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1.
Endocrine ; 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38833202

ABSTRACT

PURPOSE: This study aims to analyze the distribution of plasma aldosterone, renin activity, deoxycorticosterone (DOC), cortisol, cortisone, and 24 h urinary aldosterone (24 h-uAld) levels based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. MATERIALS AND METHODS: Plasma and 24 h urine were collected from 129 healthy volunteers in Northeast China. The effect of sodium intake, age, gender, blood sampling time on plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC to PRA ratio (ARR), DOC, cortisol, cortisone, cortisol to cortisone ratio, and 24 h-uAld were investigated by nonparametric test, multiple linear regression and Harris-Boyd's standard deviate test. RESULTS: There was no significant difference observed in 24 h-uAld, PAC (AM), PRA(AM), ARR (AM), DOC (AM), cortisol (AM), cortisone (AM), and cortisol to cortisone (AM) between high and low sodium intake group. Significant differences were observed between morning and afternoon sampling groups in terms of PAC, ARR, DOC, cortisol, and cortisone. Reference intervals (RIs) of 24 h-uAld, PAC (AM) were recommended to be partitioned by gender. RI of PRA was recommended age stratification. CONCLUSION: We recommend that the same reference interval could be used regardless of sodium intake. Gender is the main influence factor for 24 h-uAld, PAC, and ARR. Age is key influence factor for PRA.

2.
Infect Med (Beijing) ; 3(2): 100107, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38872909

ABSTRACT

Tuberculosis is a chronic infectious disease, caused by Mycobacterium tuberculosis, that seriously endangers human health. Skeletal tuberculosis is the most common type of extrapulmonary tuberculosis and tuberculous arthritis is the second most common type of skeletal tuberculosis. We report a case series of patients with tuberculous arthritis, two of whom had no joint disease in the past and presented as monoarthritis. The final patient had a history of rheumatoid arthritis, with polyarthritis that was aggravated during treatment with glucocorticoids and immunosuppressive drugs. This series of cases can contribute to early diagnosis and treatment with appropriate infection control measures.

3.
Angew Chem Int Ed Engl ; : e202407307, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38868977

ABSTRACT

Small organic photothermal reagents (PTAs) with absorption bands located in the second near-infrared (NIR-II, 1000-1700 nm) window are highly desirable for effectively combating deep-seated tumors. However, the rarely reported NIR-II absorbing PTAs still suffer from a low molar extinction coefficient (MEC, ε), inadequate chemostability and photostability, as well as the high light power density required during the therapeutic process. Herein, we developed a series of boron difluoride bridged azafulvene dimer acceptor-integrated small organic PTAs. The B-N coordination bonds in the π-conjugated azafulvene dimer backbone endow it the strong electron-withdrawing ability, facilitating the vigorous donor-acceptor-donor (D-A-D) structure PTAs with NIR-II absorption. Notably, the PTAs namely OTTBF shows high MEC (7.21× 104 M-1 cm-1), ultrahigh chemo- and photo-stability. After encapsulated into water-dispersible nanoparticles, OTTBF NPs can achieve remarkable photothermal conversion effect under 1064 nm irradiation with a light density as low as 0.7 W cm-2, which is the lowest reported NIR-II light power used in PTT process as we know. Furthermore, OTTBF NPs have been successfully applied for in vitro and in vivo deep-seated cancer treatments under 1064 nm laser. This study provides an insight into the future exploration of versatile D-A-D structured NIR-II absorption organic PTAs for biomedical applications.

4.
BMC Pediatr ; 24(1): 390, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38858617

ABSTRACT

BACKGROUND: Oculocutaneous albinism (OCA) is a group of autosomal recessive hereditary disorders that affect melanin biosynthesis, resulting in abnormalities in hair, skin, and eyes. Retinopathy of prematurity (ROP) is a proliferative retinopathy mainly observed in premature infants with low birth weight and early gestational age, but it can also affect full-term infants or children with normal weight, particularly in developing countries. The coexistence of ROP and OCA is rare. There is limited documentation regarding treatment approaches, with few studies reporting positive outcomes with laser treatment due to the absence of melanin pigment. This study discusses the treatment challenges in a female infant diagnosed with ROP and OCA, and underscores the importance of genetic analysis in guiding therapeutic decisions for this rare comorbid condition. CASE PRESENTATION: The study presents a case of ROP occurring concurrently with OCA. Genetic testing revealed two variants, c.727C > T (p.R243C) and c.1832 T > C (p.L611P), in the OCA2 gene, inherited from the patient's mother and father, respectively. The identified mutations were consistent with a diagnosis of OCA2, classified as a subtype of OCA. The patient initially received intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection, followed by laser photocoagulation therapy for a recurrent event. A favorable outcome was observed during the 2-month follow-up period. CONCLUSIONS: The co-occurrence of ROP and OCA is a rare phenomenon, and this is the first recorded case in the Chinese population. The current case supports the use of laser as the primary treatment modality for ROP in OCA2 patients with partial pigmentation impairment. Furthermore, genetic analysis can aid in predicting the effectiveness of laser photocoagulation in this patient population.


