Development Of New Drugs Research Articles

Bioanalytical methods in doping controls: a review.

The analytical and technological approaches employed in doping analysis are constantly reviewed and updated to allow for keeping pace with progresses in pharmaceutical and medicinal research and the therein inherent options of misuse as performance enhancing drugs or methods. Enormous changes, improvements, and developments have been achieved in recent years, particularly, but not exclusively, in the bioanalytical sector. Several of these new strategies are examined systematically in this review using examples from the World Anti-Doping Agency (WADA) list of banned substances and methods. The review includes, among others, the application of sophisticated new in-vitro models mimicking multi compartment models, investigation into new long-term metabolites for anabolic agents, the impact of a distinct gene mutation on the analysis of erythropoietin, studies on the development of new therapeutic protein-based drugs with myostatin inhibiting properties, methods applying the new molecular biological section used to uncover gene doping, and finally new approaches uncovering the prohibited use of autologous blood transfusion. All of these challenges and investigations support the ongoing progress in modern doping controls in the future and will help to fill the gap between the advance of cheating athletes and sport drug testing.

Computational Modeling of Pharmaceuticals with an Emphasis on Crossing the Blood–Brain Barrier

The discovery and development of new pharmaceutical drugs is a costly, time-consuming, and highly manual process, with significant challenges in ensuring drug bioavailability at target sites. Computational techniques are highly employed in drug design, particularly to predict the pharmacokinetic properties of molecules. One major kinetic challenge in central nervous system drug development is the permeation through the blood–brain barrier (BBB). Several different computational techniques are used to evaluate both BBB permeability and target delivery. Methods such as quantitative structure–activity relationships, machine learning models, molecular dynamics simulations, end-point free energy calculations, or transporter models have pros and cons for drug development, all contributing to a better understanding of a specific characteristic. Additionally, the design (assisted or not by computers) of prodrug and nanoparticle-based drug delivery systems can enhance BBB permeability by leveraging enzymatic activation and transporter-mediated uptake. Neuroactive peptide computational development is also a relevant field in drug design, since biopharmaceuticals are on the edge of drug discovery. By integrating these computational and formulation-based strategies, researchers can enhance the rational design of BBB-permeable drugs while minimizing off-target effects. This review is valuable for understanding BBB selectivity principles and the latest in silico and nanotechnological approaches for improving CNS drug delivery.

Study on the mechanism of plant metabolites to intervene oxidative stress in diabetic retinopathy

Diabetic retinopathy is the main microvascular complication of diabetes and the first blinding eye disease in the working-age population. Oxidative stress is an important pathogenesis of diabetic retinopathy. Plant metabolites can be divided into two types: primary metabolites and secondary metabolites, secondary metabolites are the main active components and important sources for developing new drugs. It has unique effect in the treatment of diabetic retinopathy. However, the research on the intervention mechanism of plant metabolites in diabetic retinopathy are still relatively shallow, which limit the application of plant metabolites. With the deepening of research, more and more plant metabolites have been reported to play a role in treating diabetic retinopathy through anti-oxidative stress, including polyphenols, polysaccharides, saponins, alkaloids, etc. Therefore, this article reviewed the potential of plant metabolites in the treatment of diabetic retinopathy in the last 10 years and elucidated their mechanism of action. We hope to provide some references for the application of plant metabolites and provide valuable resources for the research and development of new drugs for diabetic retinopathy.

Current Trends in Clinical Trials of Prodrugs

The development of new drugs is a lengthy and complex process regarding its conception and ideation, passing through in silico studies, synthesis, in vivo studies, clinical trials, approval, and commercialization, with an exceptionally low success rate. The lack of efficacy, safety, and suboptimal pharmacokinetic parameters are commonly identified as significant challenges in the discovery of new drugs. To help address these challenges, various approaches have been explored in medicinal chemistry, including the use of prodrug strategies. As a well-established approach, prodrug design remains the best option for improving physicochemical properties, reducing toxicity, and increasing selectivity, all while minimizing costs and saving on biological studies. This review article aims to analyze the current advances using the prodrug approach that has allowed the advance of drug candidates to clinical trials in the last 10 years. The approaches presented here aim to inspire further molecular optimization processes and highlight the potential of this strategy to facilitate the advancement of new compounds to clinical study phases.

