Safe Agent Research Articles

A Review on the Antimutagenic and Anticancer Effects of Cysteamine.

Cancer is one of the leading causes of death worldwide. First-line treatments usually include surgery, radiotherapy, and/or systemic therapy. These methods can be associated with serious adverse events and can be toxic to healthy cells. Despite the new advances in cancer therapies, there is still a continuous need for safe and effective therapeutic agents. Cysteamine is an aminothiol endogenously synthetized by human cells during the degradation of coenzyme-A. It has been safely used in humans for the treatment of several pathologies including cystinosis and neurodegenerative diseases. Cysteamine has been shown to be a potent antimutagenic, anticarcinogenic, and antimelanoma in various in vitro and in vivo studies, but a review on these aspects of cysteamine's use in medicine is lacking in the current literature. The efficacy of cysteamine has been shown in vitro and in vivo for the treatment of different types of cancer, such as gastrointestinal cancer, pancreatic cancer, sarcomas, hepatocellular carcinoma, and melanoma, leading to the significant reduction of lesions and/or the increase of survival time. Although the mechanisms of action are not fully understood, possible explanations are (i) free radical scavenging, (ii) alteration of the tumor cell proliferation by affecting nucleic acid and protein synthesis or inhibition of DNA synthesis, and (iii) hormone regulation. In conclusion, regarding the high safety profile of cysteamine and the current literature data presented in this article, cysteamine might be considered as an interesting molecule for the prevention and the treatment of cancer. Further clinical studies should be performed to support these data in humans.

Control the carcinogenic bacteria with new polysaccharides from agricultural wastes

Agriculture activities industries produce a huge amount of waste every year. Agricultural wastes are a great source of natural polysaccharides characterized by accessibility, biocompatibility, and ease of modification. Finding new safe antibacterial agents has become one of the top priorities of health organizations worldwide. This priority emerged from the antibiotic resistance pathogenic bacteria hazard. Carcinogenic bacteria are one of the most dangerous antibiotic-resistant pathogenic bacteria. This study tries to investigate the antibacterial activity of polysaccharides from some agricultural wastes against carcinogenic bacteria related to gastrointestinal cancers. We determined the antibacterial activity (in terms of minimum inhibitory concentration (MIC)) and the biofilm reduction capacity. We studied the mechanism of the antibacterial activity by determining the effect of the MIC of the extracted polysaccharides on the plasma membrane permeability and the bacterial DNA content. All extracted polysaccharides showed effective antibacterial activity with low MICs ranging from 2 to 20 μg/mL. The barely straw polysaccharides showed the highest MIC (19.844 μg/mL) against Bacteroides fragilis, while the grape bagasse showed the lowest MIC (2.489 μg/mL) against Helicobacter pylori. The extracted polysaccharide showed high antibiofilm activity. Their capacity to reduce the formation of the pathogenic biofilm ranged from 75 to 95%. Regarding the antibacterial mechanism, the extracted polysaccharides showed destructive action on the DNA and the plasma membrane permeability. The bacterial DNA change percent after the treatment with the different polysaccharides ranged from 29% to −58%. The plasma membrane permeability increased by a high percentage, ranging from 92% to 123%. Agricultural waste polysaccharides are a promising antibacterial agent against antibiotic-resistant carcinogenic bacteria.

Cytotoxic Evaluation and Elucidation of Dammarane-Type Triterpenoids Isolated from the Exocarp of Aglaia cucullata (Meliaceae)

