedicated insights and practical suggestions to put in practice the elements of circular economy, ecological innovation, and cleaner production, which are essential in order to drive the decarbonization of the built environment.

GSH-related enzyme activity and tumor relation: glutathione peroxidase and glutathione reductase status under hypoxia in HepG2 cells

Abstract Objectives In hepatocellular carcinoma (HCC), tumorigenesis, hypoxia and reactive oxygen species (ROS) play a crucial role in altering the tumor microenvironment (TME). Until now, the time-dependent alteration of hypoxia-inducible factor-1α (HIF-1α), the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR) under hypoxic conditions in HCC were not clear. Consequently, our main target was to investigate the role of GPx and GR status in HCC cell line (HepG2) under hypoxic conditions. Methods HIF-1α protein levels in cell lysates were determined by ELISA assay and protein expressions were identified using western blot. GPx and GR activity levels of the cell lysates were measured spectrophotometrically. Results HIF-1α protein levels were determined under normoxic and hypoxic conditions (p<0.001). Also, HIF-1α protein levels and expressions were observed under time-dependent hypoxic conditions, the HIF-1α protein level is found to be reached its peak point at 4 h in the HepG2 cell line. We also have detected decreased activity levels of GPx and increased GR activity levels under hypoxia for 4 h (p<0.001). Conclusions More than 4 h of exposure to hypoxic environment reducted the HIF-1α levels in HCC cells. According to the results, we suggest the ideal exposure time to hypoxic conditions as 4 h for the HepG2 cell line. In addition, hypoxia also stimulated the activity levels of GPx and GR. Our results suggest that the activity levels of GPx and/or GR enzymes may be therapeutic targets in the hypoxia-dependent HCC tumorigenesis process.

Hydrogen sulfide improves endothelial barrier function by modulating the ubiquitination degradation of KLF4 through TRAF7 S-sulfhydration in diabetic aorta

Anomalous vascular endothelium significantly contributes to various cardiovascular diseases. VE-cadherin plays a vital role in governing the endothelial barrier. Krüppel-like factor 4(KLF4), as a transcription factor, which binds the VE-cadherin promoter and enhances its transcription. Tumor necrosis factor receptor-associated factor 7 (TRAF7) is an E3 ubiquitin ligase that has been shown to modulate the degradation of KLF4. H2S can covalently modify cysteine residues on proteins through S-sulfhydration, thereby influencing the structure and functionality of the target protein. However, the role of S-sulfhydration on endothelial barrier integrity remains to be comprehensively elucidated. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates endothelial integrity and its underlying mechanism.In this study, we observed that protein S-sulfhydration was reduced in the endothelium during diabetes and TRAF7 was the main target. Overexpression of TRAF7-Cys327 mutant could mitigate the endothelial barrier damage by weakening TRAF7 interaction with KLF4 and reducing ubiquitination degradation of KLF4. In conclusion, our research demonstrates that H2S plays a pivotal role in regulating S-sulfhydration of TRAF7 at Cys327. This regulation effectively inhibits the ubiquitin-mediated degradation of KLF4, resulting in an upregulation of VE-cadherin levels. This molecular mechanism contributes to the prevention of endothelial barrier damage.

Alternative substitutions of N332 in HIV-1AD8 gp120 differentially affect envelope glycoprotein function and viral sensitivity to broadly neutralizing antibodies targeting the V3-glycan.

Glycan attached to amino acid asparagine at position 332 of HIV-1 envelope glycoproteins is a main target of a subset of broadly neutralizing antibodies that block HIV-1 infection. Here, we defined the contribution of different amino acids at this position to Env antigenicity, stability on ice, and conformational states.

Deciphering the multi-functional role of Indian propolis for the management of Alzheimer's disease by integrating LC-MS/MS, network pharmacology, molecular docking, and in-vitro studies.

The conventional one-drug-one-disease theory has lost its sheen in multigenic diseases such as Alzheimer's disease (AD). Propolis, a honeybee-derived product has ethnopharmacological evidence of antioxidant, anti-inflammatory, antimicrobial and neuroprotective properties. However, the chemical composition is complex and highly variable geographically. So, to leverage the potential of propolis as an effective treatment modality, it is essential to understand the role of each phytochemical in the AD pathophysiology. Therefore, the present study was aimed at investigating the anti-Alzheimer effect of bioactive in Indian propolis (IP) by combining LC-MS/MS fingerprinting, with network-based analysis and experimental validation. First, phytoconstituents in IP extract were identified using an in-house LC-MS/MS method. The drug likeness and toxicity were assessed, followed by identification of AD targets. The constituent-target-gene network was then constructed along with protein-protein interactions, gene pathway, ontology, and enrichment analysis. LC-MS/MS analysis identified 16 known metabolites with druggable properties except for luteolin-5-methyl ether. The network pharmacology-based analysis revealed that the hit propolis constituents were majorly flavonoids, whereas the main AD-associated targets were MAOB, ESR1, BACE1, AChE, CDK5, GSK3β, and PTGS2. A total of 18 gene pathways were identified to be associated, with the pathways related to AD among the topmost enriched. Molecular docking analysis against top AD targets resulted in suitable binding interactions at the active site of target proteins. Further, the protective role of IP in AD was confirmed with cell-line studies on PC-12, in situ AChE inhibition, and antioxidant assays.

