Toxic Action Research Articles

Biochemistry, Mechanistic Intricacies, and Therapeutic Potential of Antimicrobial Peptides: An Alternative to Traditional Antibiotics.

The emergence of drug-resistant strains of pathogens becomes a major obstacle to treating human diseases. Antibiotics and antivirals are in the application for a long time but now these drugs are not much effective anymore against disease-causing drugresistant microbes and gradually it is becoming a serious complication worldwide. The development of new antibiotics cannot be a stable solution to treat drug-resistant strains due to their evolving nature and escaping antibiotics. At this stage, antimicrobial peptides (AMPs) may provide us with novel therapeutic leads against drug-resistant pathogens. Structurally, antimicrobial peptides are mostly α-helical peptide molecules with amphiphilic properties that carry the positive charge (cationic) and belong to host defense peptides. These positively charged AMPs can interact with negatively charged bacterial cell membranes and may cause the alteration in electrochemical potential on bacterial cell membranes and consequently lead to the death of microbial cells. In the present study, we will elaborate on the implication of AMPs in the treatment of various diseases along with their specific structural and functional properties. This review will provide information which assists in the development of new synthetic peptide analogues to natural AMPs. These analogues will eliminate the limitations of natural AMPs like toxicity and severe hemolytic activities.

Heart Failure with Preserved Ejection Fraction and Cardiac Amyloidosis in the Aging Heart

Heart Failure with Preserved Ejection Fraction (HFpEF) is one of the most frequent causes of heart failure in the world’s population (about 19–55%), and is commonly associated with a high rate of hospitalization (almost 70–80%) and with increased mortality (40–50% in a 5-year timeframe). The elderly are more often affected, with higher rates of hospitalizations than young people, and currently almost 70% of the population aged 65 years old has HFpEF. An increase in cardiomyocyte stiffness, thus resulting in diastolic dysfunction, increased filling pressures and heart failure with preserved ejection fraction are characteristics features of the disease. In addition, among the various causes of HFpEF, cardiac amyloidosis (CA) can provoke diastolic dysfunction and increased wall stiffness directly from intercellular deposition of insoluble proteic substances and their toxic activity. Totally, almost 30 different proteins are able to form deposits, but the most frequently involved are transthyretin and misfolded monoclonal immunoglobulin light chains, which bring to two clinical conditions called transthyretin amyloidosis (ATTR) and light-chain amyloidosis (AL). Although there has been increasing attention on ATTR-CA in recent years, the actual prevalence remains underestimated, especially in people of advanced age, as well as its real impact as a cause of HFpEF, and only data derived from autoptic exams are currently available. Moreover, CA itself often mimics HFpEF, and some conflicting data on the use of predictive scores are described in the literature. The close relationship between HFpEF and CA, especially in older population and the main pathophysiological mechanisms which bond these two conditions are described in this focused review. The need to screen red flags for ATTR-CA in elderly patients with HFpEF is urgently advised, because a prompt recognition of the disease can optimize the approach to the disease with an early therapeutic, life-saving choice.

HLX07 alone or combined with serplulimab, cisplatin and 5-fluorouracil for advanced esophageal squamous cell carcinoma: A phase 2 study.

The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), but few later-line treatments are available. Here we evaluated the therapeutic efficacy of the recombinant, humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC. This open-label, non-randomized, two-cohort, phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks (Q2W). Patients with no prior systemic therapy received HLX07 (1,000 mg, day 1) and serplulimab (200 mg, day 1) intravenously Q2W for up to 2 years, concurrently with cisplatin (50 mg/m2, day 1) for up to 8 cycles and 5-fluorouracil (1,200 mg/m2, days 1-2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Overall, 50 patients were enrolled. In the HLX07 monotherapy group, ORR was 15.0% (3/20), and the median PFS was 1.5 months (95% confidence interval [CI], 1.3 to 3.7). The median duration of response was not reached, and the rate of patients showing an objective response lasting at least 6 months was 66.7% (95% CI, 5.4 to 94.5). Two (10.0%, 2/20) patients experienced grade 3-4 treatment-related adverse events (TRAEs), including hypomagnesemia, hypocalcemia, and fatigue. No patient experienced grade 5 TRAEs. In the HLX07 combination group, the ORR was 60.0% (18/30), and the median PFS was 7.8 months (95% CI, 3.3 to 9.1). Fourteen (46.7%, 14/30) patients experienced grade 3-4 TRAEs, and one (3.3%, 1/30) patient died due to serplulimab-related pneumonitis. HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC. Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC. This trial was registered at Clinicaltrials.gov (NCT05221658).

