Low Toxicity Research Articles

Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin adjuvants.

Antimicrobial resistance (AMR) is a formidable global health challenge. Multidrug-resistant (MDR) Gram-negative bacterial infections are of primary concern due to diminishing treatment options and high morbidity and mortality. Colistin, a polymyxin family antibiotic, is a last-resort treatment for MDR Gram-negative infections, but its wider use has resulted in escalating resistance. In 2022, using a screening approach, we discovered that a [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP)-containing compound selectively re-sensitized various MDR Gram-negative bacteria to colistin. Initial structure-activity relationship (SAR) studies confirmed that bisanilino ODP compounds are colistin adjuvants with low mammalian toxicity. Herein, we report our extended SAR studies on a wide range of ODP analogs bearing alkyl- or arylalkylamines. Specifically, we discovered two new compounds, 5q and 8g, with potent colistin-potentiating activity and low mammalian toxicity in a wide range of clinically relevant pathogens.

Clinical outcomes analysis of image-guided brachytherapy as definitive treatment for inoperable endometrial cancer

ObjectivesThis study evaluates the efficacy and toxicity of image-guided brachytherapy combined with or without external beam radiotherapy (IGBT ± EBRT) as definitive treatment for patients with inoperable endometrial cancer (IOEC), in addition to establishing a risk classification to predict prognosis.MethodsFifty-one IOEC patients who underwent IGBT ± EBRT at Peking Union Medical College Hospital from January 2012 to December 2021 were retrospectively analyzed, of which 42 patients (82.4%) were treated with IGBT + EBRT and 9 patients (17.6%) with IGBT alone. Establishing risk classification based on FIGO 2009 staging and biopsy pathology, stage III/IV, non-endometrioid, or Grade 3 endometrioid cancer were included in the high-risk group (n = 25), and stage I/II with Grade 1–2 endometrioid cancer was included in the low-risk group (n = 26).ResultsThe median follow-up time was 58.0 months (IQR, 37.0–69.0). Clinical complete remission (CR) was achieved in 92.2% of patients after radiotherapy (n = 47). The cumulative incidences of locoregional and distant failure were 19.6% (n = 10) and 7.8% (n = 4), respectively. A total of 20 patients died (39.2%), including 10 cancer-related deaths (19.6%) and 10 comorbidity-related deaths (19.6%). The 5-year locoregional control (LRC), time to progression (TTP), overall survival (OS), and cancer-specific survival (CSS) were 76.9%, 71.2%, 59.4%, and 77.0%, respectively. No Grade 3 or above acute or late toxicities were reported. In univariate analysis, LRC, TTP, and CSS were significantly higher in the low-risk group than in the high-risk group (P < 0.05). After adjusting for age, number of comorbidities, radiotherapy modality, and chemotherapy, the low-risk group was still significantly better than the high-risk group in terms of LRC (HR = 6.10, 95% CI: 1.18–31.45, P = 0.031), TTP (HR = 8.07, 95% CI: 1.64–39.68, P = 0.010) and CSS (HR = 6.29, 95% CI: 1.19–33.10, P = 0.030).ConclusionsIGBT ± EBRT is safe and effective as definitive treatment for IOEC patients, achieving satisfactory locoregional control, favorable survival outcomes, and low toxicity. Risk classification based on FIGO 2009 staging and biopsy pathology is an independent prognostic factor for LRC, TTP, and CSS.

Cardioprotective effects of cinnamoyl imidazole on apoptosis and oxidative stress in hypoxia/reoxygenation-induced H9C2 cell lines.