Aglaia cucullata is a mangrove plant with a tropical Asian distribution. It is used as traditional medicine for the treatment of diarrhea, inflammation, skin diseases, and heart diseases. Several compounds isolated from A. cucullata have demonstrated cytotoxic activity against various human cancer cells. Cancer therapies such as surgery, chemo-, and radiotherapy have many side effects. However, the use of natural bioactive compounds such as triterpenoid in cancer treatment can be used as an alternative to reduce these side effects. Therefore, the discovery of bioactive compounds from plants is very important to improve aspects of discovery and development of sustainable new anticancer drug candidates. Here, we report the chemical structures of seven known dammarane-type triterpenoids (1–7) isolated from A. cucullata exocarp and evaluate their cytotoxicity against B16-F10 melanoma skin cancer cells. The isolated compounds included cabraleahydroxylactone 3α-acetate (1), (20S)-20-hydroxydammar,24-en-3α-ol (2), (20S)-20-hydroxydammar,24-en-3-on (3), methyl 20(S)-hydroxy-3,4-secodammar-4(28),24-diene-3-oic acid (4), 3-epi ocotillol II (5), cabraleone (6), and ocotillone (7). The n-hexane extract was found to be active against B16-F10 cells, exhibiting an IC50 value of 7.85 ± 0.22 µg/mL. Fractionation of this extract subsequently identified the compound (20S)-20-hydroxydammar 24-en-3-on (3) as an active substance with an IC50 value of 21.55 ± 0.25 µM, comparing favorably with the positive control cisplatin (12.90 µg/mL; 43.00 µM). These results provide further evidence of the genus Aglaia as a source of cytotoxic cancer drug leads. In addition, compound 3 has potential as a convincing therapeutic agent for further research in the context of sustainable drug development, especially the development of new safe cancer chemotherapeutic agents.

Phytochemical composition, toxicological profiling and effect on pup birth weight of Corchorus olitorius leaf extract in rats: Implications for fetal macrosomia control

Ethnopharmacological relevanceCorchorus olitorius is used in ethnomedicine to arrest threatened miscarriage, ease labour, and promote smooth childbirth. Aim of the studyTo evaluate the phytochemical composition, toxicity profile, and effect of Corchorus olitorius L. leaf extract (COLE) on fetal macrosomia control in rats. Materials and methodsThe chemical constituents of COLE were determined using gas chromatography-mass spectrometry (GC-MS). A single dose of up to 5000 mg/kg was administered in the acute toxicity test, and the rats were monitored for 14 days. In the sub-acute toxicity study, rats were treated with the extract for 28 days, and liver function, renal function, lipid profile, and serum antioxidant parameters, coupled with liver and kidney histology, were used to assess the toxicity potential of the extract. In the pup birth weight study, treatment of pregnant rats lasted until the birth of pups and continued for an extra 4 weeks. Rats in group 1 served as a control, whereas rats in groups 2, 3, and 4 received daily doses of 200, 400, and 800 mg/kg body weight of COLE, respectively, via oral gavage. ResultsBioactive compounds such as D-limonene, phytol, hexadecanoic acid, 9-octadecenoic acid (Z), dodecanoic acid, and ethyl 9,12,15-octadecatrienoate with well-known pharmacological activities were detected. LD50 of COLE was >5000 mg/kg. COLE decreased body weight and increased red blood cell, packed cell volume, and haemoglobin values when compared with the control (p < 0.05). COLE significantly decreased alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase but did not cause any significant (p > 0.05) changes in other biochemical (liver and kidney) parameters when compared to control. COLE decreased total cholesterol, triglycerides, low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol when compared with the control (p < 0.05). Birth weights of pups were significantly decreased in the COLE-treated groups when compared with the control (p < 0.05), but the observed difference terminated by the fourth week of weaning. ConclusionThe results showed that COLE is not toxic but has several bioactive compounds with known pharmacological activities and therefore may be a safe oral agent for fetal macrosomia control.

Efficient and safe use of a slow-release Mn material for three sequential crops of rice in Cd-contaminated paddy soils

Traditional passivators reduce the effectiveness of Cd by ion exchange, chemisorption, and complexation in soil. However, traditional passivators have defects such as easy aging and poor durability, which not only reduce the treatment efficiency but also increase the risk of primary soil environmental pollution. For this reason, considering that Mn and Cd have physiological antagonism in rice, sepiolite-supported manganese ferrite (SMF) was prepared in this study to improve passivation persistence. The passivation mechanism, effect and duration of SMF were explored. The results showed that SMF has a dense and small pore structure and that the surface is rough, which provides abundant adsorption sites for Cd2+ adsorption. When the SMF adsorbs Cd2+, ions or functional groups in the material, such as MnOOH*, will exchange with Cd2+ to form Cd(OH)2 and other internal complexes. Indoor pure soil cultivation experiments showed that 0.1 % SMF can reduce the effective Cd content of soil by 41.32 %, demonstrating the efficiency of SMF. The three-crop rice experiments in pots showed that SMF could increase soil pH and continuously increase the content of available Mn in soil. Increasing the content of available Mn reduces the ability of rice to absorb Cd. In addition, the three-cropping rice experiments also indicated that the passivation effect of SMF materials on Cd-contaminated paddy fields was long-lasting and stable and that SMF is a more efficient and safe Cd passivation agent.

