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Nano Letters Apr 2022Treatments for low colorectal cancer (CRC) remain a great challenge due to the heavy physical and psychological burdens of colostomy, strong drug toxicity in...
Treatments for low colorectal cancer (CRC) remain a great challenge due to the heavy physical and psychological burdens of colostomy, strong drug toxicity in chemotherapy, and myelosuppression-/chemoradiation-related gastrointestinal symptoms. In this study, a highly biosafe and effective tumor cell dissociation-based low CRC treatment modality has been verified on both PDOs and colorectal tumor models . Notably, controllable EDTA release at the tumor sites was achieved by the LDH degradation in response to a slightly acidic microenvironment of low CRC tumors. Resultantly, the intratumoral E-cadherin for intercellular junctions of low CRC tumors was effectively destroyed via Ca depletion by released EDTA from the interlayers, initiating remarkable tumor cell dissociation and resultant tumor disaggregation/removal via defecation. Dissociated tumor cells were prevailingly enveloped by LDH/EDTA, which prevented them from readhering to adjacent tissues, providing an unprecedented, efficient and safe therapeutic modality for low CRC, which will benefit patients suffering low CRC.
Topics: Cadherins; Cell Line, Tumor; Colorectal Neoplasms; Edetic Acid; Humans; Tumor Microenvironment
PubMed: 35333538
DOI: 10.1021/acs.nanolett.1c04797 -
Journal of Immunology Research 2022The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis...
BACKGROUND
The leading cause of mortality in patients with Marfan syndrome (MFS) is thoracic aortic aneurysm and dissection. Notch signaling is essential for vessel morphogenesis and function. However, the role of Notch signaling in aortic pathology and aortic smooth muscle cell (SMC) differentiation in Marfan syndrome (MFS) is not completely understood.
METHODS
RNA-sequencing on ascending aortic tissue from a mouse model of MFS, , and wild-type controls was performed. Notch 3 expression and activation in aortic tissue were confirmed with real-time RT-PCR, immunohistochemistry, and Western blot. and wild-type mice were treated with a -secretase inhibitor, DAPT, to block Notch activation. Aortic aneurysms and rupture were evaluated with connective tissue staining, ultrasound, and life table analysis.
RESULTS
The murine RNA-sequencing data were validated with mouse and human MFS aortic tissue, demonstrating elevated Notch3 activation in MFS. Data further revealed that upregulation and activation of Notch3 were concomitant with increased expression of SMC contractile markers. Inhibiting Notch3 activation with DAPT attenuated aortic enlargement and improved survival of mice. DAPT treatment reduced elastin fiber fragmentation in the aorta and reversed the differentiation of SMCs.
CONCLUSIONS
Our data demonstrated that matrix abnormalities in the aorta of MFS are associated with increased Notch3 activation. Enhanced Notch3 activation in MFS contributed to aortic aneurysm formation in MFS. This might be mediated by inducing a contractile phenotypic change of SMC. Our results suggest that inhibiting Notch3 activation may provide a strategy to prevent and treat aortic aneurysms in MFS.
Topics: Animals; Aorta; Aortic Aneurysm; Diamines; Disease Models, Animal; Elastin; Fibrillin-1; Humans; Marfan Syndrome; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Targeted Therapy; Myocytes, Smooth Muscle; Receptor, Notch3; Thiazoles
PubMed: 35211631
DOI: 10.1155/2022/7538649 -
Ticks and Tick-borne Diseases May 2022Two multiplex SYBR Green based real-time PCR assays were standardized and evaluated to detect DNA from four canine haemoparasites (Babesia gibsoni, Babesia vogeli,...