This study explored the effects of cinnamoyl imidazole on alleviating oxidative stress and apoptosis in hypoxia/reoxygenation (H/R)-induced H9C2 cells, using computational analysis with in-vitro validation. Computational techniques, including SwissADME and Swiss Target Prediction, were employed to predict the ADME properties and to identify targets of cinnamoyl imidazole. Differential gene expression (DEG) analysis was conducted on myocardial infarction (MI) datasets obtained from the Gene Expression Omnibus. Gene enrichment and molecular simulation studies were done to focus on apoptotic pathways. The computational findings were validated through In vitro experiments on H9C2 cardiomyocytes subjected to 8 h of hypoxia followed by 24 h of reoxygenation. Antioxidant enzyme levels (catalase, GST, GSH-Px, and SOD), mitochondrial membrane potential (ΔΨm), caspase-3 activity, and the expression of CASP3, MAPK8, JAK2, and BCL2L1 were assessed. Cinnamoyl imidazole has demonstrated favourable pharmacokinetic properties, characterized by high gastrointestinal absorption and low toxicity with negative toxicity for organ endpoints. Molecular docking studies revealed the strong binding affinities for CASP3, MAPK8, and JAK2. In vitro results showed a significant increase in cell viability (94.7 % at 10 μM, p < 0.001) and antioxidant enzyme activity, along with a 64.3 % reduction in caspase-3 activity at 1000 μM (p < 0.01). Cinnamoyl imidazole treatment preserved mitochondrial membrane potential, downregulated pro-apoptotic genes CASP3 and MAPK8, and upregulated the anti-apoptotic gene BCL2L1. Cinnamoyl imidazole effectively mitigates oxidative stress and apoptosis in H/R-induced H9C2 cells, enhancing cell viability and antioxidant defenses while maintaining mitochondrial integrity.

Self-Assembling Peptides for Vaccine Adjuvant Discovery

Vaccination is credited as a significant medical achievement contributing to the decline in morbidity and mortality of infectious diseases. Traditional vaccines composed of inactivated and live-attenuated whole pathogens confer the induction of potent and long-term immune responses; however, traditional vaccines pose a high risk of eliciting autoimmune and allergic responses as well as inflammations. New modern vaccines, such as subunit vaccines, employ minimum pathogenic components (such as carbohydrates, proteins, or peptides), overcome the drawbacks of traditional vaccines and stimulate effective immunity against infections. However, the low immunogenicity of subunit vaccines requires effective immune stimulants (adjuvants), which are an indispensable factor in vaccine development. Although there are several approved adjuvants in human vaccines, the challenges of matching and designing appropriate adjuvants for specific vaccines, along with managing the side effects and toxicity of existing adjuvants in humans, are driving the development of new adjuvants. Self-assembling peptides are a promising biomaterial rapidly emerging in the fields of biomedicine, vaccination and material science. Here, peptides self-assemble into ordered supramolecular structures, forming different building blocks in nanoparticle size, including fibrils, tapes, nanotubes, micelles, hydrogels or nanocages, with great biostability, biocompatibility, low toxicity and effectiveness at controlled release. Self-assembling peptides are effective immunostimulatory agents used in vaccine development to enhance and prolong immune responses. This review describes the predominant structures of self-assembling peptides and summarises their recent applications as vaccine adjuvants. Challenges and future perspectives on self-assembled peptides as vaccine adjuvants are also highlighted.

Research Progress on Immunomodulatory Effects of Poly (Lactic-co- Glycolic Acid) Nanoparticles Loaded with Traditional Chinese Medicine Monomers.

Immunomodulatory mechanisms are indispensable and key factors in maintaining the balance of the environment in humans. When the immune function of the immune system is impaired, autoimmune diseases occur. Excessive body fatigue, natural aging of the human body, malnutrition, genetic factors and other reasons cause low immune function, due to which the body is prone to being infected by bacteria or cancer. Clinically, the existing therapeutic drugs still have problems such as high toxicity, long treatment cycle, drug resistance and high price, so we still need to explore and develop a high efficiency and low toxicity drug. Poly(lactic-co-glycolic acid) (PLGA) refers to a nontoxic polymer compound that exhibits excellent biocompatibility. Traditional Chinese medicine (TCM) monomers come from natural plants, and have the characteristics of high efficiency and low toxicity. Applying PLGA to TCM monomers can make up for the defects of traditional dosage forms, improve bioavailability, reduce the frequency and dosage of drug use, and reduce toxicity and side effects, thus having the characteristics of sustained release and targeting. Accordingly, PLGA nanoparticles loaded with TCM monomers have been the focus of development. The previous research on drug loading advantages, preparation methods, and immune regulation of TCM PLGA nanoparticles is summarized in the following sections.