The Anti-lung Cancer Mechanism of Qingzao Jiufei Decoction was Studied based on Network Pharmacology, Molecular Docking, and Experimental Verification.

Lung cancer (LC) is one of the most common cancers in the world, with both its incidence and mortality rates ranking at the top position among all types of cancers, posing a serious threat to human health. Qingzao Jiufei Decoction (QD) has been used clinically to treat lung cancer, but its mechanism of action remains unclear. This study aims to elucidate the potential pharmacological mechanisms of QD in treating LC through network pharmacology, molecular docking, molecular dynamics simulation (MDS), and animal experiment validation. Active components of QD were screened utilizing the TCMSP and HREB databases, and potential targets were predicted using network pharmacology methods. Relevant targets for LC were identified from the Genecards, OMIM, and TTD databases. Intersecting targets between QD and LC were imported into the STRING 12.0 database and Cytoscape 3.10.0 software to create proteinprotein interaction (PPI) network diagrams, and Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted through using the DAVID database to identify core active components and key targets. Molecular docking was employed to assess the binding affinity of core active components with key targets in lung cancer, and MDS was used to evaluate the stability of the target-active component complexes. An in vivo lung cancer model was used to verify the therapeutic effects of QD, and Western blot analysis was used to confirm the pharmacological mechanisms of QD in treating lung cancer. Network pharmacology analysis has identified 9 core components and 9 key targets. GO and KEGG analyses have revealed a total of 185 signaling pathways, with the PI3K-Akt signaling pathway and MAPK signaling pathway being the two most significantly enriched pathways. Molecular docking results showed that all 9 core components and 9 key targets exhibited significant binding activity (binding energy < -5 kcal/mol). MDS study further simulated and confirmed strong and stable interactions between targets and active components. In an in vivo lung cancer model, QD significantly inhibited tumor growth, while Western blot analysis demonstrated that QD exerted its therapeutic effects on lung cancer by inhibiting the phosphorylation of ERK, JNK, and p38 in the MAPK signaling pathway. This experimental study found that QD can significantly inhibit the growth of lung cancer through a multifaceted approach involving various components, targets, and pathways, providing a foundation for the development and clinical application of new drugs targeting lung cancer for QD. Furthermore, it offers valuable insights into anti-tumor research with Traditional Chinese Medicine (TCM) and facilitates a more comprehensive interpretation of TCM principles through the lens of modern science.

Knockin’ on Cell’s Door: Influenza A Virus Adsorption and Its Pharmacological Inhibition

Influenza A virus (IAV) is a widespread human respiratory pathogen that contributes significantly to morbidity and mortality worldwide. The adsorption of the virus into the cell surface is the earliest stage of its replication cycle. The key role of N-linked sialic acids (SIAs) as receptors for binding to IAV’s hemagglutinin (HA) has long been acknowledged. The molecular specificity of this interaction is a key factor in host range, pathogenicity, and transmissibility of various IAV subtypes. Along with this, a number of recent studies have introduced significant complexity into the picture of IAV adsorption and revealed a multitude of new molecules on host cell surfaces to serve as receptors and/or co-receptors for IAV attachment. For successful internalization of the adsorbed virus, downstream signal transduction is necessary to activate effector endocytosis mechanisms. In recent years, our understanding of the sophistication and variability of signal transduction pathways in the virus attachment site has significantly expanded, with the help of research techniques like fluorescence imaging of individual viruses in real-time, dominant-negative mutants, siRNA knockdowns, protein kinase selective inhibitors, phosphoproteome profiling, and others. These approaches deepen our knowledge of the molecules involved in the early stages of the IAV life cycle and also serve as the basis for the development of new effective antiviral drugs. In our review, we analyze recent publications on the mechanisms of IAV adsorption, newly discovered receptors for virus attachment, and signal transmission in the site of the adsorbed virion. Besides this, we consider new data on the development of selective inhibitors as antiviral drugs aimed at both viral and cellular factors of IAV adsorption.

