Molecular Targets Research Articles

Prioritizing weeds for biological control development in the western USA: Results from the adaptation of the biological control target selection system

Nonnative invasive plants (weeds) negatively impact native ecosystems, and their effects are likely to increase with continuing global trade. Biological weed control has been employed as a cost-effective and sustainable management option for weeds in the USA since 1902. Biological control programs require careful prioritization of target weeds to ensure the most appropriate targets are selected to obtain the greatest beneficial outcomes with available resources. The Biological Control Target Selection (BCTS) system was developed by researchers in South Africa as an objective, transparent approach to prioritizing new weed biological control targets. The BCTS system was recently modified and applied to 295 state-regulated weeds in the western USA for which no biological control agents have yet been released. This paper presents the results of that application, identifying the most suitable candidates for new biological control programs as well as problematic weeds for which the likelihood of successful biological control is low.Top-ranked species in the western USA are biennial or perennial weeds that occur in stable habitats, are established in more than one state, have traits deemed difficult to control with conventional methods, have large negative impacts and no conflicts of interest outside of the horticultural industry, and have substantial information available on potential biocontrol agents. Fifteen of the 20 top-ranked species are already targets of ongoing biological control programs in the USA. When species with current programs are excluded from the analysis, the next 20 top-ranked species largely differ by having less information available on potential biological control agents and having native or economically important congeners in the USA. Results from this framework provide valuable insights to the prioritization of current and future biocontrol research programs in the western USA.

Signature analysis of high-throughput transcriptomics screening data for mechanistic inference and chemical grouping.

High-throughput transcriptomics (HTTr) uses gene expression profiling to characterize the biological activity of chemicals in in vitro cell-based test systems. As an extension of a previous study testing 44 chemicals, HTTr was used to screen an additional 1,751 unique chemicals from the EPA's ToxCast collection in MCF7 cells using 8 concentrations and an exposure duration of 6 h. We hypothesized that concentration-response modeling of signature scores could be used to identify putative molecular targets and cluster chemicals with similar bioactivity. Clustering and enrichment analyses were conducted based on signature catalog annotations and ToxPrint chemotypes to facilitate molecular target prediction and grouping of chemicals with similar bioactivity profiles. Enrichment analysis based on signature catalog annotation identified known mechanisms of action (MeOAs) associated with well-studied chemicals and generated putative MeOAs for other active chemicals. Chemicals with predicted MeOAs included those targeting estrogen receptor (ER), glucocorticoid receptor (GR), retinoic acid receptor (RAR), the NRF2/KEAP/ARE pathway, AP-1 activation, and others. Using reference chemicals for ER modulation, the study demonstrated that HTTr in MCF7 cells was able to stratify chemicals in terms of agonist potency, distinguish ER agonists from antagonists, and cluster chemicals with similar activities as predicted by the ToxCast ER Pathway model. Uniform manifold approximation and projection (UMAP) embedding of signature-level results identified novel ER modulators with no ToxCast ER Pathway model predictions. Finally, UMAP combined with ToxPrint chemotype enrichment was used to explore the biological activity of structurally related chemicals. The study demonstrates that HTTr can be used to inform chemical risk assessment by determining in vitro points of departure, predicting chemicals' MeOA and grouping chemicals with similar bioactivity profiles.

Application of Nanoparticles in the Diagnosis and Treatment of Colorectal Cancer.

Colorectal cancer is a common malignant tumor with high morbidity and mortality rates, imposing a huge burden on both patients and the healthcare system. Traditional treatments such as surgery, chemotherapy and radiotherapy have limitations, so finding more effective diagnostic and therapeutic tools is critical to improving the survival and quality of life of colorectal cancer patients. While current tumor targeting research mainly focuses on exploring the function and mechanism of molecular targets and screening for excellent drug targets, it is crucial to test the efficacy and mechanism of tumor cell therapy that targets these molecular targets. Selecting the appropriate drug carrier is a key step in effectively targeting tumor cells. In recent years, nanoparticles have gained significant interest as gene carriers in the field of colorectal cancer diagnosis and treatment due to their low toxicity and high protective properties. Nanoparticles, synthesized from natural or polymeric materials, are NM-sized particles that offer advantages such as low toxicity, slow release, and protection of target genes during delivery. By modifying nanoparticles, they can be targeted towards specific cells for efficient and safe targeting of tumor cells. Numerous studies have demonstrated the safety, efficiency, and specificity of nanoparticles in targeting tumor cells, making them a promising gene carrier for experimental and clinical studies. This paper aims to review the current application of nanoparticles in colorectal cancer diagnosis and treatment to provide insights for targeted therapy for colorectal cancer while also highlighting future prospects for nanoparticle development.