Synergistic Effect of Silver Nanoparticles with Antibiotics for Eradication of Pathogenic Biofilms.

The increase in nosocomial multidrug resistance and biofilm-forming bacterial infections led to the search for new alternative antimicrobial strategies other than traditional antibiotics. Silver nanoparticles (AgNP) could be a viable treatment due to their wide range of functions, rapid lethality, and minimal resistance potential. The primary aim of this study is to prepare silver nanoparticles and explore their antibacterial activity against biofilms. AgNPs with specific physicochemical properties such as size, shape, and surface chemistry were prepared using a chemical reduction technique, and then characterized by DLS, SEM, and FTIR. The activity of AgNPs was tested alone and in combination with some antibiotics against MDR Gram-negative and Gram-positive planktonic bacterial cells and their biofilms. Finally, mammalian cell cytotoxicity and hemolytic activity were tested using VERO and human erythrocytes. The findings of this study illustrate the success of the chemical reduction method in preparing AgNPs. Results showed that AgNPs have MIC values against planktonic organisms ranging from 0.0625 to 0.125 mg/mL, with the greatest potency against gram-negative bacteria. It also effectively destroyed biofilm-forming cells, with minimal biofilm eradication concentrations (MBEC) ranging from 0.125 to 0.25 mg/ml. AgNPs also had lower toxicity profiles for the MTT test when compared to hemolysis to erythrocytes. Synergistic effect was found between AgNPs and certain antibiotics, where the MIC was dramatically reduced, down to less than 0.00195 mg/ml in some cases. The present findings encourage the development of alternative therapies with high efficacy and low toxicity.

Mini‐review of developments in the chemical modification of plant‐derived photosensitizing drug hypocrellin and its biomedical applications

AbstractPhotodynamic and photothermal therapy have emerged as standard treatments for a range of tumors and microvascular diseases. However, a significant gap remains in the clinical availability of photosensitizers. Among the vast array of photosensitizers, hypocrellin–a plant‐derived photosensitizing drug–stands out as a potential candidate. It boasts straightforward preparation and purification processes, high phototoxicity, low toxicity in the absence of light, and rapid metabolism within the body. However, hypocrellin's limited water solubility and weak absorption in the phototherapeutic window pose challenges to its use in treating solid tumors. Given the limited number of reviews on this subject, a thorough investigation of hypocrellin is essential. This review focuses on the efforts of scientists to address these challenges through chemical modifications of hypocrellin and its co‐assembly with hydrophilic drug delivery vehicles. A notable advantage of hypocrellin over other photosensitizers is its amenability to modification, resulting in pure monomeric derivatives. Recent studies have shown that modifying specific functional groups on hypocrellin's parent ring can yield more potent derivatives, positioning it as a highly promising strategy in tumor therapy. Beyond its therapeutic potential, this review also explores the diverse applications of hypocrellin, including its role in bacterial and fungal inactivation, as well as its efficacy in treating malignant tumors. Additionally, the utilization of nanoparticles as carriers for modified hypocrellin presents new possibilities for clinical applications. This review offers a detailed examination of recent developments in hypocrellin modification, highlighting its potential to advance photodynamic therapy and a wider range of biomedical applications.

Bismuth(III) Triflate, Bi(OTf)3: Green and Reusable Catalyst for One‐Pot Synthesis of Fused Nitrogen/Oxygen Heterocycle Derivatives

AbstractThere is an increasing demand for the development of catalytic reagents that are nontoxic due to the growing environmental concerns in the present organic transformation. Bismuth(III) compounds have significant potential as catalysts for a range of organic synthesis due to their low toxicity, strong Lewis acid catalytic activity, and great flexibility. In this research work, a series of various chemically and pharmacologically important six‐membered fused nitrogen‐/oxygen‐based heterocycle derivatives were efficiently prepared via a one‐pot multicomponent reaction starting from aromatic aldehydes, malononitrile, and barbituric acid in presence of green and reusable Lewis catalyst bismuth(III) triflate, that is, Bi(OTf)3 in EtOH/H2O (1:1) media. Bi(OTf)3 has the additional benefit of being reusable catalyst, ready availability, eco‐friendliness, and easy to handle to obtain corresponding products in excellent yields (83%–94%). Structure of all synthesized products was characterized on the basis of FT‐IR, 1H‐NMR, 13C‐NMR, and ESI–MS analysis.