Outlier Detection and Prediction in Evolving Communities

Community detection in social networks is of great importance and is used in a variety of applications such as recommendation systems and targeted advertising. While detecting dense groups with high levels of connectivity and similar interests between their members is the main target of traditional network analysis, finding network members with quite different behavior than the majority of nodes is important as well. These nodes are known as outliers, and their accurate detection can be very useful; when outliers are marked as noisy nodes, their early exclusion from analysis can lead to high computational profits. On the other hand, they can represent interesting components that call for further investigation to find the reasons for their outlying behavior and possible ways to include them in a neighboring community. Both community and outlier detection are challenging in temporal environments where changes occur in real time; thus, dynamic methods need to be deployed rather than to static methods. In our work, we take into account the content of the network, in contrast to most of related studies, where only the network’s structure contributes to community formation. We define an adaptive outlier score to be assigned to each node in order to quantify its outlierness, and introduce a complete online community detection algorithm that analyzes both the network’s structure and content while at the same time detecting community outliers. To evaluate our method, we retrieved and processed two real datasets regarding social networks with temporal and content information. Experimental results show that our method is capable of detecting outliers in real-time evolving communities and provides an outlier score which is a better metric of each node’s outlierness compared to widely used metrics. Finally, experimental results indicate that our method is suitable for predicting the status of future nodes based on their current outlier score.

Patterns of variability of species composition of catches from the russian fishing vessels in the south-eastern Pacific ocean for 2015–2022

The work provides information on the patterns of species composition of catches from the Russian fishing vessels conducted fishing of jack mackerel (Trachurus murphyi Nichols 1920), chub mackerel (Scomber japonicus Houttuyn 1782) and redbait (Emmelichthys spp.) in the South-Eastern Pacific Ocean outside the economic zones of the coastal States. According to scientific observations, an analysis of the composition of species caught by the Russian fishing vessels is given. When fishing in the pelagic zone over ocean depths, jack mackerel was the main target species, chub mackerel formed the bycatch. At the same time, the proportion of chub mackerel in catches in the northern parts was higher than in the southern ones. When fishing on seamounts of the Nazca Ridge, catches were dominated by redbait with jack mackerel and alfonsino (Beryx splendens Lowe, 1834) as bycatch. According to the similarity of the species composition of catches, three areas – 1) all the Southern and Central subareas and part of the Northern subarea; 2) seamounts of Nazca ridge; 3) part of the Northern subarea near the border of the EEZ of Peru between 17–20°S, were singled out using the cluster analysis method.

Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain.

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.6, Nav1.7, and Nav1.8. In this study, we screened in virtual hits from dihydrobenzofuran and 3-hydroxyoxindole hybrid molecules against Navs via a veratridine (VTD)-based calcium imaging method. The results showed that one of the molecules, 3g, could inhibit VTD-induced neuronal activity significantly. Voltage clamp recordings demonstrated that 3g inhibited the total Na+ currents of DRG neurons in a concentration-dependent manner. Biophysical analysis revealed that 3g slowed the activation, meanwhile enhancing the inactivation of the Navs. Additionally, 3g use-dependently blocked Na+ currents. By combining with selective Nav inhibitors and a heterozygous expression system, we demonstrated that 3g preferentially inhibited the TTX-S Na+ currents, specifically the Nav1.7 current, other than the TTX-R Na+ currents. Molecular docking experiments implicated that 3g binds to a known allosteric site at the voltage-sensing domain IV(VSDIV) of Nav1.7. Finally, intrathecal injection of 3g significantly relieved mechanical pain behavior in the spared nerve injury (SNI) rat model, suggesting that 3g is a promising candidate for treating chronic pain.