The benefits and potential of pre-emptive weed biological control: Three case studies in Queensland, Australia

Invasive weed species can have significant impacts on agriculture, biodiversity and livelihoods. The cost and feasibility of managing these species using conventional means can be prohibitive depending on the size of the infestations or the habitats in which they invade. Under these conditions, biological control is seen as a viable, sustainable means to manage many weeds. However, biological control can take many years and at considerable cost to achieve the desired level of control, due to the numerous steps that are involved, including native range surveys and host-specificity testing of potential agents. Pre-emptive biological control targeting particularly high-risk species prior to their arrival in a country or emerging weeds can be cost-effective, especially if the respective biological control agents have been utilized in other countries. While pre-emptive biological control of arthropods has been investigated previously, there are few examples of pre-emptive biological control of weed species. The invasive weed species, Chromolaena odorata, Mikania micrantha and Coccinia grandis have all been or are currently targets of pre-emptive biological control in Australia. Research on the gall fly Cecidochares connexa was initiated prior to its host, C. odorata being detected in Australia. Cecidochares connexa was eventually released in Australia to control C. odorata, after initial research on the agent found it to be suitably host specific and effective against the target weed. Cecidochares connexa has also been released in numerous other countries in Africa, Asia and the Pacific, where it is providing very good control. Australia funded research on the rust Puccinia spegazzinii as part of a project involving Fiji and Papua New Guinea while the target weed, M. micrantha was a target for eradication in Queensland. The rust was later approved for release in Australia to control M. micrantha following additional host-specificity testing. However, research funded by Australia overseas suggests that the rust may not be able to suppress M. micrantha populations below current levels. Consequently, while P. spegazzinii has been released in numerous countries now, it has not yet been field released in Australia. Biological control research in Australia on C. grandis is relatively new as the weed is relatively minor and not yet declared a target for biological control. Consequently, no biological control agents have yet been released in the country. Pre-emptive biological control of C. odorata and M. micrantha has been particularly cost-effective, not just for Australia, but subsequently for numerous other countries where these weeds were well-established and problematic and the respective biological control agents were later released.

In-silico Studies, Synthesis, and Antacid Activities of Magnesium (II) Complexes.

Nowadays, acidity is a severe problem worldwide caused by excessive gastric acid secretion by the stomach and proximal intestine. Antacids are drugs capable of buffering stomach acid. Therefore, in our research work, we have reported the in-silico studies, synthesis, characterization, and evaluation of antacid activities of magnesium (II) complexes via the acid-base neutralization process. In this research, some magnesium complexes were synthesized and their antacid behavior was compared with marketed products. Also, in-silico studies were performed on H+/K+ ATPase (Proton pump). All synthesized compounds were characterized by various spectroscopic techniques like UV-Vis, FT-IR, XRD, and DSC techniques. Spectroscopic analysis results showed that the semicarbazone ligand shows keto-enol isomerism and forms a coordinated stable complex with magnesium ions in the crystalline phase. The FT-IR results confirmed the presence of Mg-O stretching, N-H bending, and C=N stretching vibrations in Mg (II) complexes. The antacid activities of Mg (II) complexes were excellent as compared to the semicarbazone ligand and comparable with that of marketed antacid drugs like ENO, and Pantop-D. Insilco studies also confirmed that semicarbazone ligand and its Mg (II) complexes were both found to be fitted into the active sites of molecular targets, and Mg (II) complexes showed better binding affinities towards macromolecular as compared to semicarbazone ligand.

1,3,4-Oxadiazole Scaffold in Antidiabetic Drug Discovery: An Overview.

Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. With the increasing number of cases of diabetes and drug-resistant diabetes, there is an urgent need to develop new potent molecules capable of combating this cruel disease. Medicinal chemistry concerns the discovery, development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level. Oxadiazole-based derivatives have come up as a potential option for antidiabetic drug research. Oxadiazole is a five-membered heterocyclic organic compound containing two nitrogen atoms and one oxygen atom in its ring. Oxadiazole hybrids have shown the ability to improve glucose tolerance, enhance insulin sensitivity, and reduce fasting blood glucose levels. The mechanisms underlying the antidiabetic effects of oxadiazole involve the modulation of molecular targets such as peroxisome proliferator-activated receptor gamma (PPARγ), α-glucosidase, α-amylase and GSK-3β which regulate glucose metabolism and insulin secretion. The present review article describes the chemical structure and properties of oxadiazoles and highlights the antidiabetic activity through action on different targets. The SAR for the oxadiazole hybrids has been discussed in this article, which will pave the way for the design and development of new 1,3,4-oxadiazole derivatives as promising antidiabetic agents in the future. We expect that this article will provide comprehensive knowledge and current innovation on oxadiazole derivatives with antidiabetic potential and will fulfil the needs of the scientific community in designing and developing efficacious antidiabetic agents.

Chemical Probes Review: Choosing the Right Path Towards Pharmacological Targets in Drug Discovery, Challenges and Future Perspectives.

Chemical probes are essential for academic research and target validation for disease identification. They facilitate drug discovery, target function investigation, and translation studies. A chemical probe provides starting material that can accelerate therapeutic values and safety measures for identifying any biological target in drug discovery. Essential read outs depend on their versatility in biochemical testing, proving the hypothesis, selectivity, specificity, affinity towards the target site, and valuable in new therapeutic approaches. Disease management will depend upon chemical probes as a primitive tool to ascertain the physicochemical stability for in vivo and in vitro studies useful for clinical trials and industrial application in the future. For cancer research, bacterial infection, and neurodegenerative disorders, chemical probes are integrated circuits which are on pipeline for the drug discovery process Furthermore, pharmacological modulators incorporate activators, crosslinkers, degraders, and inhibitors. Reports accessed depend on their structural, mechanical, biochemical, and pharmacological characterization in drug discovery research. The perspective for designing any chemical probes concludes with the utilization of drug discovery and identification of the potential target. It focuses mainly on evidence-based studies and produces promising results in successfully delivering novel therapeutics to treat cancers and other disorders at the target site. Moreover, natural product pharmacophores like rapamycin, cephalosporin, and α-lactamase are utilized for drug discovery. Chemical probes revolutionize computational-based study design depending on identifying novel targets within the database framework. Chemical probes are the clinical answers for drug development and goforward tools in solving other riddles for scientists and researchers working in this industries.

Dual COX-2/TNF-α Inhibitors as Promising Anti-inflammatory and Cancer Chemopreventive Agents: A Review

: Cyclooxygenases (COX) play a pivotal role in inflammation and are responsible for the production of prostaglandins (PGs). Two types of COXs have been identified as key biological targets for drug design: Constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) target COX-1, while selective COX-2 inhibitors are designed for COX-2. These COX isoforms are involved in multiple physiological and pathological pathways throughout the body. Overproduction of tumor necrosis factor-alpha (TNF-α) plays a role in COX-2's inflammatory activity. Tumor necrosis factor-alpha can contribute to cardiac fibrosis, heart failure, and various cancers by upregulating the COX-2/PGE2 axis. Therefore, suppressing COX activity has emerged as a potentially effective treatment for chronic inflammatory disorders and cancer. This review explores the mechanisms of TNF-α-induced COX-2/PGE2 expression, a significant pathophysiological feature of cancer development. Furthermore, we summarize chemical compounds with dual COX-2/TNF-α inhibitory actions, providing an overview of their structure-activity relationship. These insights may contribute to the development of new generations of dual-acting COX-2/TNF-α inhibitors with enhanced efficacy.