Effect of ionic bonding on luminescence properties of histidine maleic anhydride derivatives

Polymeric materials exhibiting room-temperature phosphorescent (RTP) have attracted wide attention for their easy synthesis, low toxicity, and applications in various fields such as data encryption, cell imaging, information security and other fields. Nevertheless, the conventional ways of preparing such materials are mainly focused on doping, which may suffer from phase separation, poor compatibility, and lack of effective methods to promote intersystem crossing and suppress the nonradiative deactivation rates. Herein, a series of polymers with fluorescence and phosphorescence dual emission were prepared by simple radical solution copolymerization. Through rigid ion-bonded cross-linked networks and cross-linked hydrogen-bonded networks between the polymer chains, the non-radiative jumps and achieve ultra-long phosphorescence lifetimes were able to suppress. By suppressing non-radiative transitions through rigid ion-bonded cross-linked networks and intermolecular hydrogen-bonding networks between polymer chains, ultra-long phosphorescence is achieved. Impressively, a LRTP lifetime of up to 815.38 ms in polymers under ambientconditions is set up. Moreover, in this study, phosphorescence emission can be easily tuned by balancing ion radius and charge states. These results outline the construction of polymeric materials, endowing traditional polymers with new characteristics and promising potential applications.

Rebalancing immune homeostasis in combating disease: the impact of medicine food homology plants and gut microbiome

BackgroundGut microbiota plays an important role in multiple human physiological processes and an imbalance in it, including the species, abundance, and metabolites can lead to diseases. These enteric microorganisms modulate immune homeostasis by presenting a myriad of antigenic determinants and microbial metabolites. Medicinal and food homologous (MFH) plants, edible herbal materials for both medicine and food, are important parts of Traditional Chinese Medicine (TCM). MFH plants have drawn much attention due to their strong biological activity and low toxicity. However, the interplay of MFH and gut microbiota in rebalancing the immune homeostasis in combating diseases needs systematic illumination. PurposeThe review discusses the interaction between MFH and gut microbiota, including the effect of MFH on the major group of gut microbiota and the metabolic effect of gut microbiota on MFH. Moreover, how gut microbiota influences the immune system in terms of innate and adaptive immunity is addressed. Finally, the immunoregulatory mechanisms of MFH in regulation of host pathophysiology via gut microbiota are summarized. MethodsLiterature was searched, analyzed, and collected using databases, including PubMed, Web of Science, and Google Scholar using relevant keywords. The obtained articles were screened and summarized by the research content of MFH and gut microbiota in immune regulation. ResultsThe review demonstrates the interaction between MFH and gut microbiota in disease prevention and treatment. Not only do the intestinal microorganisms and intestinal mucosa constitute an important immune barrier of the human body, but also lymphoid tissue and diffused immune cells within the mucosa participate in the response of innate immunity and adaptive immunity. MFH modulates immune regulation by affecting intestinal flora, helps maintain the balance of the immune system and interfere with the occurrence and development of a broad category of diseases. ConclusionBeing absorbed from the gastrointestinal tract, MFH can have profound effects on gut microbiota. In turn, the gut microbiota also actively participate in the bioconversion of complex constituents from MFH, which could further influence their physiological and pharmacological properties. The review deepens the understanding of the relationship among MFH, gut microbiota, immune system, and human diseases and further promotes the progression of additional relevant research.