PsAF5 functions as an essential adapter for PsPHB2-mediated mitophagy under ROS stress in Phytophthora sojae

Host-derived reactive oxygen species (ROS) are an important defense means to protect against pathogens. Although mitochondria are the main intracellular targets of ROS, how pathogens regulate mitochondrial physiology in response to oxidative stress remains elusive. Prohibitin 2 (PHB2) is an inner mitochondrial membrane (IMM) protein, recognized as a mitophagy receptor in animals and fungi. Here, we find that an ANK and FYVE domain-containing protein PsAF5, is an adapter of PsPHB2, interacting with PsATG8 under ROS stress. Unlike animal PHB2 that can recruit ATG8 directly to mitochondria, PsPHB2 in Phytophthora sojae cannot recruit PsATG8 to stressed mitochondria without PsAF5. PsAF5 deletion impairs mitophagy under ROS stress and increases the pathogen’s sensitivity to H2O2, resulting in the attenuation of P. sojae virulence. This discovery of a PsPHB2-PsATG8 adapter (PsAF5) in plant-pathogenic oomycetes reveals that mitophagy induction by IMM proteins is conserved in eukaryotes, but with differences in the details of ATG8 recruitment.

Integration of airborne magnetic and geological data for mineral prospectivity mapping in the Ambam-Amvom rainforest area, Archean Ntem Complex, southern Cameroon

The accurate mapping of mineral resources in rainforest areas is challenging due to dense vegetation and thick lateritic cover obscuring rock outcrops. This study utilized airborne magnetic survey data to map geological features and target mineral resources in the Ambam-Amvom area at the NW margin of the Congo craton. Linear and non-linear filtering algorithms were used, including reduction to the equator (RTE), upward continuation (UC) at 1000 m and 2000 m, first vertical derivative (FVD), and analytic signal (AS). Field surveys were carried out for sampling and petrographic investigations. The TMI map showed magnetic signals varying from -4489 nT to 2317 nT, while the RTE map displayed magnetic signals varying from -2984 nT to 3528 nT. The RTE-Reg map exhibited anomaly signal variations ranging between -2704 nT and +3637 nT and between -2829 and +3864 nT, respectively for UC at 1000 m and 2000 m. Geological structures were interpreted from the FVD, AS, and TMI-RTE images, and linear structures of regional extend mainly trend NW-SE, E-W, and NE-SW. Field investigations revealed that the study area comprises iron formations, amphibolite, gneiss, gabbro, biotite granite, and charnockite. The bulk chemical composition of iron formations showed a high content of TFe, averaging 39.80 wt.% for itabirite, 53.79 wt.% for hematite-geothite ore and 59.63 wt.% for quartz-hematite ore. The zones of peak magnetic anomalies coincided with the occurrence of the greenstone belt, and the integration of aeromagnetic and geological data led to the identification of three main target zones for iron ore minimization. High fracture density zones within the research were identified as high prospective targets for gold mineralization. The study's findings highlight the high potential of the Ntem Complex for mineral resources and provide valuable information for future research and development.

Pendampingan Mahasiswa MBKM KKNT dalam Perencanaan Daerah Wisata Kuta Rayat, Kecamatan Naman Teran, Kabupaten Karo

The village tourism program continues to grow as alternative tourism is expected to make a positive contribution to community development. Efforts to develop and manage resources must be directed so that they can fulfill economic, social, and aesthetic aspects while maintaining the integrity and or preservation of ecology, biodiversity, culture, and living systems. Kuta Rayat is one of the villages in the Naman Teran sub-district, Karo Regency, North Sumatra Province, Indonesia. Kuta Rayat Village is one of the villages planned to become a tourist village. The mentoring activities were carried out in 2023 and involved academics and students of the Architectural Engineering Study Programme of Universitas Panca Budi Medan. The mentoring method was carried out through Focus Group Discussion (FGD). The results of the assistance explained that tourism villages have an important role for many aspects, one of which is spurring the potential for the growth of the creative economy in the local environment, as well as opening up employment opportunities for residents who are close to tourist sites. Kuta Rayat Village has a lot of potential to be developed into a tourist area. Through the development of the potential of existing resources, villages in Indonesia, especially the Karo Regency area, are expected to become attractive and sustainable tourist destinations and the main target of tourism village development is to improve the welfare of the surrounding community.