Myricetin 3-rhamnoside retards the proliferation of hormone-independent breast cancer cells by targeting hyaluronidase

Breast cancer is the second-leading cause of cancer-related death in women and the most often diagnosed malignancy. As the majority of chemotherapeutic medications are associated with recurrence, drug resistance, and side effects, scientists are shifting to beneficial agents for prevention and treatment, such as natural molecules. Myricetin 3-rhamnoside, a natural flavonol glycoside is known for diverse pharmacological activities but fewer reports describe the antiproliferative ability. The study aims to investigate the antiproliferative efficacy and target [hyaluronidase (HYAL) and ornithine decarboxylase (ODC), two poor breast cancer prognostic markers] modulatory potential of myricetin 3-rhamnoside on breast cancer cell lines using cytotoxicity assays and in silico docking, molecular dynamics analysis, cell-free and cell-based test methods. Myricetin 3-rhamnoside significantly retard the growth of MDA-MB-231 cells in SRB (IC50 88.64 ± 7.14 µM) and MTT (56.26 ± 8.50 µM) assay. It suppressed the transition of cells to the S-phase by inducing arrest in the G0/G1 phase with a fold change of 1.10. It shows robust binding interaction with ODC (-7.90 kcal/mol) and HYAL (-9.46 kcal/mol) and inhibits ODC (15.22 ± 2.61 µM) and HYAL (11.92 ± 2.89 µM) activity, but in a cell-based assay, the prominent response was observed against HYAL (21.46 ± 4.03 µM). Besides, it shows a 1.38 fold-down regulation of HYAL and forms a stable complex with HYAL. The binding pocket for myricetin 3-rhamnoside and the simulation pocket during the simulation are identical, indicating that myricetin 3-rhamnoside is actively blocking hyaluronidase. The computational prediction suggests it is a safe molecule. These observations imply that myricetin 3-rhamnoside could be used as a pharmacophore to design and synthesize a novel and safe agent for managing hormone-independent breast cancer. Communicated by Ramaswamy H. Sarma

A Review on the Synthesis and Anticancer Potentials of Imidazothiazole Derivatives.

Cancer is one of the severe diseases in which abnormal cells divide and proliferate in an uncontrolled manner without any regulation. Globally cancer is among the leading causes of death; according to a recent report of by the WHO, around 10 million people died in 2018 due to cancer. It has also been reported that by 2040, approximately 30 million new cases will be reported every year. The increase in the incidences of cancer is taking a toll on the health care system worldwide. Considerable scientific literature is available on anticancer agents but newer therapeutic strategies are still required in this field to address novel approaches to drug design and discovery to counter this problem. Imidazothiazole represents a privileged scaffold in medicinal chemistry and provides the medicinal chemist the possibility to modulate the physiochemical properties of the lead compound. In recent times, imidazothiazole scaffold is broadly explored for its anticancer activity, which acts through various mechanisms such as EGFR, B-RAF, DHFR kinase inhibition and tubulin polymerization inhibition and other molecular mechanisms of action. Due to their feasible synthetic accessibility and promising pharmacological profile, it has attracted various medicinal chemists to explore and develop imidazothiazole derivatives as potent and safe anticancer agents. In the present article, we have reviewed various potent imidazothiazole scaffold-based derivatives reported as anticancer agents, their synthetic strategies, Structure Activity Relationship (SAR), mechanism of action, and molecular docking along with their future perspective. This review will be very useful for medicinal chemists for drug design and development of imidazothiazole-based potent antiproliferative agents.