Experimental and theoretical simulations to examine the influence of nonionic surfactant on the corrosion control of mild steel in hydrochloric acid

The increasing demand for corrosion prevention strategies that are both effective and sustainable is part of the research the background. Nonionic surfactants offer a potential replacement for traditional corrosion inhibitors. These surfactants are well-known for their low toxicity and biodegradability. The research involved conducting experimental tests (such as weight loss, polarization and impedance spectroscopy) and theoretical computations to investigate the role of nonionic surfactant (polyoxyethylene (7) tribenzyl phenyl ether) (PETPE) in controlling the corrosion of mild steel in hydrochloric acid (1.0 M HCl) environment. The results of the study demonstrated that PETPE exhibited significant corrosion inhibition properties for mild steel in HCl solution. The inhibition efficiency of PETPE was found to increase with increasing PETPE concentration. PETPE is an excellent corrosion inhibitor because it significantly reduces the rate of corrosion, as seen by the notable inhibition efficiency result (95.4%) at a relatively low dose of PETPE (100 ppm). Thermodynamic studies were used to discuss the fundamental mechanisms that control PETPE-acid interactions. The adsorption process followed Langmuir adsorption isotherm, indicating a monolayer adsorption of the PETPE on the mild surface. Theoretical computations confirm the strong inhibition behavior of PETPE. The innovative feature of this research is its comprehensive strategy, which integrates experimental studies and theoretical simulations to evaluate the impact of PETPE on the corrosion control of mild steel in hydrochloric acid. The combined effort has the ability to supply valuable knowledge into the mechanisms of corrosion that will lead to the establishment of powerful corrosion control strategies.

A novel carbon quantum dot (CQD) synthesis method with cost-effective reactants and a definitive indication: Hot bubble synthesis (HBBBS)

Carbon quantum dots (CQDs) are carbon-based biocompatible quantum dots that have low toxicity, are more soluble in water, have broad application areas, and the surface modification of these can be performed easily. In this study, we present a new CQD synthesis method with cost-effective reactants that can be easily found in laboratories are used. Besides, there is a definitive indication (bubble) for CQD production, unlike the other methods in the literature. The purification method of the CQDs was also optimized in this study. In the beginning of the synthesis, 3 times centrifugation (x3 CF) of the mixture was performed and the optimization of the purification method indicated that x3 CF before 3 days of dialysis membrane tubing (x3 CF & 3 DM) resulted in the formation of the purest CQDs. The characterization of the CQDs was done utilizing UV–VIS spectrophotometer, Fourier Transfer Infrared Spectroscopy (FT-IR), Zetasizer, fluorescence microscopy, Dynamic Light Scattering (DLS), Scanning Electron Microscope (SEM), Energy Dispersive Spectroscopy (EDS), and Transmission Electron Microscopy (TEM). It was concluded that the CQD formation depends on the mixing of sulphuric acid:acetone (2:1) ratio in a hot (140-165 °C) and an inert environment, and bubble coverage of the mixture surface(30-60 s). The bubble formation due to the reaction between sulphuric acid and pure acetone at high temperatures gives the developed method’s name of “Hot Bubble Synthesis” (HBBBS).

Preparation of a nanofiber membrane loaded with Melastoma dodecandrum Lour. Extract for rapid hemostasis

Melastoma dodecandrum Lour. is a plant with a rapid hemostatic effect that is mainly distributed in Guizhou, Guangxi, Guangdong, and other provinces in China. In this study, we prepared a new rapid hemostatic wound dressing using Melastoma dodecandrum Lour. extract (MDLE). Nanofiber membranes (PVA/CS/MDLE) consisting of polyvinyl alcohol (PVA), chitosan (CS), and different doses of MDLE were prepared using an electrospinning method.Then, each group of nanofiber membranes was characterized using SEM, FTIR, and XRD. The diameters of PVA/CS, PVA/CS/2.8 %-MDLE, PVA/CS/5.5 %-MDLE, and PVA/CS/8.2 %-MDLE were 207.2 ± 36.65 nm, 313.3 ± 68.14 nm, 350.0 ± 80.55 nm, and 371.1 ± 82.84 nm, respectively. PVA/CS/2.8 %-MDLE exhibited the greatest mechanical strength, while PVA/CS/5.5 %-MDLE exhibited the greatest elongation at break. PVA/CS/5.5 %-MDLE and PVA/CS/8.2 %-MDLE exhibited significant bacteriostatic effects and inhibited Staphylococcus aureus more effectively than Escherichia coli. The PVA/CS/8.2 %-MDLE group had a significant hemostatic effect (P < 0.001), and all groups exhibited hydrophilicity, swelling ratios, and low toxicity. As the drug concentration increased, the time required for hemostasis decreased. Overall, these findings demonstrated that the PVA/CS/MDLE has great potential as a wound dressing. To our knowledge, this is the first time that a functional nanofiber with rapid hemostasis has been successfully prepared using MDLE.

Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines

Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (SN), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC50: 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC50: 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense, the causative agent of nagana, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.

Treatment outcomes among patients with isoniazid mono-resistant tuberculosis in Mumbai, India: A retrospective cohort study

BackgroundTuberculosis (TB) remains a significant cause of mortality globally, with India accounting for 27% of the estimated number of people with TB. Multidrug-resistant TB (MDR-TB) and isoniazid (INH) resistance pose additional challenges to effective treatment. We aimed to describe treatment outcomes of INH mono-resistant TB patients under programmatic conditions in Mumbai, India. MethodsThis retrospective cohort study was conducted at Shatabdi Hospital in Mumbai between 2019–2021.We described the clinical and demographic characteristics, treatment outcomes, and risk factors for unfavourable outcomes among patients with INH mono-resistant TB treated with rifampicin, ethambutol, pyrazinamide, and levofloxacin (LfxREZ) for a duration of 6 months. ResultsAmong 3105 patients with drug-resistant TB initiated on treatment, 217 (7 %) had INH mono-resistant TB. Of these, 54 % (117/217) were female, with a median age of 26 years (interquartile range: 20–40). The majority (88 %; 191/217) presented with pulmonary TB, and most (87 %; 188/217) had favourable treatment outcomes, including treatment completion (52 %; 112/217) and cure (35 %; 76/217). Unfavourable outcomes, including treatment failure (2.3 %; 5/217), loss to follow-up (9.2 %; 20/217), or death (1.8 %; 4/217), were observed in 13 % (29/217) of patients. A total of ten (5 %) patients experienced at least one non-severe adverse drug reaction. Factors associated with unfavourable outcomes included severe thinness (p = 0.019) and male gender (p = 0.012). ConclusionTreating INH mono-resistant patients with LfxREZ resulted in satisfactory outcomes and low toxicity. It is important to rule out drug resistance to INH while determining the treatment regimen.

Highly efficient coke dust suppressant with anti-freezing capabilities

Stockpiled coke is prone to wind-blowing emissions, leading to economic losses and environmental pollution which imposes severe threats to human health. While various polysaccharide-based dust suppressants have been explored to resolve this issue, they often suffer from ineffective control of wettability, poor coverage, and suppression effect in extreme weather conditions, and require additional use of cross-linking agents and surfactants due to their weak interaction with coke. Herein, we present coke dust suppressants comprising polyethyleneimine (PEI), starch, and glycerol to address these shortcomings. Our detailed investigations show that the low toxicity, cationic polymer (PEI) electrostatically interacts with the coke, increasing the wettability and promoting aggregation. Moreover, PEI hydrogen-bonds with starch to form a stable film and enhances the water-retention capability. Furthermore, the addition of glycerol lowers the freezing point to −13 °C, preventing coke loss caused by freezing during transportation and energy loss associated with dismantling the frozen coke. Wind erosion tests and bomb calorimeter results reveal that the coke dust suppressant exhibits superior wind resistance and does not interfere with the coke combustion.

De Novo Biosynthesis of L-Azetidine-2-Carboxylic Acid in Escherichia coli Strains for Powdery Mildew Treatment.

L-Azetidine-2-carboxylic acid (L-Aze), a natural nonproteinogenic amino acid found widely in plants, has recently been identified as an environmentally friendly agent for controlling powdery mildew with low toxicity. In this study, a biological route for L-Aze production via the methionine salvage pathway (Yang Cycle) was first in silico designed for Escherichia coli. Subsequently, systematic engineering strategies were employed to enhance the production efficiency, including the enhancement of the 5-phosphoribosyl 1-pyrophosphate (PRPP) supply, construction of the ATP-adenine cycle, and engineering of the strain's resistance to L-Aze. The final strain produced L-Aze from glucose with a titer of 568.5 mg/L. The antifungal activity of the produced L-Aze in the fermentation broth was also confirmed for treating powdery mildew in cucurbits. This approach not only provides a sustainable and green route for pesticide production to control powdery mildew but also expands our understanding of the exogenous construction of the Yang Cycle in E. coli.