Cyclodepsipeptides: Isolation, Bioactivities, Biosynthesis and Total Synthesis

Cyclodepsipeptides, mainly derived from marine organisms and soil microorganisms, are amphiphilic molecules consisting of short oligopeptides with fatty acid tails attached to form a macrocyclic structure. Studies on the activity of cyclodepsipeptides have shown that they have cytotoxicity, antibacterial and anthelmintic effects, and are widely used in biological control, drug development, environmental remediation and disease treatment. Cyclodepsipeptides play a prominent role in the development of new drugs and drug lead compounds, especially as antibiotics with great medicinal potentiall, and are slowly seeping into the public consciousness. The biosynthesis of cyclodepsipeptides is mainly based on the synthesis of non-ribosomal peptide synthases, and selection of key regulatory enzymes for homologue regulation and biosynthetic strategies using genetic engineering and metabolic engineering approaches. The biosynthesis method is miniaturised, recyclable, and safer. The total synthesis methods of cyclodepsipeptides are mainly combined solid-liquid phase methods, which synthesise cyclodepsipeptides faster and are easy to purify. This paper reviews the biological activities of cyclodepsipeptides, their biosynthesis, and total synthesis.

A Review on Carbazole and Its Derivatives as Anticancer Agents From 2013 to 2024.

Carbazole, a natural alkaloid, has been recognized as an effective anticancer agent for over 40 years. However, only a limited number of carbazole-based compounds have received FDA approval for cancer treatment. Current cancer therapies are often associated with significant side effects, causing physical, emotional, and financial burdens for patients. Additionally, despite advancements, cancer prevention and treatment remain challenging due to suboptimal clinical outcomes. The development of new drugs is crucial for achieving safer and more effective cancer therapies. This review focuses on various carbazole derivatives and hybrid composites, highlighting their interactions with distinct receptors and their mechanisms of anticancer action, along with a general structure-activity relationship (SAR). It also emphasizes carbazole-based compounds employed in chemoprevention, which aim to delay or prevent malignant progression. By covering carbazole derivatives and their anticancer potential from 2013 to the present, along with their current clinical status, this study offers valuable insights and updates for researchers in the field.

Oncomine panel testing in the clinical management of colorectal cancer: An Irish experience.

212 Background: Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. It has been hypothesized that the molecular signatures of EOCRC could differ from those of late onset CRC (LOCRC). Next Generation Sequencing (NGS) using the Oncomine Precision Assay is a useful tool to guide treatment decisions based on the presence or absence of oncogene drivers. While not all of these mutations currently influence the clinical management of CRC patients, ongoing research on the function of these genes and the development of new drugs could offer insights into patient prognosis, treatment choices and prediction of therapy resistance. Methods: Of &gt;1500 CRC identified between 2010 and 2024, we investigated the clinical and genetic characteristics of 38 EOCRC and 41 LOCRC cases. All cases were microsatellite stable and staged I-III. NGS was performed with the Ion Torrent Genexus integrated platform using the Oncomine 45-gene Precision Assay panel. DNA hotspot mutations and copy number variations (CNVs) were assessed, followed by the classification of clinically relevant mutations using the genetic variant OncoKB database. Results: There were 38 EOCRC and 41 LOCRC cases. The age range was 27 to 49 and 50 to 91, with median ages of 44 and 72, in the EOCRC and LOCRC groups, respectively. Based on the stratification of NGS mutation levels as per the OncoKB classification, all patients in both groups (100%) had level 1 actionable mutations. NRAS wild type (WT) status was present in 100% of patients in both groups. However, differences were observed in KRAS status: 84% (32/38) of EOCRC were KRAS WT, while only 65% (27/41) of LOCRC were KRAS WT. While 3 % (n=1) of the EOCRC cohort had an ERBB2 amplification, none were detected in the LOCRC group. BRAF V600E mutations were present in 11% (4/38) of EOCRC and 12% (5/41) of LOCRC. Level 4 mutations were detected in 18% (n=7) of EOCRC, all of which were PIK3CA mutations, while these were seen in 24% (n=10) of the LOCRC group, including 9 PIK3CA mutations and 1 FGFR1 mutation. Regarding concurrent mutations, 2 patients in the EOCRC group had two mutations each: one with concurrent KRAS and PIK3CA mutations, and another with concurrent JAK2 and KRAS mutations. The LOCRC group had a higher incidence of concurrent mutations, with 8 patients affected: 6 had concurrent KRAS and PIK3CA mutations, and 2 had concurrent BRAF and PIK3CA mutations. Conclusions: Our study demonstrates that EOCRC have higher KRAS WT status and fewer concurrent mutations compared to LOCRC, who exhibit more frequent KRAS non-G12C oncogenic mutations. It also underscores the importance of routine NGS mutation panel analysis in CRC management. Additionally, identifying specific mutations in patients that relapse can guide targeted therapies, potentially improving outcomes and offering personalized treatment options.