Subject(s)
Albinism, Oculocutaneous , Retinopathy of Prematurity , Humans , Female , Albinism, Oculocutaneous/genetics , Albinism, Oculocutaneous/complications , Albinism, Oculocutaneous/therapy , Retinopathy of Prematurity/genetics , Retinopathy of Prematurity/therapy , Retinopathy of Prematurity/complications , Infant, Newborn , Membrane Transport Proteins/genetics , Mutation , Angiogenesis Inhibitors/therapeutic use , Laser Coagulation , Bevacizumab/therapeutic use
5.
J Mater Chem B ; 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38860876

ABSTRACT

Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.

6.
Angew Chem Int Ed Engl ; : e202408586, 2024 Jun 09.
Article in English | MEDLINE | ID: mdl-38853460

ABSTRACT

Understanding the properties of the precursor can provide deeper insight into the crystallization and nucleation mechanisms of perovskites, which is vital for the solution-process device performance. In this work, we conducted a detailed investigation into the photophysics properties of all-inorganic perovskite (CsPbBr3) precursors in a broad concentration and various solvents. The precursor gradually transformed from the solution state into the colloidal state and exhibited aggregation-induced emission (AIE) character as the concentration increased. The aggregative luminescence from the precursors originates from the polybromide plumbous that is formed through the coordination of solvent molecules to the lead metal center. Two adducts with monodentate (PbBr2⋅solvent) and bidentate (PbB2⋅2solvent) ligands can be obtained based on the coordination capability, accompanied by a red and green emission with photoluminescence peak at 610 and 565 nm, respectively. Furthermore, the aggregative luminescence intensity and color could be regulated by changing the solvent and precursor ratio. Besides, we discussed the difference between the molecular aggregate in the organic system and the ionic aggregate in the inorganic system. The fluorescence that is sensitive to Pb²âº coordination reported here could be applied to screen perovskite additives and judge the precursor aging.

7.
Nat Cell Biol ; 26(6): 1003-1018, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38858501

ABSTRACT

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.


Subject(s)
Brain Neoplasms , Glioblastoma , Isocitrate Dehydrogenase , RNA-Binding Proteins , Tumor Microenvironment , Glioblastoma/pathology , Glioblastoma/genetics , Glioblastoma/metabolism , Glioblastoma/drug therapy , Humans , Brain Neoplasms/pathology , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/drug therapy , Animals , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Cell Line, Tumor , Mice , Mutation , Antineoplastic Agents/pharmacology , Xenograft Model Antitumor Assays , Cell Proliferation , Gene Expression Regulation, Neoplastic
8.
Pestic Biochem Physiol ; 202: 105971, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38879290

ABSTRACT

Paraquat (PQ) poisoning leads to irreversible fibrosis in the lungs with high mortality and no known antidote. In this study, we investigated the effect of the SET and MYND domain containing 2 (SMYD2) on PQ-induced pulmonary fibrosis (PF) and its potential mechanisms. We established an in vivo PQ-induced PF mouse model by intraperitoneal injection of PQ (20 mg/kg) and in vitro PQ (25 µM)-injured MLE-12 cell model. On the 15th day of administration, tissue injury, inflammation, and fibrosis in mice were evaluated using various methods including routine blood counts, blood biochemistry, blood gas analysis, western blotting, H&E staining, ELISA, Masson staining, and immunofluorescence. The findings indicated that AZ505 administration mitigated tissue damage, inflammation, and collagen deposition in PQ-poisoned mice. Mechanistically, both in vivo and in vitro experiments revealed that AZ505 treatment suppressed the PQ-induced epithelial-mesenchymal transition (EMT) process by downregulating GLI pathogenesis related 2 (GLIPR2) and ERK/p38 pathway. Further investigations demonstrated that SMYD2 inhibition decreased GLIPR2 methylation and facilitated GLIPR2 ubiquitination, leading to GLIPR2 destabilization in PQ-exposed MLE-12 cells. Moreover, rescue experiments conducted in vitro demonstrated that GLIPR2 overexpression eliminated the inhibitory effect of AZ505 on the ERK/p38 pathway and EMT. Our results reveal that the SMYD2 inhibitor AZ505 may act as a novel therapeutic candidate to suppress the EMT process by modulating the GLIPR2/ERK/p38 axis in PQ-induced PF.