Two multiplex SYBR Green based real-time PCR assays were standardized and evaluated to detect DNA from four canine haemoparasites (Babesia gibsoni, Babesia vogeli, Ehrlichia canis and Hepatozoon canis), along with internal controls from dogs from selected districts of Punjab state, India. Amplicons of 126 bp, 337 bp, 234 bp and 106 bp corresponding to B. gibsoni (18S rRNA gene), B. vogeli (18S rRNA gene), E. canis (virB9 gene), and H. canis (18S rRNA gene) were obtained, without any non-specific amplification. Microscopic evaluation of 200 blood samples from dogs revealed the prevalence of B. gibsoni, E. canis and H. canis as 1.5%, 1.5% and 1.0%, respectively, while with the multiplex real-time PCR assays the values for B. gibsoni, B. vogeli, E. canis, and H. canis were 8.0%, 1.5%, 3.5% and 23.5%, respectively, with concurrent infections of B. gibsoni and H. canis (3.5%); E. canis and H. canis (2.0%) and B. gibsoni, B. vogeli, E. canis, and H. canis (0.5%). The diagnostic sensitivity of the multiplex real-time PCR assays with respect to microscopy in the detection of B. gibsoni, E. canis and H. canis was 100% while the specificity for B. gibsoni, B. vogeli, E. canis, and H. canis was 93%, 100%, 98% and 77%, respectively, revealing the respective strength of agreement as ″fair″, ″slight″, ″moderate″ and ″slight″ by kappa value statistics, and the data were statistically significant, for detection of B. gibsoni and E. canis infections, by Fisher's exact test. The analytical sensitivity of the multiplex PCR assays in detection of DNAs was 8.59 × 10 and 9.9 × 10 copies for B. vogeli and E. canis, respectively, and 1.15 × 10 and 3.41 × 10 copies for B. gibsoni and H. canis, respectively. Assessment of risk factors viz. age, sex, breed, season and locations showed no significant association with the prevalence of these haemoparasites except for B. vogeli, E. canis and H. canis where significant associations were found for location, age and breed, respectively by multiplex real-time PCR assays.
Topics: Animals; Benzothiazoles; Diamines; Dog Diseases; Dogs; Multiplex Polymerase Chain Reaction; Quinolines; Real-Time Polymerase Chain Reaction; Ticks
PubMed: 35305431
DOI: 10.1016/j.ttbdis.2022.101937 -
Plant Physiology Mar 2022Growth promotion induced by the endosymbiont Piriformospora indica has been observed in various plants; however, except growth phytohormones, specific functional...
Growth promotion induced by the endosymbiont Piriformospora indica has been observed in various plants; however, except growth phytohormones, specific functional metabolites involved in P. indica-mediated growth promotion are unknown. Here, we used a gas chromatography-mass spectrometry-based untargeted metabolite analysis to identify tomato (Solanum lycopersicum) metabolites whose levels were altered during P. indica-mediated growth promotion. Metabolomic multivariate analysis revealed several primary metabolites with altered levels, with putrescine (Put) induced most significantly in roots during the interaction. Further, our results indicated that P. indica modulates the arginine decarboxylase (ADC)-mediated Put biosynthesis pathway via induction of SlADC1 in tomato. Piriformospora indica did not promote growth in Sladc1-(virus-induced gene silencing of SlADC1) lines of tomato and showed less colonization. Furthermore, using LC-MS/MS we showed that Put promoted growth by elevation of auxin (indole-3-acetic acid) and gibberellin (GA4 and GA7) levels in tomato. In Arabidopsis (Arabidopsis thaliana) adc knockout mutants, P. indica colonization also decreased and showed no plant growth promotion, and this response was rescued upon exogenous application of Put. Put is also important for hyphal growth of P. indica, indicating that it is co-adapted by both host and microbe. Taken together, we conclude that Put is an essential metabolite and its biosynthesis in plants is crucial for P. indica-mediated plant growth promotion and fungal growth.
Topics: Basidiomycota; Chromatography, Liquid; Gene Expression Regulation, Plant; Plant Roots; Putrescine; Tandem Mass Spectrometry
PubMed: 34791442
DOI: 10.1093/plphys/kiab536 -
Inorganic Chemistry Aug 2023Diamine ligands are effective structural scaffolds for tuning the reactivity of transition-metal complexes for catalytic, materials, and phosphorescent applications and...