Toxicity and Repellency of (E/Z)-3-Butylidenephthalide: A Natural Compound Isolated from Ligusticum porteri Root Extract Evaluated Against Imported Fire Ants (Hymenoptera: Formicidae)

Imported fire ants are pests of significant importance, especially in the southern United States. We tested (E/Z)-3-butylidenephthalide, a natural compound that was isolated from the ethanolic extract of Ligusticum porteri roots, as a repellent and toxicant against workers of imported fire ants. A series of serial concentrations, starting from 156 µg/g until failure, were tested using digging bioassays. Workers removed significantly less sand from the vials treated with (E/Z)-3-butylidenephthalide as compared to the ethanol control. Based on sand removal data, (E/Z)-3-butylidenephthalide treatment resulted in a more significant digging suppression against red imported fire ant workers at concentrations ranging between 19.5 and 0.6 µg/g than the solvent control whereas sand removal at 0.3 µg/g was similar with the solvent control. Black imported fire ants showed repellency at serial concentrations ranging between 19.5 and 0.15 µg/g whereas the hybrid imported fire ants showed repellency between 19.5 and 4.9 µg/g. In DEET treatments, red and black imported fire ants showed repellency at dosages of 125 to 62.5 µg/g, whereas the treatment failed at the dose of 15.6 µg/g in hybrid fire ants. (E/Z)-3-butylidenephthalide with LC50 values of 11 and 16.4 µg/g was toxic against red and black imported fire ants, respectively, followed by hybrid imported fire ants (LC50 = 104.7 µg/g). Fipronil with LC50 values of 0.49, 0.33, and 0.53 µg/g against red, black, and hybrid fire ants, respectively, was more toxic than (E/Z)-3-butylidenephthalide. In residual bioassay, toxic activity lasted for 3 weeks at dosages of 250 and 500 μg/g against HIFA. In residual bioassay, toxic activity lasted for 3 weeks at dosages of 250 and 500 μg/g against HIFA. The high repellency and toxicity of (E/Z)-3-butylidenephthalide against imported fire ants makes it a natural compound of interest for further evaluation under natural field conditions.

Antibacterial action of novel zeolite-based compositions depends upon doping with Ag(+) and Сu(2+) cations

Recently, there is a growing interest to exploration of sorption and catalytic properties of solid nanomaterials, in particular natural zeolites, as well as to study of their antimicrobial effects with the aim of potential using them as a principal component of disinfection and degassing remedies. The purpose of this work was to study the antimicrobial action of compositions based on the Transcarpathian clinoptilolite (CL) doped with Ag+ and Сu2+ cations or Ag microparticles (MPs). These compositions were subjected to mechanochemical modification in ethanol medium and with the addition of plant (Actinidia arguta) extract used as an antioxidant. Mechanochemical treatment (MChT) of all forms of CL MPs led to their grinding which caused better contact of CL with bacterial cells, while an increased content of larger pores improved their access to the active sites on the surface of the CL MPs. Treatment of CL samples with metallic silver used as a dopant with the help of the extract of Actinidia arguta plant did not increase the antibacterial activity regardless of treatment time. Treatment of AgNO3 with ethanol slightly increased the antibacterial action of the CL MPs towards Gram-positive bacteria and decreased it towards Gram-negative bacteria. The CL samples doped with copper and treated with ethanol and plant (Actinidia arguta) extract demonstrated comparable toxic action towards Bacillus subtilis regardless of grinding conditions. While such a treatment caused a significant decrease in the antibacterial activity towards Staphylococcus aureus and Pseudomonas aeruginosa strains, compared to the action of samples that were not treated with that plant extract. To address the potential biochemical mechanisms of the antibacterial action of the created zeolite-based compositions, their influence on generation of the reactive oxygen species (ROS) was studied using diphenylpicrylhydrazyl (DPH) fluorescent dye. Most versions of the CL composites demonstrated time-dependent antioxidant effect comparable with the effect of the ascorbic acid used as a positive control. Thus, the ROS generation is not the mechanism that is responsible for the antibacterial action of the created CL-based compositions. Probably, that action is explained by the peculiarities of interaction of doped CL microparticles with the surface of the bacterial cells. Keywords: antimicrobial action, clinoptilolite-based compositions, doping with Ag+ and Сu2+ cations, physicochemical treatment