Subject(s)
Epithelial-Mesenchymal Transition , Paraquat , Pulmonary Fibrosis , Animals , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Epithelial-Mesenchymal Transition/drug effects , Mice , Paraquat/toxicity , Male , p38 Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Signaling System/drug effects , Mice, Inbred C57BL , Cell Line , Histone-Lysine N-Methyltransferase/metabolism , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Histone-Lysine N-Methyltransferase/genetics
9.
Cureus ; 16(5): e60372, 2024 May.
Article in English | MEDLINE | ID: mdl-38883073

ABSTRACT

Erythroderma, also known as exfoliative dermatitis, is a rarely reported atypical cutaneous manifestation of adult-onset Still's disease (AOSD). We present the case of erythroderma in association with AOSD that was steroid dependent and responded to tocilizumab therapy. Skin rash, pruritis, and related laboratory findings were significantly improved upon the addition of tocilizumab, while prednisolone was successfully tapered to an ever-lowest maintenance level. To our knowledge, this is the first to report the sole therapeutic effect of tocilizumab in erythroderma related to AOSD.

10.
Polymers (Basel) ; 16(10)2024 May 08.
Article in English | MEDLINE | ID: mdl-38794508

ABSTRACT

Bacterial infections have a serious impact on public health. It is urgent to develop antibacterial hydrogels with good biocompatibility to reduce the use of antibiotics. In this study, poly(lipoic acid-co-sodium lipoate)-phytic acid (P(LA-SL)-PA) hydrogels are prepared by a simple mixture of the natural small molecules lipoic acid (LA) and phytic acid (PA) in a mild and green reaction environment. The crosslinking network is constructed through the connection of covalent disulfide bonds as well as the hydrogen bonds, which endow the injectable and self-healing properties. The P(LA-SL)-PA hydrogels exhibit an adjustable compression modulus and adhesion. The in vitro agar plates assay indicates that the antibacterial rate of hydrogels against Escherichia coli and Staphylococcus aureus is close to 95%. In the rat-infected wound model, the P(LA-SL)-PA hydrogels adhere closely to the tissue and promote epithelialization and collagen deposition with a significant effect on wound healing. These results prove that the P(LA-SL)-PA hydrogels could act as effective wound dressings for promoting the healing of infected wounds.

11.
Front Pharmacol ; 15: 1377836, 2024.
Article in English | MEDLINE | ID: mdl-38818379

ABSTRACT

Testicular torsion is a critical urologic condition for which testicular detorsion surgery is considered irreplaceable as well as the golden method of reversal. However, the surgical treatment is equivalent to a blood reperfusion process, and no specific drugs are available to treat blood reperfusion injuries. Salidroside (SAL) is one of the main effective substances in rhodiola, which has been shown to have antioxidant and antiapoptosis activities. This study was designed to determine whether SAL exerted a protective effect on testicular ischemia-reperfusion (I/R) injury. In this study, the I/R injury model of the testes and reoxygenation (OGD/R) model were used for verification, and SAL was administered at doses of 100 mg/kg and 0.05 mmol/L, respectively. After the experiments, the testicular tissue and TM4 Sertoli cells were collected for histopathologic and biochemical analyses. The results revealed that SAL improves the structure of testicular tissue and regulates the oxidation-antioxidation system. To further understand the molecular mechanisms of SAL in treating testicular I/R injuries, transcriptomics and metabonomics analyses were integrated. The results show that the Nfr2/HO-1/GPX4/ferroptosis signaling pathway is enriched significantly, indicating that it may be the main regulatory pathway for SAL in the treatment of testicular I/R injuries. Thereafter, transfection with Nrf2 plasmid-liposome was used to reverse verify that the Nfr2/HO-1/GPX4/ferroptosis signaling pathway was the main pathway for SAL anti-testicular I/R injury treatment. Thus, it is suggested that SAL can protect against testicular I/R injuries by regulating the Nfr2/HO-1/GPX4 signaling pathway to inhibit ferroptosis and that SAL may be a potential drug for the treatment of testicular I/R injuries.