Decoding KRAS dynamics: Exploring the impact of mutations and inhibitor binding.

KRAS (Kirsten rat sarcoma viral oncogene homologue), the most common mutated protein in human cancers, is the leading cause of morbidity and mortality. Before Sotorasib (AMG-510) was approved for non-small cell lung cancer treatment in 2020, the oncogenic KRAS mutations were believed to be non-druggable. High-resolution X-ray crystal structures of GDP-bound KRAS mutants with and without inhibitor are resolved and deposited in the Protein Data Bank (PDB). Nevertheless, to develop inhibitors targeting oncogenic KRAS mutants, understanding the dynamics of protein conformations and respective binding sites is crucial. In the present study, multiple molecular dynamics (MD) simulations were conducted on wild-type and mutant KRAS structures to understand how G12C or G12D mutations lead to the stabilization of the active state and how KRAS inhibitors lock the mutated conformations in their inactive state. The study found that the guanosine diphosphate (GDP)-bound KRAS mutants, G12C and G12D, were locked in the inactive state, in terms of stability, when the KRAS inhibitors, AMG-510 and MRTX1133, respectively, bind to the respective Switch-II (S-II) pocket. Covalent inhibitor AMG-510 locked the inactive GDP-bound KRASG12C mutant more efficiently when compared to the non-covalent inhibitor MRTX1133. The Cα atom distance between key highly dynamic amino acids from P-loop, Switch-I, and Switch-II domains, lying within 4Å of the inhibitor, were stable in the KRAS mutant with bound inhibitors (AMG-510 or MRTX1133), but were varying largely in the absence of any inhibitor throughout the microsecond simulation. According to the per-residue energy decomposition results, S-II amino acids in inhibitor-free KRASG12C and KRASG12D mutants showed larger variations in energy values as compared to AMG-510-bound KRASG12C and MRTX1133-bound KRASG12D, respectively. For example, the inhibitor-free KRASG12C exhibited larger variations in energy values in the S-II residues, namely, Thr58, Gln61, Glu63, and Arg68, as compared to the AMG-510-bound KRASG12C. The study found that the higher stability of AMG-510 in torsion angles was due to its covalent nature of binding to the KRASG12C mutant. The S-II amino acids, namely, Thr58, Glu63, and Arg68 remained stable in AMG-510-bound KRASG12C. The study showed that AMG-510 binding significantly stabilizes the amino acids surrounding it, surpassing that of MRTX1133. The insights gained in the present study is expected to be useful in the design and development of new KRAS-targeted drugs.

Molecular mechanism of Gancao Xiexin Decoction regulating EMT and suppressing hepatic metastasis of gastric cancer via the TGF-β1/SMAD pathway.

