Stronger contractility and smaller bladder capacity are common symptoms in ketamine cystitis (KC). This study investigates the association between expression levels of transient receptor potential ...cation channel subfamily V (TRPV) proteins and the clinical characteristics of KC. Bladder tissues were obtained from 24 patients with KC and four asymptomatic control subjects. Video urodynamic parameters were obtained before surgical procedures. The TRPV proteins were investigated by immunoblotting, immunofluorescence staining, and immunohistochemistry. The Pearson test was used to associate the expression levels of TRPV proteins with clinical characteristics of KC. The expression level of TRPV1 and TRPV4 was significantly higher in the severe KC bladders than in mild KC or control bladders. The TRPV1 proteins were localized in all urothelial cell layers, and TRPV4 was located in the basal cells and lamina propria. The expression of TRPV1 was negatively associated with maximal bladder capacity (r = - 0.66, P = 0.01). The expression of TRPV4 was positively associated with the velocity of detrusor pressure rise to the maximum flow rate (r = 0.53, P = 0.01). These observations suggest smaller bladder capacity and stronger contractility in KC are associated with an elevated expression of TRPV1 and TRPV4, respectively.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The global rise of multidrug-resistant
strains, especially those that are resistant to carbapenems and produce metallo-β-lactamases, poses a critical challenge in clinical settings owing to limited ...treatment options. While bacteriophages show promise in treating these infections, their use is hindered by scarce resources and insufficient genomic data. In this study, we isolated ECLFM1, a novel
phage, from sewage water using a carbapenem-resistant clinical strain as the host. ECLFM1 exhibited rapid adsorption and a 15-min latent period, with a burst size of approximately 75 PFU/infected cell. Its genome, spanning 172,036 bp, was characterized and identified as a member of
. In therapeutic applications, owing to a high multiplicity of infection, ECLFM1 showed increased survival in zebrafish infected with
. This study highlights ECLFM1's potential as a candidate for controlling clinical
infections, which would help address challenges in treating multidrug-resistant strains and contribute to the development of alternative treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Presenilin-1 (PSEN1) is a crucial subunit within the γ-secretase complex and regulates β-amyloid (Aβ) production. Accumulated evidence indicates that n-butylidenephthalide (BP) acts effectively to ...reduce Aβ levels in neuronal cells that are derived from trisomy 21 (Ts21) induced pluripotent stem cells (iPSCs). However, the mechanism underlying this effect remains unclear. This article aims to investigate the possible mechanisms through which BP ameliorates the development of Alzheimer’s disease (AD) and verify the effectiveness of BP through animal experiments. Results from RNA microarray analysis showed that BP treatment in Ts21 iPSC-derived neuronal cells reduced long noncoding RNA (lncRNA) CYP3A43-2 levels and increased microRNA (miR)-29b-2-5p levels. Bioinformatics tool prediction analysis, biotin-labeled miR-29b-2-5p pull-down assay, and dual-luciferase reporter assay confirmed a direct negative regulatory effect for miRNA29b-2-5p on lnc-RNA-CYP3A43-2 and PSEN1. Moreover, BP administration improved short-term memory and significantly reduced Aβ accumulation in the hippocampus and cortex of 3xTg-AD mice but failed in miR-29b-2-5p mutant mice generated by CRISP/Cas9 technology. In addition, analysis of brain samples from patients with AD showed a decrease in microRNA-29b-2-5p expression in the frontal cortex region. Our results provide evidence that the LncCYP3A43-2/miR29-2-5p/PSEN1 network might be involved in the molecular mechanisms underlying BP-induced Aβ reduction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Acinetobacter baumannii is an opportunistic pathogen that significantly causes hospital-acquired infections. Due to its multidrug resistance, treating infections caused by this pathogen is ...challenging. Recently, phages have gained attention as a potential alternative to antibiotics in treating bacterial infections. While lytic phages are preferred in therapy, the use of temperate phages for this purpose has received less attention. This study characterized a novel temperate phage vB_AbaM_ABMM1 (ABMM1) with antibacterial activity toward A. baumannii. ABMM1 