Diamine ligands are effective structural scaffolds for tuning the reactivity of transition-metal complexes for catalytic, materials, and phosphorescent applications and have been leveraged for biological use. In this work, we report the synthesis and characterization of a novel class of cyclometalated [C^N] Au(III) complexes bearing secondary diamines including a norbornane backbone, (2,3)-,-dibenzylbicyclo[2.2.1]heptane-2,3-diamine, or a cyclohexane backbone, (1,2)-,-dibenzylcyclohexane-1,2-diamine. X-ray crystallography confirms the square-planar geometry and chirality at nitrogen. The electronic character of the conformationally restricted norbornane backbone influences the electrochemical behavior with redox potentials of -0.8 to -1.1 V, atypical for Au(III) complexes. These compounds demonstrate promising anticancer activity, particularly, complex , which bears a benzylpyridine organogold framework, and supported by the bicyclic conformationally restricted diaminonorbornane, shows good potency in A2780 cells. We further show that a cellular response to evokes reactive oxygen species (ROS) production and does not induce mitochondrial dysfunction. This class of complexes provides significant stability and reactivity for different applications in protein modification, catalysis, and therapeutics.
Topics: Female; Humans; Gold; Antineoplastic Agents; Cell Line, Tumor; Ovarian Neoplasms; Crystallography, X-Ray; Diamines; Norbornanes; Ligands
PubMed: 37530672
DOI: 10.1021/acs.inorgchem.3c02066 -
International Journal of Pharmaceutics Apr 2023Therapeutic liquid mixtures, as deep eutectic systems, are considered a sustainable strategy that can be useful for the modification and enhancement of the...
Therapeutic liquid mixtures, as deep eutectic systems, are considered a sustainable strategy that can be useful for the modification and enhancement of the pharmacokinetics and pharmacodynamics of different active ingredients. In this study, we assessed the stability and antibacterial activity of therapeutic liquid formulations prepared with anti-tuberculosis drugs. Tuberculosis therapy presents various pitfalls related, for example, to the administration of prolonged regimens of multiple drugs, different severe adverse effects, low compliance of the patient to treatment and the development of drug resistance. During this study, it was possible to assess the physicochemical stability of the formulations for 6 months, by polarized optical microscopy, H NMR and FTIR-ATR. Furthermore, the mixtures present an antibacterial effect against a drug-susceptible Mycobacterium tuberculosis strain (H37Rv). This was particularly evident for the mixtures with ethambutol incorporated, making them interesting to pursue with further studies and evaluation of clinical applicability. Upon infection, it was also observed that a single and higher dose appears to be more effective than lower separate doses, which could allow the production of patient-friendly formulations.
Topics: Humans; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Ethambutol
PubMed: 36965645
DOI: 10.1016/j.ijpharm.2023.122862 -
Food Chemistry May 2021A rapid, low-cost, and selective method for simultaneous and direct determination of maneb group residues (containing ethylenebis and propylenebis dithiocarbamates) in...
A rapid, low-cost, and selective method for simultaneous and direct determination of maneb group residues (containing ethylenebis and propylenebis dithiocarbamates) in fruit by liquid chromatography coupled to tandem mass spectrometry was developed and validated in the current study. The results showed the maneb group could be melt and stabilized by 5 v% ethylenediamine for 60 days keeping in conventional refrigerators, in which a stable and ionizable pentadentate ligand complex was considered to be formed by the bidentate diamine and sulfhydryl followed by Density Functional Theory calculation. The validated method showed a sensitive quantification limits (0.03 mg/kg), a steady recovery (82.1%-91.0%) and an excellent precision (2.7%-4.3% RSD). This method is applied to analyze fruit samples and achieved satisfactory results. Therefore, this method can be proposed as a robust analytical method of maneb group in fruit, and can be adapted to detect other compounds with sulfhydryl group.