12.
Chem Commun (Camb) ; 60(46): 5960-5963, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38767007

ABSTRACT

A cationic aggregation-induced emission photosensitizer (AIE-PS) MNNPyBB has been reported to have antibacterial effects against both Gram-positive and Gram-negative bacteria. The bacterial kill mechanism has been investigated and elucidated. In a methicillin-resistant Staphylococcus aureus subcutaneous infection model, wound closure has been achieved with normal re-epithelialization and preserved skin morphology.


Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Photosensitizing Agents , Methicillin-Resistant Staphylococcus aureus/drug effects , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Animals , Mice , Staphylococcal Infections/drug therapy , Boron Compounds/chemistry , Boron Compounds/pharmacology
13.
Nat Commun ; 15(1): 4647, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38821919

ABSTRACT

Controllable photofluorochromic systems with high contrast and multicolor in both solutions and solid states are ideal candidates for the development of dynamic artificial intelligence. However, it is still challenging to realize multiple photochromism within one single molecule, not to mention good controllability. Herein, we report an aggregation-induced emission luminogen TPE-2MO2NT that undergoes oxidation cleavage upon light irradiation and is accompanied by tunable multicolor emission from orange to blue with time-dependence. The photocleavage mechanism revealed that the self-generation of reactive oxidants driving the catalyst-free oxidative cleavage process. A comprehensive analysis of TPE-2MO2NT and other comparative molecules demonstrates that the TPE-2MO2NT molecular scaffold can be easily modified and extended. Further, the multicolor microenvironmental controllability of TPE-2MO2NT photoreaction within polymer matrices enables the fabrication of dynamic fluorescence images and 4D information codes, providing strategies for advanced controllable information encryption.

14.
ACS Biomater Sci Eng ; 10(6): 3935-3945, 2024 06 10.
Article in English | MEDLINE | ID: mdl-38741453

ABSTRACT

Achieving underwater adhesion possesses a significant challenge, primarily due to the presence of interfacial water, which restricts the potential applications of adhesives. In this study, we present a straightforward and environmentally friendly one-pot approach for synthesizing a solvent-free supramolecular TPFe bioadhesive composed of thioctic acid, proanthocyanidins, and FeCl3. The bioadhesive exhibits excellent biocompatibility and photothermal antibacterial properties and demonstrates effective adhesion on various substrates in both wet and dry environments. Importantly, the adhesive strength of this bioadhesive on steel exceeds 1.2 MPa and that on porcine skin exceeds 100 kPa, which is greater than the adhesive strength of most reported bioadhesives. In addition, the bioadhesive exhibits the ability to effectively halt bleeding, close wounds promptly, and promote wound healing in the rat skin wound model. Therefore, the TPFe bioadhesive has potential as a medical bioadhesive for halting bleeding quickly and promoting wound healing in the biomedical field. This study provides a new idea for the development of bioadhesives with firm wet adhesion.


Subject(s)
Wound Healing , Animals , Wound Healing/drug effects , Rats , Swine , Tissue Adhesives/chemistry , Tissue Adhesives/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Rats, Sprague-Dawley , Adhesives/chemistry , Adhesives/pharmacology , Skin/drug effects , Skin/injuries , Skin/pathology , Wound Closure Techniques
15.
Int J Colorectal Dis ; 39(1): 62, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684561