Role of common variants and new genes associated with arrhythmogenic cardiomyopathy

Abstract Introduction Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiac disease, predominantly affecting males, characterized by fibro-fatty myocardial replacement mainly in the right ventricle. It leads to 5% sudden cardiac death in affected young adults (<25 yo) without an implantable cardioverter defibrillator. Early diagnosis is crucial for appropriate clinical management to reduce mortality and prevent disease progression. Rare variants in desmosomal genes (PKP2,DSC2,DSG2,DSP and JUP) are found in 50% of cases. However, challenges persist since we observe a low penetrance in relatives (28-58%) and a high variability in expressivity and severity annihilating any preventive strategy. Objective We aim to decipher the genetic architecture of ACM by investigating the role of common variants in disease susceptibility/severity and to idendify new genes associated to ACM. Method A Genome Wide Association Study (GWAS) was performed on 1079 ACM index patients and 7305 controls, followed by conditional analysis. New candidate genes were knocked out (KO) in Zebrafish and/or hiPSC using CRISPR/Cas9. Impedance and external field potential measurements were performed on hiPSC derived cardiomyocytes (CM-hiPSC). Results The GWAS identified 5 significant loci (Figure 1, P<5.10-8), including 2 desmosomal genes (PKP2 a n d DSG2) and 3 new candidates (KLF12, CTNNA3, and ARL17B/WNT3). Conditional analysis revealed 3 additional loci with suggestive p-values (P<1.10-6), highlighting 3 new susceptible loci. Among them, we uncovered key non-coding regulatory regions near desmosomal genes (DSC2 and DSG2). Initial findings in PKP2-KO zebrafish present hearts with structural defects, while CM-hiPS KLF12-KO(-/-) exhibited altered interbeat interval and relaxation time compared to isogenic controls. Conclusion Our findings reveal ACM's complex genetic architecture, implicating common variants in disease susceptibility. A polygenic risk score will be implemented to improve patient risk stratification. Three novel loci/genes for ACM as well as specific regulatory regions of desmosomal genes have been highlighted. Their functional studies in isogenic hiPSC and Zebrafish models will offer new insights in ACM underlying molecular mechanism and potential therapeutic targets.

From complexity to clarity: development of CHM-FIEFP for predicting effective components in Chinese herbal formulas by using big data.

The presence of complex components in Chinese herbal medicine (CHM) hinders identification of the primary active substances and understanding of pharmacological principles. This study was aimed at developing a big-data-based, knowledge-driven in silico algorithm for predicting central components in complex CHM formulas. Network pharmacology (TCMSP) and clinical (GEO) databases were searched to retrieve gene targets corresponding to the formula ingredients, herbal components, and specific disease being treated. Intersections were determined to obtain disease-specific core targets, which underwent further GO and KEGG enrichment analyses to generate non-redundant biological processes and molecular targets for the formula and each component. The ratios of the numbers of biological and molecular events associated with a component were calculated with a formula, and entropy weighting was performed to obtain a fitting score to facilitate ranking and improve identification of the key components. The established method was tested on the traditional CHM formula Danggui Sini Decoction (DSD) for gastric cancer. Finally, the effects of the predicted critical component were experimentally validated in gastric cancer cells. An algorithm called Chinese Herb Medicine-Formula vs. Ingredients Efficacy Fitting & Prediction (CHM-FIEFP) was developed. Ferulic acid was identified as having the highest fitting score among all tested DSD components. The pharmacological effects of ferulic acid alone were similar to those of DSD. CHM-FIEFP is a promising in silico method for identifying pharmacological components of CHM formulas with activity against specific diseases. This approach may also be practical for solving other similarly complex problems. The algorithm is available at http://chm-fiefp.net/.

Modulation of p300 acetylation to protect against doxorubicin-induced cardiotoxicity