Isolation and characterization of a novel phage vB_BceS_LY1 and its application to control newly isolated Bacillus cereus in milk and rice

Bacillus cereus is an important foodborne pathogen that causes food poisoning and other non-gastrointestinal infections, which could cause nausea, vomiting and diarrhea. Phages have antibacterial potential to control this pathogen, especially antibiotic resistant ones. In this study, a novel lytic Bacillus cereus phage, vB_BceS_LY1 (LY1), a new genus of the subfamily Gutmannvirinae under Caudoviricetes, was isolated from a sewage treatment plant in China. It had a large burst size of 230 PFU·Cell−1, was stable over a wide range of temperatures (4–50 °C) and pH (5–11), and was UV-resistant for 65 min. No antibiotic resistance, virulence, or lysogeny-associated genes were observed. Results showed that the phage LY1 had a good biological basis and application potential. For bacteria control, it could significantly inhibit the growth of Bacillus cereus not only in Tryptic Soy Broth, but also in milk and rice. When in the milk, phage LY1 could control the Bacillus cereus even below the detection limit at high MOI (>1000) in 12 h (4 °C). Particularly, the bacteriostatic effect reached 100% within 12 h in rice. In conclusion, phage LY1 with a high lysis capacity and stability, is considered as a novel safe and prospective biocontrol agent against Bacillus cereus.

Interaction Affinity Between Flavonoids Against Cytokines Interleukin 12 in Diabetes Mellitus

Background: Interleukin 12 can destroy insulin-producing cells, suppresses IL4 production, and can stimulate the formation of Thelper1. Quercetin is a flavonoid suitable to be chosen as the lead compound for development of safe anti-diabetic agent because in addition to its anti-diabetic effect, quercetin shows also protective effect in pancreas track.Objective: This research aims to study the docking models of certain flavonoids and to predict the quercetin and triterpene derivatives inhibition activity on Interleukin12.Method: The molecular docking method was used using the PyRx program with the Autodock Vina menu.Results: IL-12 bond affinity with Dextromethoorpene results -7 kcal/mol as the highest affinity value energy while the lowest energy is -6.1 kcal/mol, IL-12 bond affinity value with Quercetin with the highest affinity value energy is -9 kcal/mol, and the lowest energy is -7.8kcal/mol. The affinity value IL-12 bond and triterpene with the highest affinity value is energy -7 .9 kcal/mol, and the lowest energy is -7.4 kcal/molConclusion: Quercetin, has hydrogen bonds and hydrophobic bonds, where the ligand of the Quercetin compound is the ligand that has the ability to form the best interactions and bonds with IL-12 receptors (4OG9)

The frequency and associated factors of infusion-related reactions to rituximab for patients with rheumatoid arthritis

Objectives: Rituximab is an effective biological agent for treating patients with rheumatoid arthritis (RA). Rheumatologists can avoid rituximab therapy because of infusion-related reactions (IRR). There is a lack of data about rituximab-related IRR, especially in rituximab-naïve patients with RA; therefore, we aimed to determine the frequency and associated factors of rituximab-related IRR in these patients. Methods: Baseline demographic, laboratory, and treatment data were noted. One course of rituximab was used in two infusions to 95 rituximab-naïve patients with RA. Standardized premedication was administered before infusions. Rates, severity, and management of IRR were recorded. Efficacy and infections were also noted if there were. Results: Ninety-four of 95 patients completed the rituximab course successfully. We observed a total of 23 IRRs in 20 patients. The frequency of IRR was 12.1%, and serious IRR was 0.52%. Grade 1-2-3 IRRs had a rate of 52.2%, 30.4%, and 17.4%, respectively; grade 4 or 5 IRR wasn’t detected. Age &amp;lt;60 years, anti-CCP &amp;lt;200U/ml and absence of biologic agent use before rituximab was significantly higher in patients with IRR than without IRR (p=0.01, p=0.002, p=0.01 respectively). We found out that if only the disease age is above 60 months, it is protective against IRR as per the results of multivariate model analysis. Conclusion: Results supported that rituximab is a safe biological agent option for patients with RA at secondary central hospitals. Identified risk factors of IRR need to be corroborated in larger studies for safer rituximab therapy.

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates.

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic isletallotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

Exploring the Synergistic Effect of Simvastatin in Oral Health Applications: A Literature Review.