Topics: Chromatography, Liquid; Ethylenediamines; Fruit; Maneb; Tandem Mass Spectrometry
PubMed: 33338835
DOI: 10.1016/j.foodchem.2020.128774 -
Environmental Research Mar 2022In this work, graphene oxide-p-Phenylenediamine nanocomposites of two different ratios of Graphene oxide: p-Phenylenediamine (1:1 and 1:5) were prepared and...
In this work, graphene oxide-p-Phenylenediamine nanocomposites of two different ratios of Graphene oxide: p-Phenylenediamine (1:1 and 1:5) were prepared and characterized by using analytical, spectroscopic and microscopic studies (GO-pPD 11 and GO-pPD 15). These nanocomposites were employed as fluorescent chemosensors for sensing potential cations. Remarkably, graphene oxide-p-Phenylenediamine nanocomposites of ratio 1:1 (GO-pPD 15) was selective and sensitive to Ag ions, whereas the graphene oxide-p-Phenylenediamine nanocomposites of ratio 1:5 (GO-pPD 15) was selective to Ceions. A possible mechanism as switch "off-on" is proposed built on the inhibition of the photo induced electron transfer process in both the fluorescent probes in detecting the metal ions. In addition, interference studies were performed with the help of competitive complexation analysis and no significant interference were found by other potentially competing cations. The pH studies revealed that both the chemosensors can be used at the physiological pH for the ion detection and also the detection time was within 2-3 min. Both the chemosensors show good reversibility and hence the sensors can be used for multiple times. The newer nanocomposites were then utilized in the real water sample analysis as to check its real level application purpose.
Topics: Graphite; Ions; Nanocomposites; Phenylenediamines
PubMed: 34437851
DOI: 10.1016/j.envres.2021.111914 -
European Journal of Medicinal Chemistry Jan 2022Inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-κB signaling, with the potential to...
Inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-κB signaling, with the potential to treat B-cell lymphoma and autoimmune diseases. We describe the discovery and optimization of (1s,4s)-N,N'-diaryl cyclohexane-1,4-diamines, a novel series of allosteric MALT1 inhibitors, resulting in compound 8 with single digit micromolar cell potency. X-ray analysis confirms that this compound binds to an induced allosteric site in MALT1. Compound 8 is highly selective and has an excellent in vivo rat PK profile with low clearance and high oral bioavailability, making it a promising lead for further optimization.
Topics: Allosteric Regulation; Animals; Cyclohexanes; Diamines; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Rats; Structure-Activity Relationship
PubMed: 34742013
DOI: 10.1016/j.ejmech.2021.113925 -
Journal of Agricultural and Food... Jul 2023Severe plant virus diseases lead to poor harvests and poor crop quality, and the lack of effective suppressive drugs makes plant disease control a huge challenge....
Severe plant virus diseases lead to poor harvests and poor crop quality, and the lack of effective suppressive drugs makes plant disease control a huge challenge. Natural product-based structural simplification is an important strategy for finding novel pesticide candidates. According to our previous research on the antiviral activities of harmine and tetrahydroharmine derivatives, a series of chiral diamine compounds were designed and synthesized by means of structural simplification using diamines in natural products as the core structure in this work, and the antiviral and fungicidal activities were investigated. Most of these compounds displayed higher antiviral activities than those of ribavirin. Compounds and displayed higher antiviral activities than ningnanmycin at 500 μg/mL. The antiviral mechanism research revealed that compounds and could inhibit virus assembly by binding to tobacco mosaic virus (TMV) CP and interfere with the assembly process of TMV CP and RNA transmission electron microscopy and molecular docking. Further fungicidal activity tests showed that these compounds displayed broad-spectrum fungicidal activities. Compounds , , , and with excellent fungicidal activities against f.sp. can be considered as new fungicidal candidates for further research. The current work provides a reference to the development of agricultural active ingredients in crop protection.
Topics: Antiviral Agents; Structure-Activity Relationship; Diamines; Molecular Docking Simulation; Fungicides, Industrial; Tobacco Mosaic Virus; Biological Products; Drug Design
PubMed: 37433073
DOI: 10.1021/acs.jafc.3c01247