Validation of ethnopharmacological findings of Aegle marmelos (L.) Correa through phytochemical screening and bioactivity assay

For centuries, medicinal plants have been integral to human health and well-being across the world. Aegle marmelos (Rutaceae), a medicinal plant indigenous to Nepal, holds substantial ethnomedicinal use among indigenous communities in South Asian countries. Present study aimed to explore the integration of contemporary scientific analysis of the phytochemical composition and bioactivity of A. marmelos leaf extracts harvested from Nepal with traditional ethnopharmacological knowledge. Leaf extracts of A. marmelos were subjected to phytochemical analysis utilizing mass spectrometry. The extracts underwent in vitro evaluation for antimicrobial, antidiabetic, antioxidant, and toxicity activities. Hexane fraction was found to possess volatile oils, polyphenols, and tannins, while other fractions were found to have alkaloids, terpenoids, coumarins, flavonoids, glycosides, saponins, and reducing sugars. Further analysis of the hexane fraction identified 21 compounds with over 90 % accuracy. The main phytoconstituents were 9,12,15-octadecatrienoic acid methyl ester (24.25 %), hexadecanoic acid (10.89 %), methylcyclohexane (8.39 %), methyl ester (4.26 %), and caryophyllene (4.10 %). The methanol extract exhibited significant antibacterial activity against Staphylococcus aureus and Escherichia coli. Additionally, the methanol extract demonstrated pronounced cytotoxic effects against brine shrimp, with an LC50 value of 50.11 µg/mL. The 1,1-diphenyl-2-picryl hydrazyl assay revealed both methanol and acetone extract to have notable antioxidant activity, with IC50 values of 90.63 ± 1.47 µg/mL and 89.93 ± 2.52 µg/mL, respectively. Remarkably, the acetone extract displayed superior antidiabetic activity compared to acarbose, with an IC50 value of 13.50 ± 0.79 µg/mL. Our findings proves A. marmelos leaf extracts to harbor significant bioactive constituents, suggesting their potential as sources of natural compounds for applications in medicine and healthcare.

In vivo delivery of PBAE/ZIF-8 enhances the sensitivity of colorectal cancer to doxorubicin through sh-LncRNA ASB16-AS1.

The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.

Microbial depolymerization of Kraft lignin for production of Vanillic acid by indigenous ligninolytic strains

Lignin is a potential renewable source for the production of many value-added bio-products through bacterial depolymerization. In this study, Kraft lignin (KL) was depolymerized by indigenous potential ligninolytic strains to obtain the optimum amount of Vanillic acid. Initially, fifteen bacterial strains were isolated from decaying wood mixed soil to assess their lignin degradation efficiency. Five potential lignin-degrading microbes (RW-B2, RW-B4, RW-B9, RW-B11 and RW-B15) were identified by nutrient enrichment technique. RW-B15 was observed as a dominant strain sharing a 99 % resemblance to Bacillus megaterium sp. Optimum temperature and bacterial inoculum concentration were noted as 35 °C and 1 %, respectively. Mixed microbial culture of five potential ligninolytic strains showed better KL degradation than pure culture due to different metabolic capacities, enzymatic mechanisms and synergetic impact among the association members. The KL degradation study was conducted with different KL concentrations (500–2000 mg/l) at optimum temperature using 1 % inoculums. The production of Vanillic acid increased from 60.1 to 199.9 mg/l with increasing concentration of KL from 500 to 2000 mg/l. The maximum production of Vanillic acid was obtained on 3rd day of degradation and it decreased thereafter which is probably due to an increase in microbial toxicity and enzymatic activity. However, the COD level continuously decreased for all KL concentrations with degradation time till the last day. The pH of the KL solution slightly decreased on 3rd day due to the acidic nature of Vanillic acid. GC-MS analysis confirmed the presence of Vanillic acid and showed the presence of other monomeric compounds formed after KL degradation.