ABSTRACT

OBJECTIVE: The efficacy of single-incision plus one-port laparoscopic surgery (SILS + 1) versus conventional laparoscopic surgery (CLS) for colorectal cancer treatment remains unclear. This study compares the short-term and long-term outcomes of SILS + 1 and CLS using a high-quality systematic review and meta-analysis. METHOD: Literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, drawing from PubMed, Embase, Web of Science, and the Cochrane Library until December 10, 2023. Statistical analysis was conducted using RevMan and Stata. RESULT: The review and meta-analysis included seven studies with 1740 colorectal cancer patients. Compared to CLS, SILS + 1 showed significant improvements in operation time (WMD = - 18.33, P < 0.00001), blood loss (WMD = - 21.31, P < 0.00001), incision length (WMD = - 2.07, P < 0.00001), time to first defecation (WMD = - 14.91, P = 0.009), time to oral intake (WMD = - 11.46, P = 0.04), and time to ambulation (WMD = - 11.52, P = 0.01). There were no significant differences in lymph node harvest, resection margins, complications, anastomotic leakage, hospital stay, disease-free survival, overall survival, and postoperative recurrence. CONCLUSIONS: Compared to CLS, SILS + 1 demonstrates superiority in shortening the surgical incision and promoting postoperative recovery. SILS + 1 can provide a safe and feasible alternative to CLS.


Subject(s)
Colorectal Neoplasms , Laparoscopy , Humans , Colorectal Neoplasms/surgery , Treatment Outcome , Operative Time , Postoperative Complications/etiology , Length of Stay , Female , Male , Neoplasm Recurrence, Local , Middle Aged
16.
Int J Biol Macromol ; 268(Pt 2): 131637, 2024 May.
Article in English | MEDLINE | ID: mdl-38636748

ABSTRACT

Bacterial-infected wound repair has become a significant public health concern. This study developed a novel 3D-printed piezocatalytic SF-MA/PEGDA/Ag@BT (SPAB) hydrogels were fabricated by using digital light processing. These hydrogels exhibited high consistency, mechanical properties and good biocompatibility. Besides, the SPAB hydrogels exhibited excellent piezocatalytic performance and thus could induce piezoelectric polarization under ultrasound to generate reactive oxygen species (ROS). The SPAB hydrogels possessed an antibacterial rate of 99.23% and 99.96% for Escherichia coli and Staphylococcus aureus, respectively, under 5 min of ultrasonic stimulation (US) in vitro. The US-triggered piezocatalytic performance could increase antibacterial activity and improve the healing process of the infected wound. Therefore, the 3D printed piezocatalytic SPAB hydrogels could be unutilized as wound dressing in the field of bacterial-infected wound repair.


Subject(s)
Anti-Bacterial Agents , Escherichia coli , Hydrogels , Printing, Three-Dimensional , Staphylococcus aureus , Wound Healing , Hydrogels/chemistry , Hydrogels/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Escherichia coli/drug effects , Staphylococcus aureus/drug effects , Wound Healing/drug effects , Wound Infection/drug therapy , Wound Infection/microbiology , Catalysis , Animals , Reactive Oxygen Species/metabolism , Humans , Polyethylene Glycols/chemistry , Ultrasonic Waves
17.
J Med Chem ; 67(10): 8309-8322, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38669059

ABSTRACT

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 1 , Drug Design , Liver Cirrhosis , Phosphodiesterase Inhibitors , Pyrimidines , Animals , Cyclic Nucleotide Phosphodiesterases, Type 1/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 1/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Humans , Rats , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/therapeutic use , Phosphodiesterase Inhibitors/chemistry , Male , Structure-Activity Relationship , Rats, Sprague-Dawley , Molecular Docking Simulation , Molecular Structure
18.
Biomater Res ; 28: 0013, 2024.
Article in English | MEDLINE | ID: mdl-38617751

ABSTRACT

Background: Fibrosis and inflammation due to ureteropelvic junction obstruction substantially contributes to poor renal function. Urine-derived stem-cell-derived exosomes (USC-Exos) have therapeutic effects through paracrine. Methods: In vitro, the effects of USC-Exos on the biological functions of HK-2 and human umbilical vein endothelial cells were tested. Cell inflammation and fibrosis were induced by transforming growth factor-ß1 and interleukin-1ß, and their anti-inflammatory and antifibrotic effects were observed after exogenous addition of USC-Exos. Through high-throughput sequencing of microRNA in USC-Exos, the pathways and key microRNAs were selected. Then, the antifibrotic and anti-inflammatory effects of exosomal miR-122-5p and target genes were verified. The role of the miR-122-5p/SOX2 axis in anti-inflammatory and antifibrotic effects was verified. In vivo, a rabbit model of partial unilateral ureteral obstruction (PUUO) was established. Magnetic resonance imaging recorded the volume of the renal pelvis after modeling, and renal tissue was pathologically analyzed. Results: We examined the role of USC-Exos and their miR-122-5p content in obstructive kidney injury. These Exos exhibit antifibrotic and anti-inflammatory activities. SOX2 is the hub gene in PUUO and negatively related to renal function. We confirmed the binding relationship between miR-122-5p and SOX2. The anti-inflammatory and antifibrotic effects of miR-122-5p were inhibited, indicating that miR-122-5p has anti-inflammatory and antifibrotic effects by inhibiting SOX2 expression. In vivo, the PUUO group showed typical obstructive kidney injury after modeling. After USC-Exo treatment, the shape of the renal pelvis shown a remarkable improvement, and inflammation and fibrosis decreased. Conclusions: We confirmed that miR-122-5p from USC-Exos targeting SOX2 is a new molecular target for postoperative recovery treatment of obstructive kidney injury.