Abstract Background Doxorubicin (DOX) is a widely-used anti-neoplastic agent, but the most common adverse reaction to its use is cardiotoxicity(1). DOX acts by producing reactive oxygen species (ROSs) that cause DNA damage(1,2), which activates various proteins, including the tumour suppressor p53 and the acetyltransferase p300. When activated, p300 acetylates and increases the activity of p53 which leads to increased apoptotic activity(3). Cardiotoxicity results because the heart has limited mechanisms to dispose of ROSs(4), and because cardiomyocytes have a low turnover rate(5). Purpose We examined the p300 inhibitor Theracurmin (THR)(6,7) as a candidate to prevent DOX cardiotoxicity using an in-vivo mouse model, and sought to elucidate the underlying molecular mechanisms using in-vitro studies. Methods C57BL/6 mice were pre-treated with THR or vehicle (as control), then administered DOX or vehicle. Cardiac function was evaluated by echocardiography and cardiac catheterization. In vitro studies used cardiac fibroblasts (FBs) and cardiac endothelial cells (ECs) pre-treated with THR, then with DOX, as in the animal studies. Western blotting and rt-qPCR was used to quantify protein and mRNA levels of genes in the p53-p300 pathway or related to apoptosis, oxidative stress, and cell cycle control. Results DOX-treated mice showed significant decreases in left ventricular (LV) ejection fraction (LVEF, p=0.0004), fractional shortening (FS, p=0.0012), and a significant increase in end-systolic volume (ESV, p=0.0004). We also showed a significant decrease in anterior (LVAW;d, p=0.005) and posterior (LVPW;d, p=0.005) wall thickness of the LV in these mice. However, when mice were pre-treated with THR prior to DOX administration, we saw significant increases in LVEF (p=0.045) and LVPW;d (p=0.015), and a significant decrease in ESV (p=0.0047) compared to those that were not pre-treated. In-vitro analyses demonstrated a significant increase in cleaved caspase 3 protein expression in DOX-treated ECs (p=0.007), that was not prevented by THR pre-treatment. In DOX-treated FBs, we saw a reduction in AKT mRNA (p=0.017) and increases in BAX 9p=0.008), P21 (p=0.0001), and GADD45 (0.037) mRNA expression. In DOX-treated ECs, we also saw significant increases in BAX (p=0.015) and P21 (p=0.011) mRNA expression. These changes in mRNA expression were not reversed with THR pre-treatment in either cell type. Conclusion THR pre-treatment successfully mitigated functional deficits and structural deficits associated with DOX cardiotoxicity. In-vitro studies show that THR pre-treatment was not sufficient to significantly prevent changes in key molecular targets associated with apoptosis. Further studies are required to elucidate the mechanism behind the observed functional changes.Abstract OverviewAbstract Results

Functional Mechanism and Clinical Implications of lncRNA LINC-PINT in Delayed Fracture Healing

Background Fracture healing can be impeded or even compromised by various factors, resulting in a growing number of patients suffering. The lncRNA LINC-PINT has garnered attention for its latent role in enhancing fracture healing, but its specific functions in this process remain unclear. Objectives The primary objective of this study is to investigate the clinical relevance and underlying molecular mechanisms of LINC-PINT in delayed fracture healing (DFH), while also assessing its potential as an early diagnostic biomarker. Materials and methods The expression levels of LINC-PINT were measured in the serum of DFH patients and those with normal fracture healing using RT-qPCR. In MC3T3-E1 cells, the study investigated the influence on the expression of differentiation-related protein, cell viability, and apoptosis through the modulation of LINC-PINT and miR-324-3p. To elucidate the targeting relationship between LINC-PINT, miR-324-3p, and BMP2, a dual-luciferase reporter assay was employed. Results The findings revealed a significant downregulation of LINC-PINT expression in DFH patients. LINC-PINT showed high sensitivity and specificity as a diagnostic marker for DFH. In MC3T3-E1 cells, LINC-PINT overexpression markedly enhanced the expression levels of ALP, OCN, Runx2, and OPN, improved cell viability, and inhibited apoptosis. LINC-PINT negatively regulated miR-324-3p, and the effects of LINC-PINT were counteracted by miR-324-3p. LINC-PINT was found to regulate BMP2 by targeting miR-324-3p. Conclusion LINC-PINT could serve as an early diagnostic biomarker for DFH and slow the progression of DFH by modulating BMP2 through the targeted regulation of miR-324-3p. This research presents new molecular targets for the diagnosis and treatment of DFH.

Integrative 3D genomics with multi-omics analysis and functional validation of genetic regulatory mechanisms of abdominal fat deposition in chickens

Chickens are the most abundant agricultural animals globally, with controlling abdominal fat deposition being a key objective in poultry breeding. While GWAS can identify genetic variants associated with abdominal fat deposition, the precise roles and mechanisms of these variants remain largely unclear. Here, we use male chickens from two lines divergently selected for abdominal fat deposition as experimental models. Through the integration of genomic, epigenomic, 3D genomic, and transcriptomic data, we build a comprehensive chromatin 3D regulatory network map to identify the genetic regulatory mechanisms that influence abdominal fat deposition in chickens. Notably, we find that the rs734209466 variant functions as an allele-specific enhancer, remotely enhancing the transcription of IGFBP2 and IGFBP5 by the binding transcription factor IRF4. This interaction influences the differentiation and proliferation of preadipocytes, which ultimately affects phenotype. This work presents a detailed genetic regulatory map for chicken abdominal fat deposition, offering molecular targets for selective breeding.