Scoliidines: Neuroprotective Peptides in Solitary Scoliid Wasp Venoms.

A comprehensive LC-MS study examined the venom components of the solitary scoliid wasp Scolia oculata. Online mass fingerprinting showed that crude venom contains 25 small molecules (amino acids, biogenic amines, and nucleosides/nucleotides) and 45 peptides with MW 400-2700. The small molecules were identified by elemental composition analysis, and peptide sequences were determined by ESI-MS/MS and MALDI-TOF/TOF MS analyses. As major peptide components, a known peptide, β-scoliidine (DYVTVKGFSPLRKA), and three new peptides, γ-scoliidine (YVTVKGFSPLR), δ-scoliidine (YVTVKGFSPLREP) and ε-scoliidine (DYVTVKGFSPLREP) were identified, all of which are closely homologous to each other. Once the neuroprotective effects of β-scoliidine have already been described, the other three new scoliidine peptides were analyzed against oxidative stress-induced toxicity in PC12 neuronal cells by mitochondrial metabolism assay, and the structure-activity relationship was evaluated. Interestingly, pre-treatment with ε-scoliidine increased the mitochondrial metabolism of PC12 cells (106 ± 3.6%; p = 0.007) exposed to H2O2-induced oxidative stress in contrast to γ- and δ-scoliidines (77.6 ± 4.8 and 68.5 ± 4.1%, respectively) in compared to cells treated only H2O2 (75.8 ± 2.4%). These new peptides were also analyzed for enzyme inhibitor/substrate assays with angiotensin-converting enzyme (ACE), neprilysin (NEP), and acetylcholinesterase (AChE). In these assays, only δ- and ε-scoliidines increased the AChE activity (128.7 ± 3.8%; p = 0.01; and 116.8 ± 3.8% p = 0.03; respectively) in relation to basal activity (100.1 ± 1.6%). In addition, the four peptides were analyzed through in silico analysis, and none of them demonstrated possible hemolytic and toxic activities. In our study, the comprehensive LC-MS and MS/MS analyses of Scolia oculate venom identified four major peptide components of the venom β-, γ-, δ- and ε-scoliidines, and small differences in their primary structures are important to their neuroprotective properties.

Assessment of disorders of metabolic process on the base of quantification of target proteins under aerogenic influence of aluminum oxide in children