Gastric cancer (GC) is a highly malignant tumor of the digestive tract, posing a significant menace to human health. Gancao Xiexin Decoction (GCXXD), being a traditional Chinese medicine (TCM), has a good effect on inhibiting the proliferation and metastasis of GC. However, its mechanisms still need further investigation. To investigate the mechanism by which GCXXD inhibits GC metastasis through network pharmacology, and to verify through in vivo and in vitro experiments. The TCMSP and GEO databases, in combination with UPLC-MS/MS techniques, were employed to identify the hub genes, active ingredients, and critical pathways of GCXXD in the treatment of GC. Subsequently, molecular docking was conducted on both the hub genes and the core components. Finally, based on the results of the bioinformatics analysis, the role of GCXXD in inhibiting liver metastasis of GC was elucidated through in vivo and in vitro experiments, including scratch assays, Transwell assays, HE staining, immunohistochemistry, in vivo live imaging, qRT-PCR, and Western blotting. Utilizing UPLC-MS/MS and network pharmacology, we identified 20 active ingredients and 5 hub targets in the treatment of GC by GCXXD. Through KEGG analyses, GCXXD treatment of GC could through the TGF-beta pathway. In vivo and in vitro experiments, GCXXD downregulated the mRNA and protein expression level of hub genes involved in the TGF-β1/SMAD pathway and the EMT process. Additionally, GCXXD significantly reduced the incidence of liver metastases in GC. GCXXD inhibited EMT via blocking the TGF-β1/SMAD pathway, which suppressed GC cell growth and liver metastasis. This study provides data to support the treatment of liver metastasis in GC with TCM and holds significant importance for the research and development of new anticancer drugs.

A Multi-Source drug combination and Omnidirectional feature fusion approach for predicting Drug-Drug interaction events.

In the medical context where polypharmacy is increasingly common, accurately predicting drug-drug interactions (DDIs) is necessary for enhancing clinical medication safety and personalized treatment. Despite progress in identifying potential DDIs, a deep understanding of the underlying mechanisms of DDIs remains limited, constraining the rapid development and clinical application of new drugs. This study introduces a novel multimodal drug-drug interaction (MMDDI) model based on multi-source drug data and comprehensive feature fusion techniques, aiming to improve the accuracy and depth of DDI prediction. We utilized the real-world DrugBank dataset, which contains rich drug information. Our task was to predict multiple interaction events between drug pairs and analyze the underlying mechanisms of these interactions. The MMDDI model achieves precise predictions through four key stages: feature extraction, drug pairing strategy, fusion network, and multi-source feature integration. We employed advanced data fusion techniques and machine learning algorithms for multidimensional analysis of drug features and interaction events. The MMDDI model was comprehensively evaluated on three representative prediction tasks. Experimental results demonstrated that the MMDDI model outperforms existing technologies in terms of predictive accuracy, generalization ability, and interpretability. Specifically, the MMDDI model achieved an accuracy of 93% on the test set, and the area under the AUC-ROC curve reached 0.9505, showing excellent predictive performance. Furthermore, the model's interpretability analysis revealed the complex relationships between drug features and interaction mechanisms, providing new insights for clinical medication decisions. The MMDDI model not only improves the accuracy of DDI prediction but also provides significant scientific support for clinical medication safety and drug development by deeply analyzing the mechanisms of drug interactions. These findings have the potential to improve patient medication outcomes and contribute to the development of personalized medicine.

Enhancing the in vivo efficacy of anthrax vaccine using trimethylchitosan covalently coated chitosomes in a single-step microfluidic synthesis.