Atmospheric fine particulate matter (PM2.5) induces pulmonary fibrosis by regulating different cell fates via autophagy

The presence of respiratory diseases demonstrates a positive correlation with atmospheric fine particulate matter (PM2.5) exposure. The respiratory system is the main target organ affected by PM2.5, and exposure to PM2.5 elevates the likelihood of developing pulmonary fibrosis (PF). In this study, lung epithelial cell (BEAS-2B) and fibroblast (NIH-3T3) were used as in vitro exposure models to explore the mechanisms of PF. PM2.5 exposure caused mitochondrial damage in BEAS-2B cells and increased a fibrotic phenotype in NIH-3T3 cells. Epithelial cells and fibroblasts have different fates after PM2.5 exposure due to their different sensitivities to trigger autophagy. Exposure to PM2.5 inhibits mitophagy in BEAS-2B cells, which hinders the removal of damaged mitochondria and triggers cell death. In this process, the nuclear retention of the mitophagy-related protein Parkin prevents it from being recruited to mitochondria, resulting in mitophagy inhibition. In contrast, fibroblasts exhibit increased levels of autophagy, which may isolate PM2.5 and cause abnormal fibroblast proliferation and migration. Fibrotic phenotypes such as collagen deposition and increased α-actin also appear in fibroblasts. Our results identify PM2.5 as a trigger of PF and delineate the molecular mechanism of autophagy in PM2.5 induced PF, which provides new insights into the pulmonary injury.

Study on the chemical constituents and mechanism of Kai-Xin-San based on UPLC-Q-Exactive MS and network pharmacology

Ethnopharmacological relevanceVascular disease (VD) is a kind of common disease harmful to the health of the middle-aged and elderly, which has the characteristics of long treatment cycle and high recurrence rate, and without effective method to treat so far. Traditional Chinese medicine (TCM) has the characteristics of multi-components and multi-targets to treat diseases. Kai-Xin-San is a TCM formula applied for treating psychiatric diseases such as depression in China for thousands of years, and it has been used in clinical treatment of VD. But up to now, its active composition and mechanism are not clear. Aim of the studyTo explore the effective components of Kai-Xin-San, investigate the effect of Kai-Xin-San on angiogenesis, screen and verify the related targets and possible mechanisms of Kai-Xin-San against VD. Materials and methodsUPLC-Q-Exactive Orbitrap MS was performed to identify the chemical components of Kai-Xin-San. The mechanism of multi-components, multi-targets, and multi-pathways of Kai-Xin-San in the treatment of VD were explored by network pharmacology. And then, quail chick chorioallantoic membrane (qCAM) assays were used to evaluate the vascular protective activity of Kai-Xin-San. Evaluation of angiogenesis by calculating the relative vessels area. The levels of VEGFA and Akt1 in qCAM were measured by RT-PCR. Twenty-five male SD rats were randomly divided into the sham group, model group, Donepezil (0.45 mg/kg) group, Kai-Xin-San low dose group (0.1575 g/kg), Kai-Xin-San high dose group (0.63 g/kg). Two-vessel occlusion (2-VO) rat model is established to evaluate the therapeutic effect of Kai-Xin-San pretreatment. Hematoxylin-eosin (HE) staining is conducted to detect the morphological changes of neurons in the hippocampus. ResultsData showed that 62 compounds were identified in Kai-Xin-San. The network pharmacology results showed 73 compounds in Kai-Xin-San play a role in the treatment of VD, such as Ginsenoside Rh4, kaempferol, and Poricoic acid C. A total of 7 main targets are predicted, including Akt1, TNF and so on. Kai-Xin-San could increase VEGFA and Akt1 expression, promote angiogenesis and regulate the PI3K-Akt signaling pathway. The results depict that Kai-Xin-San has dose-dependently improved the cognitive function in 2-VO model rats. It has also been showed that Kai-Xin-San can rescue neuron damage in the hippocampus. ConclusionThe complex chemical components of Kai-Xin-San play a synergistic role in the treatment of VD, and involve multiple pathways and targets. To protect blood vessels by promoting angiogenesis is one of the potential mechanisms of Kai-Xin-San in the treatment of VD. This study reveals that Kai-Xin-San protects the 2-VO model rats from ischemic injury by alleviating neuron damage in the hippocampus.

An Exploration of Stages of Engagement and Pentecostal Social Theology

The Pentecostal mission has always been labeled a mission for the number of people who believe in God. The Church Center is the main target, and social-cultural involvement is left alone. Therefore, it is necessary to explore the stages of involvement and social theology of Pentecostalism so that findings can become study material for driving social missions today. This research aims to explore the theological stages and social involvement of Pentecostalism. The research method used is a descriptive qualitative one, with data collection methods using a historical approach. The research results show that Pentecostalism at its initial formation in Azusa Street 1906, still needed to be sensitive to theology and social involvement. However, entering the 21st century, Pentecostals began to expand their mission concept to social involvement issues. The main reason for this involvement was and remains the reality of poverty in Pentecostal congregation members, which needs to be improved. This article is unique because it discusses the stages of Pentecostal involvement and social theology, which can be the basis for constructing a more relevant Pentecostalism in Indonesia.