Introduction. The study of the mechanisms of the occurrence of adverse events at the molecular level, followed by the study of biological processes at the cellular, tissue, and organ level, allows further investigating the mechanism of the toxic action of chemicals to predict the development of adverse effects in humans. The purpose of the study is to evaluate disturbances in the signal-transporter pathways of metabolic processes on the base of the quantification of identified target proteins under aerogenic exposure to aluminum oxide in children. Materials and methods. Using the methods of chemical-analytical, statistical, proteomic, biochemical, histological research, and bioinformation analysis, the adverse effects were assessed in 4–7 years children and Wistar rats exposed to aerogenic and inhalation exposure to aluminum oxide (Al2O3). A comparative analysis of the results obtained in the experiment and natural conditions was carried out. Results. In children under conditions of long-term aerogenic exposure to Al2O3 at the level of 0.1–1.0 RfC, the urine concentration of the studied substance was found to be up to 2 times higher than the average comparison value and the reference value. In the experiment with chronic inhalation of Al2O3 at a dose equivalent to the real one, the aluminum urine content in rats was 3.5 times higher than the control value. Comparative analysis of proteomic maps in children revealed 23 significantly different protein spots, 8 of which had a relationship between intensity changes and an increase in Al urine concentration. In rats, 15 significantly different protein spots were found between the groups, 13 of which had a reliable relationship with the exposure marker. In natural and experimental studies, only two identical proteins were found: apolipoprotein A-I and transthyretin; increased levels of ALAT, ASAT and alkaline phosphatase, total and direct bilirubin, gamma-aminobutyric and glutamic acids, lipid hydroperoxide in the blood serum; increased MDA and decreased AOA in the blood plasma. Pathomorphological changes in the tissues of the brain, heart, and liver were confirmed in the experiment. Limitations. The research conducted allows drawing a conclusion about the effect of Al2O3 on the body only through the aerogenic route of entry. Conclusion. Based on the bioinformational analysis of the results obtained and assessment of the cause-and-effect relationships of the transformation of the proteomic profile of blood plasma under natural conditions, verified in the experiment, the leading molecular-cellular events in the development of adverse effects in the form of oxidation, imbalance of lipoprotein and neurotransmitter metabolism, and decreased neurogenesis activity were identified. Metabolic disorders are predicted in the tissues of the heart, blood vessels, liver, and brain under continued conditions of aerogenic exposure to Al2O3. The study of the cascade of events of adverse responses (from the molecular to the organ level) expands knowledge about the pathogenetic mechanisms of metabolic processes of dysregulation of signal-transporter pathways in the human body in response to the influence of a chemical factor, including Al2O3. This increases the effectiveness of early prediction of the occurrence of the disease and the development of targeted measures to prevent adverse consequences.

Acute toxicity and anti-inflammatory activity of an improved traditional medicine developed in Burkina Faso

An Improved Traditional Medicine (ITM) in capsule form presented by traditional health practitioners in Burkina Faso as used for hepatoprotective and hepatocurative treatment for viral hepatitis B. The study's main objective was to investigate the anti-inflammatory properties of this ITM, which is used in treating viral hepatitis B in traditional medicine in Burkina Faso. Phytochemical screening revealed the presence of flavonoids, saponins, tannins, coumarins, alkaloids, sterols and triterpenes. The in vitro anti-inflammatory assay inhibited LOX by 15.69 ± 0.50% at a 100 µg/mL concentration. The LD50 was estimated to be greater than 5000 mg/kg. In vivo activity using the carrageenan anti-oedema test showed good dose-dependent anti-inflammatory activity of ITM at 30, 65 and 130 mg/kg bw. After 3 hours, the extract at various doses reduced edema to over 50% inhibition. After 5 h, oedema was reduced to 85.209% at the 130 mg/kg. However, the reference acetylsalicylic acid (ASA) at 100 mg/kg bw showed a percentage of 85.048% at 5 h. The IC50 obtained after the ABTS, FRAP and LPO antioxidant tests of the phytomedicine were 351.00 µg/mL, 353.20 mM EAA/L and 81.13%. However, the IC50 with the DPPH method was higher than 104 mg/mL. The phytomedicine would have anti-inflammatory and antioxidant properties due to the presence of bioactive phytochemicals on inflammation and free radicals. Keywords: ITM, Phytochemical, Acute toxicity, Anti-inflammatory, Antioxidants

Marine Bacillus pumilus substances exhibit antimicrobial effect on multidrug-resistant Staphylococcus aureus.

This study aimed to assess the antimicrobial potential of Bp1-AdE, produced by Bacillus pumilus 64-1, and to investigate its mode of action against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Bp-1AdE, derived from sponge-associated B. pumilus, exhibited bactericidal activity at 1,550 µg ml-1 against S. aureus ATCC29213 and MRSA strains. Light and fluorescence microscopy revealed drastic cell lysis of S. aureus treated with Bp-1AdE. Scanning and transmission electron microscopy suggested that Bp-1AdE disrupts the cytoplasmic membrane. Toxicity assays showed that Bp-1AdE was non-toxic to Tenebrio molitor larvae. Liquid chromatography-mass spectrometry (LC-MS) and Global Natural Product Social (GNPS) spectral libraries identified four substances within Bp-1AdE, including aliphatic alcohols [3,4-dipentylhexane-2,5-diol and 1,1'-(4,5-dibutyl-3,6-dimethylcyclohexane-1,2-diyl)bis(ethan-1-one)] and terpenoids (cholic acid and canrenone). Bp-1AdE demonstrated selective toxicity and bactericidal activity, highlighting its potential for controlling infections caused by multidrug-resistant S. aureus strains.