adsorbs quickly, has short latent periods, and is relatively stable at various temperatures and neutral pH. ABMM1 has an icosahedral head and a contractile tail. It has a 75,731 kb circular permuted dsDNA genome containing 86 gene products with 37.3% G + C content and a mosaic arrangement typical of temperate phages. Genomic analysis confirmed that ABMM1 does not have antibiotic-resistance genes or virulence-related factors. The packaging strategy was predicted in silico, suggesting that ABMM1 represents a headful phage. Only truncated ABMM1 prophage was detected and has similarity in the genome of several A. baumannii strains. Despite its ability to integrate into the host chromosome, the high MOI of ABMM1 (MOI 10) effectively killed the host bacterial cells and reduced the fatality rate of bacterial infection in the zebrafish model. These findings indicate that ABMM1 can be an alternative treatment for A. baumannii infection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although butylidenephthalide (BP) is an efficient anticancer drug, its poor bioavailability renders it ineffective for treating drug-resistant brain tumors. However, this problem is overcome through ...the use of noninvasive delivery systems, including intranasal administration. Herein, the bioavailability, drug stability, and encapsulation efficiency (EE, up to 95%) of BP were improved by using cyclodextrin-encapsulated BP in liposomal formulations (CDD1). The physical properties and EE of the CDD1 system were investigated via dynamic light scattering, transmission electron microscopy, UV-Vis spectroscopy, and nuclear magnetic resonance spectroscopy. The cytotoxicity was examined via MTT assay, and the cellular uptake was observed using fluorescence microscopy. The CDD1 system persisted for over 8 h in tumor cells, which was a considerable improvement in the retention of the BP-containing cyclodextrin or the BP-containing liposomes, thereby indicating a higher BP content in CDD1. Nanoscale CDD1 formulations were administered intranasally to nude mice that had been intracranially implanted with temozolomide-resistant glioblastoma multiforme cells, resulting in increased median survival time. Liquid chromatography-mass spectrometry revealed that drug biodistribution via intranasal delivery increased the accumulation of BP 10-fold compared to oral delivery methods. Therefore, BP/cyclodextrin/liposomal formulations have potential clinical applications for treating drug-resistant brain tumors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Bacteriophage vB_PaP_phiPA1-3 was isolated and characterized in terms of its phenotypical, biological, and genomic characteristics against carbapenem-resistant Pseudomonas aeruginosa (CRPA)•The host ...range spectrum revealed that phiPA1-3 is a moderate host range phage that infects 20% of clinically isolated strains of P. aeruginosa, including CRPA.•Biofilm eradication and phage rescue of animals from bacterial infections were assessed to demonstrate the potential efficacy of phiPA1-3.
Multiple drug-resistant (MDR) Pseudomonas aeruginosa commonly causes severe hospital-acquired infections. The gradual emergence of carbapenem-resistant P. aeruginosa has recently gained attention. A wide array of P. aeruginosa-mediated pathogenic mechanisms, including its biofilm-forming ability, limits the use of effective antimicrobial treatments against it. In the present study, we isolated and characterized the phenotypic, biological, and genomic characteristics of a bacteriophage, vB_PaP_phiPA1-3 (phiPA1-3). Biofilm eradication and phage rescue from bacterial infections were assessed to demonstrate the efficacy of the application potential. Host range spectrum analysis revealed that phiPA1-3 is a moderate host range phage that infects 20% of the clinically isolated strains of P. aeruginosa tested, including carbapenem-resistant P. aeruginosa (CRPA). The phage exhibited stability at pH 7.0 and 9.0, with significantly reduced viability below pH 5.0 and beyond pH 9.0. phiPA1-3 is a lytic phage with a burst size of 619 plaque-forming units/infected cell at 37°C and can effectively lyse bacteria in a multiplicity of infection-dependent manner. The genome size of phiPA1-3 was found to be 73,402 bp, with a G+C content of 54.7%, containing 93 open reading frames, of which 62 were annotated as hypothetical proteins and the remaining 31 had known functions. The phage possesses several proteins similar to those found in N4-like phages, including three types of RNA polymerases. This study concluded that phiPA1-3 belongs to the