Antiproliferative Activity of an Organometallic Sn(IV) Coordination Compound Based on 1-Methylbenzotriazole against Human Cancer Cell Lines

A motivating class of compounds with interest in the research field of biological active metallopharmaceuticals for cancer treatment is based on organometallic complexes of Sn(IV), exhibiting advantages such as improved cellular uptake and body excretion, lower toxicity, and fewer side effects compared to platinum-based drugs. In this study, the mononuclear organotin coordination complex [(CH3)2SnCl2(mebta)2] was synthesized and characterized using vibrational spectroscopy (IR, Raman), 1H NMR, 13C{1H} NMR, and X-ray crystallography. Its antiproliferative properties were thoroughly assessed across an aggressive triple-negative human breast cancer cell line. Notably, comparative studies with precursor materials verified that the observed biological activity is intrinsic to the complex itself. This study highlights the compound’s ability to induce cell fate by disrupting essential cellular functions, such as proliferation. By exploring the antiproliferative effects of organotin(IV) derivatives, we introduce a novel class of Sn complexes with 1-methylbenzotriazole (mebta), demonstrating significant potential as promising antitumor agents in the field of organotin compounds.

Towards novel small-molecule inhibitors blocking PD-1/PD-L1 pathway: From explainable machine learning models to molecular dynamics simulation

Molecular design of small-molecule inhibitors targeting programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway has been recognized as an active research area by the clinical success of cancer immunotherapy. In recent years, using machine learning (ML) methods to accelerate drug design have been confirmed. However, the black box character of ML methods makes model interpretation and ligands optimization obscured. Herein, five explainable ML models were constructed by integrating five ML models with the SHAP method, where these ML models were pretrained with >4000 molecules and their R2 ranged from 0.835 to 0.86 on test set. Subsequently, the explainable ML models were employed to identify the relationship between fragments and bio-activity of a small molecule inhibitor BMS-1166, leading to the modification of BMS-1166 into 60 novel compounds. After consensus docking and ADMET test, 3 small molecules (C27, C52 and C54) with better docking scores and lower toxicity than BMS-1166 were screened out further. Finally, the improved binding affinity of C27, C52 to the PD-L1 dimer was validated by the MD simulation. Overall, this work proposed an efficient protocol on the basis of explainable ML models for designing small-molecule inhibitors targeting PD-1/PD-L1 pathway in a rational way.

Correlation of surface properties with dissolution behavior of amorphous solid dispersion of Riluzole and its pharmacodynamic evaluation

Formulation of amorphous solid dispersion (ASD) of any poorly water-soluble drug is among the most promising techniques to increase the dissolution profile of drug and hence its bioavailability. Various literatures give evidences of the role of drug-polymer interactions in the ASD systems, very little information is available about the surface properties of the drug molecule and their ASDs which contributes to a higher dissolution profile. Current work focuses on exploring the surface behavior of a poorly water-soluble drug Riluzole (RLZ) and its ASDs prepared with two highly hydrophilic polymers, polyacrylic acid (PAA), and polyvinylpyrrolidone vinyl acetate (PVP VA). Initial characterization using X-ray diffraction (XRD) revealed about the weight fraction of drug required to prepare a single-phase homogenous system with both the polymers. The saturation solubility and the dissolution studies showed an increase in RLZ solubility as well as the dissolution profile due to the presence of polymers. The role of polymers in changing the surface properties in terms of wettability and polarity were explored using contact angle method and X-ray photon spectroscopy (XPS). Additionally, the neuroprotective efficacy and dose dependent hepatotoxicity were also evaluated in male wistar rats. These studies confirmed the increase in the surface polarity and hence the enhanced ability of ASD formulations to interact with water. The in vivo studies indicated that at the current recommended dose the efficacy as well as toxicity is increased for the ASD formulation. Hence, this formulation can be given at a lower dose to achieve same therapeutic effect with lower toxicity.