Advanced glycation end-product crosslinking activates a type VI secretion system phospholipase effector protein

Advanced glycation end-products (AGE) are a pervasive form of protein damage implicated in the pathogenesis of neurodegenerative disease, atherosclerosis and diabetes mellitus. Glycation is typically mediated by reactive dicarbonyl compounds that accumulate in all cells as toxic byproducts of glucose metabolism. Here, we show that AGE crosslinking is harnessed to activate an antibacterial phospholipase effector protein deployed by the type VI secretion system of Enterobacter cloacae. Endogenous methylglyoxal reacts with a specific arginine-lysine pair to tether the N- and C-terminal α-helices of the phospholipase domain. Substitutions at these positions abrogate both crosslinking and toxic phospholipase activity, but in vitro enzyme function can be restored with an engineered disulfide that covalently links the N- and C-termini. Thus, AGE crosslinking serves as a bona fide post-translation modification to stabilize phospholipase structure. Given the ubiquity of methylglyoxal in prokaryotic and eukaryotic cells, these findings suggest that glycation may be exploited more generally to stabilize other proteins. This alternative strategy to fortify tertiary structure could be particularly advantageous in the cytoplasm, where redox potentials preclude disulfide bond formation.

Evaluation of the in vitro toxicity and anti-inflammatory activity of the methanolic extract of the leaves of Pistacia lentiscus L. harvested from northwestern Algeria.

Medicinal and aromatic plants have been used for thousands of years for their therapeutic properties, to treat various ailments and maintain health. This study was carried out to test the in vitro toxicity and anti-inflammatory activity of the methanolic extract of the leaves of Pistacia lentiscus L., native to the north-western region of Algeria. Toxicity was studied in vitro by the hemolysis test and anti-hemolytic activity on human red blood cells, while anti-inflammatory activity was assessed in vitro by the protein denaturation method. The study of toxicity by hemolysis of red blood cells showed a high rate of hemolysis at a dose of 200 mg/mL, with a hemolytic percentage of around 88.64%, while a high rate of anti-hemolysis was observed at a dose of 25 mg/mL, with an inhibition percentage of around 83.17%. Evaluation of anti-inflammatory activity revealed a high percentage of inhibition of ovalbumin denaturation, reaching 63.53% at the 2000 ug/mL dose, while the lowest percentage was obtained at the 3500 ug\mL concentration with 10.16%. This extract has a toxic substance but does not exceed the toxicity threshold which achieves significant anti-inflammatory activity with depandant doses.

Efficacy and safety of Anlotinib based neoadjuvant chemotherapy for locally advanced triple negative breast cancer (TNBC)

BackgroundAnlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.MethodsLocally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.ConclusionsAnlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms.

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms.

Construction of 2-azidacetic acid functionalized high-crystallinity fluorescent covalent organic framework: Applications in mitoxantrone and Fe3+ sensing and adsorption

Due to the dual functions of fluorescence detection and adsorption, fluorescent covalent organic frameworks (COFs) have attracted significant attention. However, common fluorescent COFs often exhibit unsatisfactory fluorescence properties and selectivity, coupled with poor solution dispersibility, which limit their effectiveness in detection and adsorption applications. In response, a novel post-modified fluorescent COF (named AZC-COF) was synthesized by connecting a fluorescent COF (COF-TB) with 2-azidacetic acid through a copper-catalyzed aide-alkyne cycloaddition (CuAAC) reaction. AZC-COF demonstrated excellent solution dispersibility and robust green fluorescence, boasting an absolute fluorescence quantum yield (QY) of 7.58%, which was 13.5 times higher than that of COF-TB. Furthermore, leveraging the active carboxylic acid and triazole sites, AZC-COF exhibited remarkable binding abilities for mitoxantrone (MIX) and Fe3+, enabling sensitive detection and efficient adsorption of them. In contrast, due to the absence of these functional sites, COF-TB showed poor detection and enrichment capabilities for MIX and Fe3+. The impressive detection and adsorption efficiencies of MIX and Fe3+ in environmental water, aquatic organism (fish) and plasma samples underscore the potential of AZC-COF as a detection-adsorption platform. Additionally, AZC-COF demonstrated low toxicity and hemolytic activity, alongside promising potential for cell imaging and detection of MIX and Fe3+, highlighting its considerable application prospect in biological systems.