Statins are the first line of treatment for hyperlipidaemia. Along with lowering lipids, it also lowers mortality and cardiovascular risk. Statins play a major role in maintaining the homeostasis of the oral cavity via a number of different mechanisms. It includes regeneration of dentin and pulp by differentiation and increased development of mineralized tissue via the bone morphogenetic proteins (BMP)-2 Pathway. It shows effective bone health by leading to osteogenic differentiation mesenchymal stem cells, by facilitating epithelization process in wound healing, anti-inflammatory, antioxidant, antimicrobial, antiviral, and fungicidal properties. To the finest of the information we have, there have been very few comprehensive studies that have investigated the effects of statin drugs on various aspects of dental and oral health. As a result, the main objective of this reviewwas to examine the effect of statins onoral health applications. According to the findings of our extensive review, statins have noteworthy and promising effects on several aspects oforal health, including dental pulp cells, chronic periodontitis, alveolar bone loss, orthodontic tooth movement, and so on. Nevertheless, it is concluded that local or even systemic administration of simvastatin should be regarded as an innovative, easily accessible, and safe therapeutic agent that has a significant impact on enhancing the oral health.

Phytochemical Components, Antioxidant and Antimicrobial Properties of Fermented Seeds of Foeniculum vulgare

Foeniculum vulgare (fennel) has been used in traditional medicine all over the world including Nigeria for a wide range of ailments. In the present study, the phytochemical analysis, antioxidant activities (by ABTS and DPPH methods), in vitro antimicrobial assays (against Staphylococcus aureus, Salmonella typhi, and Escherichia coli) using agar well diffusion method, and pH of the fermented seeds of F. vulgare were investigated. Phytochemical investigation showed the presence of tannins, terpenoids, phenols, phytosterols, alkaloids, and flavonoids. Alkaloid was absent on day 7 of the fermented seeds but was present on day 14. The antioxidant activity of the fermented sample of F. vulgare at day 14 was proportional to the concentration of the sample.The zones of inhibition (in diameter) obtained were dependent on the tested concentrations (100%, 50% and 25%) and ranged between 5mm-18mm on day 7 and 6mm- 20mm on day 14 against the test pathogens. The trend of acidity increased with the days of fermentation. Hence, with the observed antimicrobial and antioxidant activities of the fermented seeds of F. vulgare, it can be considered a relatively safe agent with a long remarkable history in traditional medicine.

(Invited) Derivatizing Fullerenes and Metallofullerenes for Biomedicine

Fullerenes and metallofullerenes are excellent building blocks for biomedicines due to their carbon-based structures that allows for biocompatible materials being built with robust C-C covalent bonds. The hexakis-Bingel reaction can introduce up to 12 functional groups onto one C60 core and provide a versatile platform for molecularly precise, “nanoparticle-like” functional materials. In this presentation we hope to report our recent utilization of the hexakisadduct platform in biomedical applications. In the first study we investigated the anti-oxidative behavior of a series of C60 derivatives, where the hexakisadduct turned out to be an excellent reactive oxygen species scavenger. Then we exemplify the ligand introduction to the hexakisadduct core with Gd metallofullerens, which leads to a series of structurally defined, efficient and safe MRI contrast agents.

Antibacterial and antioxidant activity of compounds from Citrus sinensis peels and in silico molecular docking study

The increasing prevalence of drug resistance, adverse side effects of existing antibiotics, and the resurgence of previously known infections have necessitated the search for new, safe, and effective antimicrobial agents. The peels of Citrus sinensis (300 g) were extracted using maceration and ultrasonic-assisted extraction methods with ethanol, resulting in yields of 20.99 g and 11.5 g (7%, 7.5%), respectively. Silica gel column chromatographic separation of the ethanol extract yielded N-(1,3,4,5-tetrahydroxydecan-2-y1)octanamide (1), decanoic acid (2), β-sitosterol-3-O-β-D-glucopyranoside derivative (3), and (z)-ethyl tetradec-7-enoate (4). GC-MS analysis of the essential oil detected 7 chemical components accounting for 99.84% of the total composition of which limonene was found to be the predominant constituent (87.5%). In vitro antibacterial tests revealed promising zones of inhibition by ethanol extract (12.67±0.58 mm, at 150 mg/mL), compound 4 (15.67±2.88 mm, at 6 mg/mL), and compound 1 (12.00±0.00 mm, at 6 mg/mL) against E. faecalis, S. typhimurium, and P. aeruginosa, respectively, compared to gentamicin (13.00±1.73 mm, 18.00±1.00 mm, and 16.67±1.15 mm, respectively at 10 µg/mL). DPPH radical scavenging activity indicated that compound 1 exhibited an IC50 value of 0.05 mg/mL, compared to ascorbic acid's 0.016 mg/mL. In silico molecular docking studies revealed that compounds 1 and 3 had the lowest scoring poses against E. coli DNA gyrase B enzyme, human peroxiredoxin 5, and S. aureus pyruvate kinase, respectively. These findings support traditional applications of Citrus peels in treating infectious diseases, particularly against Gram-positive strains, and highlight their potential use as antibacterial ingredients in cosmetics.