Molecular Targets of Plant-Derived Bioactive Compounds in Oral Squamous Cell Carcinoma

Background: With a significant increase in both incidence and mortality, oral cancer—particularly oral squamous cell carcinoma (OSCC)—is one of the main causes of death in developing countries. Even though there is evidence of advances in surgery, chemotherapy, and radiotherapy, the overall survival rate for patients with OSCC has improved, but by a small percentage. This may be due, on the one hand, to the fact that the disease is diagnosed when it is at a too-advanced stage, when metastases are already present. Methods: This review explores the therapeutic potential of natural herbal products and their use as adjuvant therapies in the treatment of oral cancer from online sources in databases (PubMed, Web of Science, Google Scholar, Research Gate, Scopus, Elsevier). Results: Even if classic therapies are known to be effective, they often produce many serious side effects and can create resistance. Certain natural plant compounds may offer a complementary approach by inducing apoptosis, suppressing tumor growth, and improving chemotherapy effectiveness. The integration of these compounds with conventional treatments to obtain remarkable synergistic effects represents a major point of interest to many authors. This review highlights the study of molecular mechanisms and their efficiency in in vitro and in vivo models, as well as the strategic ways in which drugs can be administered to optimize their use in real contexts. Conclusions: This review may have a significant impact on the oncology community, creating new inspirations for the development of more effective, safer cancer therapies with less toxic potential.

Phytochemical composition, in vitro cytotoxicity, and in silico docking properties of Tamarix tetragyna L.

Tamarix tetragyna is a plant grows in Mediterranean area and some Arab countries. It possesses numerous medicinal values. Purpose of our study is to explore biological activity of tamarix tetragyna extracts of both leaves and stem with investigating their phytochemical composition. The investigated extracts’ phyto-constituent composition was determined using gas chromatographic-mass spectrometric method. In addition, in vitro cytoxicity activity versus cancer cell lines such MCF-7, HepG-2, HCT-116, and A-549 was examined by MTT assay method, together with exploring its apoptosis effect by flow cytometry and western blot analysis techniques. Moreover, some phytochemical compounds were identified, and in-silico evaluated against anticancer molecular targets. Plant extracts showed good cytotoxic activity against both A-549 and HCT-116 cancer cell lines. With an IC50 value of 23.90 µg/ml that led to apoptosis and G2/M-phase arrest in A-549 cells, cytotoxicity data demonstrate leaves’ extract effectiveness against these cells. Upon GC-MS analysis, it revealed presence of some bioactive components such as Stigmast-5-en-3-ol and 2-methoxy-4-vinyl phenol, which are known for their cytotoxic activity. Our findings suggest that methanolic extracts of Tamarix tetragyna parts may have potential therapeutic uses as anticancer against A-549 cells, which opens up further avenues for investigation into its industrial applications.

Effect of Short-Term Restraint Stress on the Expression of Genes Associated with the Response to Oxidative Stress in the Hypothalamus of Hypertensive ISIAH and Normotensive WAG Rats

Normotensive and hypertensive organisms respond differently to stress factors; however, the features of the central molecular genetic mechanisms underlying the reaction of the hypertensive organism to stress have not been fully established. In this study, we examined the transcriptome profiles of the hypothalamus of hypertensive ISIAH rats, modeling a stress-sensitive form of arterial hypertension, and normotensive WAG rats at rest and after exposure to a single short-term restraint stress. It was shown that oxidative phosphorylation is the most significantly enriched process among metabolic changes in the hypothalamus of rats of both strains when exposed to a single short-term restraint stress. The analysis revealed DEGs representing both a common response to oxidative stress for both rat strains and a strain-specific response to oxidative stress for hypertensive ISIAH rats. Among the genes of the common response to oxidative stress, the most significant changes in the transcription level were observed in Nos1, Ppargc1a, Abcc1, Srxn1, Cryab, Hspb1, and Fosl1, among which Abcc1 and Nos1 are associated with hypertension, and Fosl1 and Ppargc1a encode transcription factors. The response to oxidative stress specific to hypertensive rats is associated with the activation of the Fos gene. The DEG’s promoter region enrichment analysis allowed us to hypothesize that the response to oxidative stress may be mediated by the participation of the transcription factor CREB1 (Cyclic AMP-responsive element-binding protein 1) and the glucocorticoid receptor (NR3C1) under restraint stress in the hypothalamus of both rat strains. The results of the study revealed common and strain-specific features in the molecular mechanisms associated with oxidative phosphorylation and oxidative stress response in the hypothalamus of hypertensive ISIAH and normotensive WAG rats following a single short-term restraint stress. The obtained results expand the understanding of the most significant molecular targets for further research aimed at developing new therapeutic strategies for the prevention of the consequences of acute emotional stress, taking into account the hypertensive state of the patient.

PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer.

The heterogeneity of ovarian cancer (OC) has made developing effective treatments difficult. Nowadays, hormone therapy plays a growing role in the treatment of OC; however, hormone modulators have had only limited success so far. To provide a more rigorous foundation for hormonal therapy for different OC subtypes, the current study used a series of bioinformatics approaches to analyse the expression profiles of genes encoding membrane progesterone (PGRMC1, progestins and the adipoQ receptor [PAQR] family), and androgen (zinc transporter member 9 [ZIP9], OXER1) receptors. Our work investigated also their prognostic value in the context of OC. We found differences in expression of ZIP9 and OXER1 between different OC subtypes, as well as between patient tumour and normal tissues. Expression of mRNA encoding PAQR7 and PAQR8 in a panel of OC cell lines was below the qPCR detection limit and was downregulated in tumour tissue samples, whereas high expression of PGRMC1 and PAQR4 mRNA was observed in rare subtypes of OC cell lines. In addition, chemical inhibition of PGRMC1 reduced the viability of rare OCs represented by COV434 cells. In conclusion, PGRMC1 and PAQR4 are promising targets for anticancer therapy, particularly for rare subtypes of OC. These findings may reflect differences in the observed responses of various OC subtypes to hormone therapy.

Is it Time for Multi-Drug Therapy with Combination of Therapeutic Nucleic Acids?

Therapeutic nucleic acids (TNAs) are a new class of drugs that exhibit different properties and mechanisms of action from those of small molecules or biological drugs. Over twenty oligonucleotide drugs and several COVID-19 vaccines have received regulatory approval for clinical use. A characteristic feature of these TNAs is that they are directed against one specific biological target and one specific RNA or DNA sequence. Consequently, TNAs currently used are administered as monotherapy. Due to the known advantages of multidrug therapy with low molecular weight drugs, it may be time to intensify work on such a treatment protocol, also in the case of TNAs.

Repetitive transcranial magnetic stimulation alleviates motor impairment in Parkinson’s disease: association with peripheral inflammatory regulatory T-cells and SYT6

BackgroundRepetitive transcranial magnetic stimulation (rTMS) has been used to treat various neurological disorders. However, the molecular mechanism underlying the therapeutic effect of rTMS on Parkinson’s disease (PD) has not been fully elucidated. Neuroinflammation like regulatory T-cells (Tregs) appears to be a key modulator of disease progression in PD. If rTMS affects the peripheral Tregs in PD remains unknown.MethodsHere, we conducted a prospective clinical study (Chinese ClinicalTrials. gov: ChiCTR 2100051140) involving 54 PD patients who received 10-day rTMS (10 Hz) stimulation on the primary motor cortex (M1) region or sham treatment. Clinical and function assessment as well as flow cytology study were undertaken in 54 PD patients who were consecutively recruited from the department of neurology at Zhujiang hospital between September 2021 and January 2022. Subsequently, we implemented flow cytometry analysis to examine the Tregs population in spleen of MPTP-induced PD mice that received rTMS or sham treatment, along with quantitative proteomic approach reveal novel molecular targets for Parkinson's disease, and finally, the RNA interference method verifies the role of these new molecular targets in the treatment of PD.ResultsWe demonstrated that a 10-day rTMS treatment on the M1 motor cortex significantly improved motor dysfunction in PD patients. The beneficial effects persisted for up to 40 days, and were associated with an increase in peripheral Tregs. There was a positive correlation between Tregs and motor improvements in PD cases. Similarly, a 10-day rTMS treatment on the brains of MPTP-induced PD mice significantly ameliorated motor symptoms. rTMS reversed the downregulation of circulating Tregs and tyrosine hydroxylase neurons in these mice. It also increased anti-inflammatory mediators, deactivated microglia, and decreased inflammatory cytokines. These effects were blocked by administration of a Treg inhibitor anti-CD25 antibody in MPTP-induced PD mice. Quantitative proteomic analysis identified TLR4, TH, Slc6a3 and especially Syt6 as the hub node proteins related to Tregs and rTMS therapy. Lastly, we validated the role of Treg and rTMS-related protein syt6 in MPTP mice using the virus interference method.ConclusionsOur clinical and experimental studies suggest that rTMS improves motor function by modulating the function of Tregs and suppressing toxic neuroinflammation. Hub node proteins (especially Syt6) may be potential therapeutic targets.Trial registrationChinese ClinicalTrials, ChiCTR2100051140. Registered 15 December 2021, https://www.chictr.org.cn/bin/project/edit?pid=133691Graphical rTMS is a safe and non-invasive method for Parkinson's disease. In this study, we showed the proportion of CD4+CD25+CD127- regulatory T-cells (Tregs) in the peripheral blood was significantly increased after rTMS treatment. Similar effects of rTMS treatment were verified in MPTP-induced PD mice. Proteomic analysis and RNA interference analyses identified TLR4, TH, Slc6a3 and especially Syt6 as hub node proteins that can be modulated by rTMS therapy in PD.