Hybrid random projection: Integrating dense and sparse techniques for enhanced representation in high-dimensional data

This paper introduces a novel hybrid random projection method (HRP) that effectively combines the strengths of normal random projection (NRP) and plus-minus one random projection (PMRP). By incorporating a blending parameter, HRP optimises the contributions of the NRP and PMRP, reducing the dimensions of the data while ensuring that the structure of the data is preserved. Conventional methods, such as NRP and PMRP, are recognised for their benefits; however, they also have limitations. NRP is generally accurate but can encounter difficulties with certain data types or noise. The PMRP is simple, but occasionally fails to capture complex relationships within the data. The performance of HRP is investigated through comprehensive evaluations, including simulations and real-world data analyses from key machine learning datasets, such as period change, toxicity, MNIST, and human activity recognition (HAR). We examine various factors such as sample size, dimensions of the original and reduced data, and sparsity. Distance distortion is the primary metric utilised to measure performance, and indicates how well the dataset structure is maintained after dimension reduction. In every test, HRP consistently demonstrates the least distance distortion, performing superiorly to the NRP and PMRP. This is true for a range of scenarios and datasets. HRP represents a significant advancement in dimension reduction techniques. Its ability to minimise information loss during the reduction process demonstrates its potential as a powerful tool for managing complex high-dimensional data in practical applications. This renders HRP an important development in the fields of machine learning, intelligent systems, and artificial intelligence, offering improved efficiency and precision in data analyses.

Evaluation of joint toxic action for antibiotics based on bacterial quorum sensing

Evaluation of joint toxic action for antibiotics based on bacterial quorum sensing

The mode of toxic action of ionic liquids: Narrowing down possibilities using high-throughput, in vitro cell-based bioassays

Growing concerns about the environmental impact of ionic liquids (ILs) have spurred research into their (eco)toxic effects, but studies on their mode of toxic action (MOA) still remain limited. However, understanding the MOA and identifying structural features responsible for enhanced toxicity is crucial for characterising the hazard and designing safer alternatives. Therefore, 45 ILs, with systematically varied chemical structures, were tested for cytotoxicity and two specific endpoints in reporter gene assays targeting the Nrf2-ARE mediated oxidative stress response (AREc32) and aryl hydrocarbon receptor activation (AhR-CALUX). While none of the ILs activated the reporter genes, cytotoxicity was high and markedly different between cell lines. Seven and 25 ILs proved more cytotoxic than predicted by baseline toxicity model in the AREc32 and the AhR-CALUX assays, respectively. The length of the side chain and headgroup structures of ILs altered the MOA of ILs. Cellular metabolism of the ILs, investigated by LC-MS/MS, showed side-chain oxidation of the long-chain quaternary ammonium compounds in AhR-CALUX cells and, to a lower extent, in AREc32 cells, however, this transformation could not explain the high cytotoxicity. Effect data for 72 ILs for ten endpoints retrieved from the Tox21 database identified the inhibition of aromatase activity and of mitochondrial membrane potential as potential MOAs. However, in vitro fluorimetric assays for these endpoints demonstrated that effects were activated in a non-specific manner, probably through cytotoxicity. Although many of the ILs tested induced cytotoxicity at concentrations lower than baseline toxicity, the specific MOAs responsible could not be identified. Alternatively, we suggest that the descriptors currently used may fail to define the affinity of ILs for cells. Testing of the affinity of ILs for a diverse range of biomolecules is needed to accurately describe their interactions with cells.