19.
Acta Pharmacol Sin ; 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38641745

ABSTRACT

Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1-/- mice by administration of Ang II (1 µg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to ß-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain ß-catenin protein stability by removing the K48 ubiquitin chain from ß-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of ß-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-ß-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for ß-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating ß-catenin-mediated vascular diseases.

20.
Sci Rep ; 14(1): 8429, 2024 04 10.
Article in English | MEDLINE | ID: mdl-38600101

ABSTRACT

Vulvar lichen sclerosus (VLS) is a chronic and progressive dermatologic condition that can cause physical dysfunction, disfigurement, and impaired quality of life. However, the etiology of VLS remains unknown. The vulvar skin, intestinal and vaginal microbiomes have been postulated to play important roles in the pathogenesis of this disease. The aim of this study was to compare the compositional characteristics of the vulvar skin, vagina, and gut microbiota between perimenopausal or postmenopausal VLS patients and healthy controls. The study involved six perimenopausal or postmenopausal VLS patients which were based on characteristic clinical manifestations and histologic confirmation and five healthy controls. The pruritus severity of each patient was evaluated using the NRS scale, and the dermatology-specific health-related quality of life was assessed using the Skindex-16. Metagenomic sequencing was performed, and the results were analyzed for alpha and beta diversity. LEfSe analysis were used to investigate the microbial alterations in vulvar skin, gut and vagina. KEGG databases were used to analyze differences in functional abundance. The study found significant differences in alpha diversity between the two groups in stool and vaginal samples (P < 0.05). Patients with VLS had a higher abundance of Enterobacter cloacae, Flavobacterium_branchiophilum, Mediterranea_sp._An20, Parabacteroides_johnsoniiand Streptococcus_bovimastitidis on the vulvar skin, while Corynebacterium_sp._zg-913 was less abundant compared to the control group. The relative abundance of Sphingomonas_sp._SCN_67_18, Sphingobium_sp._Ant17, and Pontibacter_sp_BT213 was significantly higher in the gut samples of patients with VLS.Paenibacillus_popilliae,Gemella_asaccharolytica, and Coriobacteriales_bacterium_DNF00809 compared to the control group. Additionally, the vaginal samples of patients with VLS exhibited a significantly lower relative abundance of Bacteroidales_bacterium_43_8, Bacteroides_sp._CAG:20, Blautia_sp._AM28-10, Fibrobacter_sp._UWB16, Lachnospiraceae_bacterium_AM25-39, Holdemania_filiformis, Lachnospiraceae_bacterium_GAM79, and Tolumonas_sp. Additionally, the butyrate-producing bacterium SS3/4 showed a significant difference compared to the controls. The study found a negative relationship between Sphingobium_sp._Ant17 in stool and Skindex-16 (P < 0.05), while Mediterranea_sp._An20 had a positive correlation with Skindex-16 (P < 0.05) in the skin. Additionally, our functional analysis revealed alterations in Aminoacyl_tRNA_biosynthesis, Glutathione_metabolism, the pentose phosphate pathway, and Alanine__aspartate_and_glutamate_metabolism in the VLS patient group. The study suggests that perimenopausal or postmenopausal patients with VLS have a modified microbiome in the vulvar skin, gut, and vagina. This modification is linked to abnormal energy metabolism, increased oxidative stress, and abnormal amino acid metabolism.


Subject(s)
Microbiota , Vulvar Lichen Sclerosus , Female , Humans , Vulvar Lichen Sclerosus/pathology , Postmenopause , Perimenopause , Quality of Life , Arrhythmias, Cardiac , Vagina/pathology
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