N4-like Schitoviridae family, can potentially eradicate P. aeruginosa biofilms, and thus, serve as a valuable tool for controlling CRPA infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Both protein kinase C (PKC) and reactive oxygen species (ROS) are well-known signaling messengers cross-talking with each other to activate mitogen-activated protein kinases (MAPKs) for progression ...of hepatocellular carcinoma (HCC). However, the underlying mechanisms are not well elucidated. Especially, whether mitochondrial ROS (mtROS) is involved and how it triggers MAPK signaling are intriguing. In this study, we found mtROS generation and phosphorylation of MAPKs were mediated by PKCδ in HCCs treated with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Heat shock protein 60 (HSP60), one of the chaperones in mitochondria was the major protein oxidized in TPA-treated HCCs. Moreover, depletion of HSP60 or expression of HSP60 cysteine mutant prevented TPA-induced phosphorylation of MAPKs. To delineate how HSP60 mediated MAPK activation, the role of Raf kinase inhibitor protein (RKIP), a negative regulator of MAPK, was investigated. TPA dissociated RKIP from HSP60 in both mitochondria and cytosol, concurrently with translocation of HSP60 and MAPK from mitochondria to cytosol, which was associated with robust phosphorylation of MAPKs in the cytosol. Moreover, TPA induced opposite phenotypical changes of HCCs, G1 cell cycle arrest, and cell migration, which were prevented by mtROS scavengers and depletion of PKCδ and HSP60. Consistently, TPA increased the migration-related genes, hydrogen peroxide inducible clone5, matrix metalloproteinase-1/3, lamininγ2, and suppressed the cell cycle regulator cyclin E1 (CCNE1) via PKCδ/mtROS/HSP60/MAPK-axis. Finally, c-jun and c-fos were required for TPA-induced expression of the migration-related genes and a novel microRNA, miR-6134, was responsible for TPA-induced suppression of CCNE1. In conclusion, PKCδ cross-talked with mtROS to trigger HSP60 oxidation for release of RKIP to activate MAPK, regulating gene expression for migration, and G1 cell cycle arrest in HCC. Targeted therapy aiming at key players like PKCδ, RKIP, and HSP60 is promising for preventing HCC progression.
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•PKC∂ and mitochondrial ROS crosstalk with each other for HCC cell migration.•Upon HSP60 oxidation, Raf-kinase inhibitory protein dissociates itself from HSP60.•Oxidized HSP60 shows mitochondria to cytosol translocation with its client proteins.•Activation of HSP60 client proteins ERK and JNK occurred robustly in the cytosol.•Novel miR-6134 targeted Cyclin E1 to exert G1 cell cycle arrest.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•The isolations of the amido-functionalized bis-bidentate nickel(II) carbene complexes Ni(R-bimy-CH2CONH)2 (bimyH = benzimidazole; R = Me (3), Et (4), Ph (5)) and the pincer-type nickel(II) carbene ...complexes Ni(Py-bimy-CH2CONH)X (Py = pyridyl; X = Cl (6), Br (7)).•A weak base sodium acetate is able to remove the amido proton of the amido-functionalized N-heterocyclic carbene ligand in the formation of complex 6.•The pincer-type nickel carbene complexes display good catalytic activity in the Kumada cross-coupling reaction.
A series of bis-bidentate nickel(II) complexes Ni(R-bimy-CH2CONH)2 (bimyH = benzimidazole; R = Me (3), Et (4), Ph (5)) bearing amido-functionalized N-heterocyclic carbene ligands, and pincer-type nickel(II) complexes Ni(Py-bimy-CH2CONH)X (X = Cl (6), Br (7)) bearing an amido- and pyridyl-functionalized N-heterocyclic carbene ligand were prepared. These complexes were characterized by NMR (1D and 2D) and single-crystal X-ray diffraction. Complexes 3-5 possess cis configuration, and the carbene ligands bound to the nickel atom through C2 carbon and NH nitrogen in a bis-bidentate coordination mode. In complexes 6 and 7, the pyridyl substituent was also N-bound to the nickel metal center resulting in a pincer-type coordination mode. As observed from the proton NMR spectra, the six-membered chelate rings in complexes 3-5 rendered the protons of the methylene moieties diastereotopic, and the cis configuration made the free rotation of the ethyl substituent in 4 and the phenyl substituent in 5 hampered by the adjacent substituent. The catalytic activity of these nickel complexes in Kumada cross-coupling of phenylmagnesium bromide with aryl chlorides was also investigated. The results indicated that pincer-type complexes 6 and 7 displayed excellent to moderate catalytic activity depending on the aryl chloride used.