Nano-calcipotriol as a potent anti-hepatic fibrosis agent.

Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.

An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants

Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)—the cellular receptor of SARS-CoV-2—into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was developed as an inhaled formulation that achieves appropriate aerodynamic properties for rodent and monkey respiratory system delivery, and we found that early administration of HH-120 by aerosol inhalation significantly reduced viral loads and lung pathology scores in male golden Syrian hamsters infected by the SARS-CoV-2 ancestral strain (GDPCC-nCoV27) and the Delta variant. Our study presents a meaningful advancement in the inhalation delivery of large biologics like HH-120 (molecular weight (MW) ~ 1000 kDa) and demonstrates that HH-120 can serve as an efficacious, safe, and convenient agent against SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 has the potential to be efficacious against additional emergent coronaviruses.

Design, synthesis, and biological evaluation of carbonyl-hydrazine-1-carboxamide derivatives as anti-hepatic fibrosis agents targeting Nur77

Hepatic fibrosis remains a great challenge clinically. The orphan nuclear receptor Nur77 is recently suggested as the critical regulator of transforming growth factor-β (TGF-β) signaling, which plays a central role in multi-organic fibrosis. Herein, we optimized our previously reported Nur77-targeted compound 9 h for attempting to develop effective and safe anti-hepatic fibrosis agents. The critical pharmacophore scaffold of pyridine-carbonyl-hydrazine-1-carboxamide was retained, while the naphthalene ring was replaced with an aromatic ring containing pyridyl or indole groups. Four series of derivatives were thus generated, among which the compound 16f had excellent binding activity toward Nur77-LBD (KD = 470 nM) with the best inhibitory activity against the TGF- β 1 activation of hepatic stellate cells (HSCs) and low cytotoxicity to normal mice liver AML-12 cells (IC50 > 80 μM). In mice, 16f displayed potent activity against CCl4-induced liver fibrosis with improved liver function. Mechanistically, 16f-mediated inactivation of HSC and suppression of liver fibrosis were associated with its enhancement of autophagic flux in a Nur77-dependent manner. Together, 16f was identified as a potential anti-liver fibrosis agent. Our study suggests that Nur77 may serve as a critical anti-hepatic fibrosis target.

Atracurium Versus Cisatracurium in the Treatment of Acute Respiratory Distress Syndrome.

Background: Neuromuscular blocking agents are one of the few medication classes that have demonstrated a clinical benefit in patients with severe acute respiratory distress syndrome (ARDS). However, most literature utilized cisatracurium, and utilization of atracurium is limited to 1 small study. Objective: The purpose of this study was to provide further evidence comparing the safety and efficacy of atracurium versus cisatracurium for the treatment of ARDS. Methods: This multicenter, retrospective, observational cohort noninferiority study was conducted at 3 hospitals within a tertiary health care system. We included subjects diagnosed with ARDS who received either atracurium or cisatracurium for at least 12 hours. The primary outcome measured the change in PaO2/FiO2 (P/F) ratio from baseline to 48 hours after initiation. Results: Baseline characteristics were similar between groups except for a higher median age and a higher proportion of subjects who were COVID-positive in the atracurium group. There were also some noted differences in the baseline P/F ratios. In a multivariable model adjusting for baseline characteristics, the change in the P/F ratio for atracurium was noninferior to cisatracurium at 24, 48, and 72 hours. A significant cost reduction, measured as cost per patient per day, was seen with the use of atracurium ($14.81-$25.16 vs $33.86-$41.91). Conclusion: Atracurium appears to be a safe and cheaper alternative agent in the management of ARDS.

Design, synthesis and evaluation of 2-pyrimidinylindole derivatives as anti-obesity agents by regulating lipid metabolism

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.