Proton ARC based LATTICE radiation therapy: feasibility study, energy layer optimization and LET optimization

Objective.LATTICE, a spatially fractionated radiation therapy (SFRT) modality, is a 3D generalization of GRID and delivers highly modulated peak-valley spatial dose distribution to tumor targets, characterized by peak-to-valley dose ratio (PVDR). Proton LATTICE is highly desirable, because of the potential synergy of the benefit from protons compared to photons, and the benefit from LATTICE compared to GRID. Proton LATTICE using standard proton RT via intensity modulated proton therapy (IMPT) (with a few beam angles) can be problematic with poor target dose coverage and high dose spill to organs-at-risk (OAR). This work will develop novel proton LATTICE method via proton ARC (with many beam angles) to overcome these challenges in target coverage and OAR sparing, with optimized delivery efficiency via energy layer optimization and optimized biological dose distribution via linear energy transfer (LET) optimization, to enable the clinical use of proton LATTICE.Approach.ARC based proton LATTICE is formulated and solved with energy layer optimization, during which plan quality and delivery efficiency are jointly optimized. In particular, the number of energy jumps (NEJ) is explicitly modelled and minimized during plan optimization for improving delivery efficiency, while target dose conformality and OAR dose objectives are optimized. The plan deliverability is ensured by considering the minimum-monitor-unit (MMU) constraint, and the plan robustness is accounted for using robust optimization. The biological dose is optimized via LET optimization. The optimization solution algorithm utilizes iterative convex relaxation method to handle the dose-volume constraint and the MMU constraint, with spot-weight optimization subproblems solved by proximal descent method.Main results.ARC based proton LATTCE substantially improved plan quality from IMPT based proton LATTICE, such as (1) improved conformity index (CI) from 0.47 to 0.81 for the valley target dose and from 0.62 to 0.97 for the peak target dose, (2) reduced esophagus dose from 0.68 Gy to 0.44 Gy (a 12% reduction with respect to 2 Gy valley prescription dose) and (3) improved PVDR from 4.15 to 4.28 in the lung case. Moreover, energy layer optimization improved plan delivery efficiency for ARC based proton LATTICE, such as (1) reduced NEJ from 71 to 56 and (2) reduction of energy layer switching time by 65% and plan delivery time by 52% in the lung case. The biological target and OAR dose distributions were further enhanced via LET optimization. On the other hand, proton ARC LATTCE also substantially improved plan quality from VMAT LATTICE, such as (1) improved CI from 0.45 to 0.81 for the valley target dose and from 0.63 to 0.97 for the peak target dose, (2) reduced esophagus dose from 0.59 Gy to 0.38 Gy (a 10.5% reduction with respect to 2 Gy valley prescription dose) and (3) improved PVDR from 3.88 to 4.28 in the lung case.Significance.The feasibility of high-plan-quality proton LATTICE is demonstrated via proton ARC with substantially improved target dose coverage and OAR sparing compared to IMPT, while the plan delivery efficiency for ARC based proton LATTICE can be optimized using energy layer optimization.