Liposomal vaccines have been developed extensively in recent years, and considerable progress has been made in the prevention of infectious diseases. Quaternary chitosan-coated liposomes were used in the present study. Liposomes coated with TMC (namely chitosomes) were synthesized in a single microfluidic step in which liposomes were formed and coated with trimethylchitosan (TMC) via covalent and/or hydrogen bonds in situ. The endocytosis of chitosomes by JAWS II dendritic cells was detected using flow cytometry. Chitosomes covalently coated with TMC were more efficiently internalized than uncoated liposomes, showed lower cytotoxicity than those coated via hydrogen bonds, and could significantly lower the cytotoxicity via protein mixing. In a BALB/c model, covalent modification of chitosomes improved the efficiency of anti-PA IgG induction via anthrax vaccine adsorbed (AnV), compared with those with hydrogen bonds and those with AnV only, where humoral immunity is dominant. These results suggest that covalently TMC-coated chitosomes serve as a promising delivery system for proteins and that they can be reproducibly obtained via rapid, cost-efficient, and automated methods with few scale-up barriers; meanwhile, their versatile practicability favors commercialization. STATEMENT OF SIGNIFICANCE: In this study, we proved that liposomes coated with TMC (namely chitosomes) via covalent bonds induced better uptake efficiency, stronger in vivo immune responses, and lower cytotoxicity than those coated via hydrogen bonds. The endocytosis efficiency and cytotoxicity of chitosomes were positively correlated with the concentration of the TMC coating. Additionally, this invention provides a facile single-step microfluidic process for the rapid, low-cost, and high-quality preparation of an innovative high-performance chitosomal delivery system that is convenient and easy to scale up. Based on these benefits, the current disclosure provides an alternative platform for the development of new chitosomal drugs.

Leveraging bibliometric analysis competencies for improved postgraduate pharmaceutical education in China

Postgraduate pharmaceutical students are at the forefront of drug development and application in China. In recent years, global pandemics, demand for the research and development of new drugs, and college and university requirements of outcome-based education (OBE) indicate that major reforms in postgraduate pharmaceutical education are essential. A currently neglected aspect of OBE in Chinese pharmaceutical education is bibliometric analysis. To establish a framework for bibliometric analysis training, the researchers searched the top 50 research works in major academic databases using the keywords &amp;ldquo;Pharmacy education&amp;rdquo; and &amp;ldquo;Framework.&amp;rdquo; Ten papers were selected that were closest to the desired paradigm. The procedures, theoretics, and goals of the frameworks in these papers were combined with the researchers&amp;rsquo; teaching and research experience to construct a bibliometric analysis competency (BAC) framework. The BAC framework, which was created to fill current gaps in postgraduate pharmaceutical education, constitutes three levels: (A) knowledge; (B) familiarization; and (C) mastering. The three levels require graduate students to (A) have a preliminary understanding of the steps of bibliometrics, (B) comprehend the literature on bibliometrics, and (C) independently apply the steps to perform bibliometric analysis, respectively. This paper also describes the theoretical setup of the BAC framework and a potential assessment system. The BAC framework provides a useful reference for the reform of Chinese pharmaceutical graduate education, and its future implementation is urgently anticipated.

Advancements in the Research of Astragalus membranaceus for the Treatment of Colorectal Cancer.

Colorectal cancer, characterized by its high incidence, concealed early symptoms, and poor prognosis at advanced stages, ranks as the third leading cause of cancer-related deaths worldwide. Astragalus membranaceus (AM) refers to the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao and Astragalus membranaceus (Fisch.) Bge. In the theory of Traditional Chinese Medicine (TCM), it is believed to have the functions of tonifying qi and lifting yang, as well as generating body fluids and nourishing blood. It can effectively treat cancer caused by the deficiency of vital energy and susceptibility to external diseases. Modern research has confirmed that the active components of AM, including Astragalus polysaccharides, flavonoids (formononetin and calycosin), Astragalus saponins (Astragaloside I and Astragaloside III), and Astragalus nanovesicles, are effective in the treatment of colorectal cancer. The mechanisms mainly involve inducing apoptosis, inhibiting tumor angiogenesis and the metastasis of cancer cells, regulating the cell cycle and tumor microenvironment, and reversing drug resistance. Moreover, it offers a synergistic enhancement when used in combination with chemotherapy, radiotherapy, targeted therapy, or surgical treatment. AM also has great potential in treating colorectal cancer when combined with other herbs. This review summarizes the relevant research findings on the treatment of colorectal cancer with AM, as well as its main pharmacological effects and molecular mechanisms, aiming to provide guidance for the development of new drugs, and offer direction for the conduct of more related research and promoting the development and application of AM.