Display omitted Amido-functionalized bis-bidentate complexes Ni(R-bimy-CH2CONH)2 (R = Me, Et, Ph) and pincer-type complexes Ni(Py-bimy-CH2CONH)X (X = Cl, Br) were prepared, and their catalytic activity of the Kumada cross-coupling was studied.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The azido-bridged molybdenum complex N(CH
3
)
4
(μ
1,1
-N
3
)
3
{Mo(η
3
-C
3
H
5
)(CO)
2
}
2
,
1
, was synthesized and its reactions with unsaturated nitriles and alkynes were investigated. The ...isolated 3 + 2 cycloaddition products were the N(2), N(3) bound tetrazolate complexes N(CH
3
)
4
(μ
1,1
-N
3
)
2
(μ-N
4
C{R}-κ
2
N
2
:
N
3
){Mo(η
3
-C
3
H
5
)(CO)
2
}
2
(R = C(CN)C(CN)
2
(
2
), C
6
H
4
NO
2
, (
3
)) and N(CH
3
)
4
(μ-N
4
C{R}-κ
2
N
2
:N
3
)
2
(μ
1,1
-N
3
){Mo(η
3
-C
3
H
5
)(CO)
2
}
2
(R = C(CN)C(CN)
2
(
4
), C
6
H
4
NO
2
(
5
)), and the N(1), N(2) bound triazolate complexes N(CH
3
)
4
(μ-N
3
C
2
{R}
2
-κ
2
N
1
:
N
2
)(μ
1,1
-N
3
)
2
{Mo(η
3
-C
3
H
5
)(CO)
2
}
2
(R = CO
2
CH
3
(
6
) and R = CO
2
CH
2
CH
3
(
7
). The reactivity of these cycloaddition reactions could be determined by the electronic properties of both metal azide and dipolarophile. In the reaction of
1
with nitriles, at most two bridging azido groups can participate in the cycloaddition reactions and elevated temperature is required for the preparations of
3
and
5
. In the case of alkynes, only one azido group is active for the reaction. These complexes are fluxional in solution, and isomers were found in
3
and
5
. The molecular structures of the above complexes were determined by single-crystal X-ray diffraction analysis, which reveals a distorted octahedral geometry around each molybdenum atom, and the two metal atoms are connected through three bridging ligands. The formation of these heterocycles demonstrated the 3 + 2 cycloaddition reaction could also be applied to the less electron-rich azido-bridged molybdenum complex.
3 + 2 cycloaddition products of bridging tetrazolato- and triazolato-complexes were isolated from the reactions of N(CH
3
)
4
(μ
1,1
-N
3
)
3
{Mo(η
3
-C
3
H
5
)(CO)
2
}
2
with various nitriles and alkynes.
Owing to the widespread emergence and proliferation of antibiotic-resistant bacteria, the therapeutic benefits of antibiotics have been reduced. In addition, the ongoing evolution of ...multidrug-resistant pathogens poses a challenge for the scientific community to develop sensitive analytical methods and innovative antimicrobial agents for the detection and treatment of drug-resistant bacterial infections. In this review, we have described the antibiotic resistance mechanisms that occur in bacteria and summarized the recent developments in detection strategies for monitoring drug resistance using different diagnostic methods in three aspects, including electrostatic attraction, chemical reaction, and probe-free analysis. Additionally, to understand the effective inhibition of drug-resistant bacterial growth by recent nano-antibiotics, the underlying antimicrobial mechanisms and efficacy of biogenic silver nanoparticles and antimicrobial peptides, which have shown promise, and the rationale, design, and potential improvements to these methods are also highlighted in this review. Finally, the primary challenges and future trends in the rational design of facile sensing platforms and novel antibacterial agents against superbugs are discussed.
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