Reinforcing Nrf2 Signaling: Help in the Alzheimer’s Disease Context

Oxidative stress plays a role in various pathophysiological diseases, including neurogenerative diseases, such as Alzheimer′s disease (AD), which is the most prevalent neuro-pathology in the aging population. Oxidative stress has been reported to be one of the earliest pathological alterations in AD. Additionally, it was demonstrated that in older adults, there is a loss of free radical scavenging ability. The Nrf2 transcription factor is a key regulator in antioxidant defense systems, but, with aging, both the amount and the transcriptional activity of Nrf2 decrease. With the available treatments for AD being poorly effective, reinforcing the antioxidant defense systems via the Nrf2 pathway may be a way to prevent and treat AD. To highlight the predominant role of Nrf2 signaling in defending against oxidative stress and, therefore, against neurotoxicity, we present an overview of the natural compounds that exert their own neuroprotective roles through the activation of the Nrf2 pathway. This review is an opportunity to promote a holistic approach in the treatment of AD and to highlight the need to further refine the development of new potential Nrf2-targeting drugs.

Latest Advancements in the Management of H3K27M-Mutant Diffuse Intrinsic Pontine Glioma: A Narrative Review

Despite recent advancements in radiotherapy for Diffuse Intrinsic Pontine Glioma (DIPG), the prognosis of this disease remains poor, highlighting the need for new treatment strategies to improve outcomes. Adding stereotactic biopsy to the diagnostic process for children with DIPG has been crucial in improving the management of this disease. Indeed, the discovery of the H3K27M mutation as a key driver of DIPG has led to the development of new drugs that are more effective than traditional ones. These include nimotuzumab (an anti-EGFR drug) and vinorelbine (a semisynthetic vinca alkaloid) in combination, Panobinostat (a histone deacetylase inhibitor), ONC201 (a drug that blocks the dopamine receptor D2 and inactivates Akt and ERK kinases), and chimeric antigen receptor (CAR) T cells. In terms of local therapy, identifying the H3K27M mutation can help us explore how genetic changes affect treatment response, recurrence patterns, and survival. Beyond the time to first recurrence, specific patterns of tumor recurrence, like leptomeningeal spread, can influence treatment plans. For example, radiotherapy can be adjusted in terms of doses and volumes, based on tumor aggressiveness. Because the H3K27M mutation is linked to higher malignancy, a slightly higher dose could be used for the second round of local irradiation. Additionally, irradiating the entire craniospinal axis could help control both local and leptomeningeal disease.

Antimicrobial activity of Lactobacillus casei on Staphylococcus pseudintermedius isolates.

Antimicrobial resistance is increasing each year. For example, in 2019 it was directly responsible for an estimated >1 million deaths. Additionally, the development of new drugs is much slower, generating enormous concerns about responses to infection in the future health scenario. Therefore, probiotics have emerged as an alternative to antibiotics. This study aimed to isolate and identify a Lactobacillus casei from healthy canine skin and investigate its antimicrobial effect on isolates of Staphylococcus pseudintermedius originating from dogs with pyoderma. L. casei was isolated from skin samples collected with a sterile cotton swab from the inner pinnae of healthy dogs. It was then cultured, identified using matrix-assisted laser desorption ionisation time-of-flight mass spectrometry, and tested against 30 different clinical isolates and one American Type Culture Collection strain of S. pseudintermedius using the spot-on-the-lawn technique. Its safety was assessed through a modified Kirby-Bauer disc diffusion susceptibility test. L. casei inhibited the growth of all isolates of S. pseudintermedius. The mean value of the inhibition halo of all isolates was 11.3 mm. A significant positive correlation (Pearson's linear correlation = 0.444; p = 0.014) was noted between the inhibitory halos formed by L. casei on the S. pseudintermedius isolates and the halos produced by the tested antimicrobial discs on the same isolates. The L. casei strain demonstrated sensitivity to all tested antimicrobials. The study indicates that using commensal bacteria from canine skin, specifically L. casei, to control bacterial infections caused by S. pseudintermedius can be a promising complementary or alternative therapy to antibiotics relevant to animal and human health.

Potential Molecular Mechanisms of Jiedutongluo Tiaoying Formula in Treating Hyperthyroidism Based on Network Pharmacology and In Vivo Experiments in Mice.

Background: "Jiedutongluo Tiaoying Formula" (JDTLTYF) TCM prescriptions can effectively treat hyperthyroidism and effectively improve the condition of patients. Methods: The main active ingredients of JDTLTYF were collected from the TCMSP database and the target was predicted. Genes related to hyperthyroidism were identified using DisGeNET, GeneCards and OMIM databases. Protein-protein interaction (PPI) network and interaction network of "formula-herb-active ingredient-target genes" was constructed. Mass spectrometry was used to identify the components. The binding of key components to the target was verified by molecular docking and molecular dynamics (MD) simulations. A hyperthyroidism mouse model was established using levothyroxine sodium tablets, and the hormone and expression levels of inflammatory factorswere examined by ELISA and western blot. Results: The key genes of JDTLTYF in the treatment of hyperthyroidism were TNF and AKT1. The results of mass spectrometry also showed that quercetin was one of the main components. The results of molecular docking and MD simulation showed that the binding free energy between AKT1 and quercetin was the lowest and the binding was stable. In vivo experimental results showed that gastric lavage with JDTLTYF could target AKT1 and TNF-α, effectively alleviate the pathological features of hyperthyroidism in mice and reduce inflammation response. Conclusion: This study elucidated the key small molecule compounds and their action targets of JDTLTYF in the treatment of hyperthyroidism. It provides a direction for the development of new drugs for clinical hyperthyroidism.

High prevalence of multidrug resistant and extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolated from urinary tract infections in the West region, Cameroon

BackgroundAntimicrobial resistance remains a worldwide health problem with serious societal and economical repercussions. Multidrug resistant and Extended-Spectrum β-Lactamase producing-Enterobacterales (ESBL-E) are pathogens of critical public health priority that urgently require the research and development of new drugs. This study aims to determine the prevalence and characterize the genes conferring resistance to β-lactams among Escherichia coli and Klebsiella pneumoniae isolated from patients with urinary tract infections (UTIs) in the West region, Cameroon.MethodsA cross-sectional study was conducted among two healthcare facilities during a four-month period from February to May, 2023. All mid-stream urine samples were collected from UTIs patients. The Escherichia coli and K. pneumoniae strains were identified using Enterosystem 18R kit following the manufacturer’s instructions. The antimicrobial susceptibility test (AST) was performed using the Kirby-Bauer disk diffusion method. The screening of ESBL production was done using ESBL ChromAgar medium combined with the double-disk synergy test (DDT). Antimicrobial resistance genes were detected using polymerase chain methods. The data analysis was performed using Excel 2016 and IBM SPSS version 20.ResultsA total of 215 urine samples were collected and analyzed during the study period. A 31.62% (68/215) prevalence of Enterobacterales was detected with prevalence of 79.41% (54/68) and 14.70% (10/68) for Escherichia coli and Klebsiella pneumoniae respectively. The overall prevalence of ESBL-Enterobacterales was 64.70% (44/68). About 82% (36/44) of isolates were MDR and high resistance level was observed for amoxicillin + clavulanic acid and ceftazidime. The resistance genes detected were blaCTX−M, and blaTEM respectively.ConclusionThe findings of this study highlight the high burden of MDR and ESBL-E. coli and K. pneumoniae isolates from UTIs. The study emphasizes the necessity of routine screening and monitoring of antimicrobial resistance in healthcare facilities and community settings. It is therefore crucial to implement antimicrobial stewardship programs in the country and infection prevention and control (IPC) measures in hospital settings.