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1.
Gut Microbes ; 16(1): 2361491, 2024.
Article in English | MEDLINE | ID: mdl-38868903

ABSTRACT

Metformin is widely used for treating type 2 diabetes mellitus (T2D). However, the efficacy of metformin monotherapy is highly variable within the human population. Understanding the potential indirect or synergistic effects of metformin on gut microbiota composition and encoded functions could potentially offer new insights into predicting treatment efficacy and designing more personalized treatments in the future. We combined targeted metabolomics and metagenomic profiling of gut microbiomes in newly diagnosed T2D patients before and after metformin therapy to identify potential pre-treatment biomarkers and functional signatures for metformin efficacy and induced changes in metformin therapy responders. Our sequencing data were largely corroborated by our metabolic profiling and identified that pre-treatment enrichment of gut microbial functions encoding purine degradation and glutamate biosynthesis was associated with good therapy response. Furthermore, we identified changes in glutamine-associated amino acid (arginine, ornithine, putrescine) metabolism that characterize differences in metformin efficacy before and after the therapy. Moreover, metformin Responders' microbiota displayed a shifted balance between bacterial lipidA synthesis and degradation as well as alterations in glutamate-dependent metabolism of N-acetyl-galactosamine and its derivatives (e.g. CMP-pseudaminate) which suggest potential modulation of bacterial cell walls and human gut barrier, thus mediating changes in microbiome composition. Together, our data suggest that glutamine and associated amino acid metabolism as well as purine degradation products may potentially condition metformin activity via its multiple effects on microbiome functional composition and therefore serve as important biomarkers for predicting metformin efficacy.


Subject(s)
Amino Acids , Bacteria , Biomarkers , Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Hypoglycemic Agents , Metformin , Purines , Humans , Metformin/pharmacology , Metformin/therapeutic use , Gastrointestinal Microbiome/drug effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/microbiology , Diabetes Mellitus, Type 2/metabolism , Amino Acids/metabolism , Male , Middle Aged , Female , Purines/metabolism , Bacteria/classification , Bacteria/metabolism , Bacteria/genetics , Bacteria/drug effects , Bacteria/isolation & purification , Biomarkers/metabolism , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/pharmacology , Aged , Adult , Treatment Outcome , Metabolomics
2.
Arthritis Res Ther ; 26(1): 121, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38879555

ABSTRACT

BACKGROUND: Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. METHODS: We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. RESULTS: Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1ß and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. CONCLUSIONS: Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.


Subject(s)
Arthritis, Experimental , Azetidines , Ganglia, Spinal , Interleukin-6 , Janus Kinases , Neuralgia , Purines , Pyrazoles , STAT3 Transcription Factor , Signal Transduction , Sulfonamides , Animals , Azetidines/pharmacology , Azetidines/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , STAT3 Transcription Factor/metabolism , Purines/pharmacology , Arthritis, Experimental/metabolism , Arthritis, Experimental/drug therapy , Ganglia, Spinal/metabolism , Ganglia, Spinal/drug effects , Neuralgia/drug therapy , Neuralgia/metabolism , Janus Kinases/metabolism , Signal Transduction/drug effects , Mice , Interleukin-6/metabolism , Male , Neurons/metabolism , Neurons/drug effects , Neurons/pathology , Mice, Inbred DBA , Inflammation/metabolism , Inflammation/drug therapy , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use
3.
Molecules ; 29(11)2024 May 28.
Article in English | MEDLINE | ID: mdl-38893418

ABSTRACT

A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.


Subject(s)
Purinergic P1 Receptor Antagonists , Humans , Structure-Activity Relationship , Purinergic P1 Receptor Antagonists/pharmacology , Purinergic P1 Receptor Antagonists/chemistry , Receptors, Purinergic P1/metabolism , Molecular Structure , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/pharmacology , Morpholines/chemistry , Morpholines/pharmacology , Purines/chemistry , Purines/pharmacology , Purines/chemical synthesis , CHO Cells
5.
Reumatismo ; 76(2)2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38916168

ABSTRACT

The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.


Subject(s)
Arthritis, Rheumatoid , Azetidines , Creatine Kinase , Purines , Pyrazoles , Sulfonamides , Humans , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/complications , Female , Purines/adverse effects , Purines/therapeutic use , Aged , Azetidines/therapeutic use , Azetidines/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Creatine Kinase/blood , Myalgia/chemically induced , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects
8.
Front Immunol ; 15: 1395288, 2024.
Article in English | MEDLINE | ID: mdl-38903518

ABSTRACT

An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the features of active stage alopecia areata, with a Severity of Alopecia Tool (SALT) score of 70%. The diagnosis was severe alopecia areata. The patient had a history of atopic dermatitis since infancy, with recurrent episodes of scattered papules and pruritus for 8 years. Initial treatment involved subcutaneous injections of dupilumab 300mg every 2 weeks for 6 months, resulting in a reduction of SALT score to 20% and improvement of atopic dermatitis symptoms. Discontinuation of Dupilumab and initiation of daily oral Baricitinib at a dose of 2mg for a duration of 5 months. According to the SALT score evaluation, the severity of hair loss was less than 10% and there was significant regrowth of hair. No significant adverse reactions were observed during the treatment period.


Subject(s)
Alopecia Areata , Antibodies, Monoclonal, Humanized , Azetidines , Dermatitis, Atopic , Purines , Pyrazoles , Sulfonamides , Humans , Alopecia Areata/drug therapy , Alopecia Areata/diagnosis , Dermatitis, Atopic/drug therapy , Female , Purines/administration & dosage , Purines/adverse effects , Child , Azetidines/administration & dosage , Azetidines/adverse effects , Azetidines/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Treatment Outcome , Severity of Illness Index , Drug Therapy, Combination
9.
Int J Mol Sci ; 25(11)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38892338

ABSTRACT

The elongation of the mesocotyl plays an important role in the emergence of maize deep-sowing seeds. This study was designed to explore the function of exogenous salicylic acid (SA) and 6-benzylaminopurine (6-BA) in the growth of the maize mesocotyl and to examine its regulatory network. The results showed that the addition of 0.25 mmol/L exogenous SA promoted the elongation of maize mesocotyls under both 3 cm and 15 cm deep-sowing conditions. Conversely, the addition of 10 mg/L exogenous 6-BA inhibited the elongation of maize mesocotyls. Interestingly, the combined treatment of exogenous SA-6-BA also inhibited the elongation of maize mesocotyls. The longitudinal elongation of mesocotyl cells was the main reason affecting the elongation of maize mesocotyls. Transcriptome analysis showed that exogenous SA and 6-BA may interact in the hormone signaling regulatory network of mesocotyl elongation. The differential expression of genes related to auxin (IAA), jasmonic acid (JA), brassinosteroid (BR), cytokinin (CTK) and SA signaling pathways may be related to the regulation of exogenous SA and 6-BA on the growth of mesocotyls. In addition, five candidate genes that may regulate the length of mesocotyls were screened by Weighted Gene Co-Expression Network Analysis (WGCNA). These genes may be involved in the growth of maize mesocotyls through auxin-activated signaling pathways, transmembrane transport, methylation and redox processes. The results enhance our understanding of the plant hormone regulation of mesocotyl growth, which will help to further explore and identify the key genes affecting mesocotyl growth in plant hormone signaling regulatory networks.


Subject(s)
Benzyl Compounds , Gene Expression Regulation, Plant , Plant Growth Regulators , Purines , Salicylic Acid , Zea mays , Zea mays/growth & development , Zea mays/drug effects , Zea mays/genetics , Zea mays/metabolism , Salicylic Acid/pharmacology , Salicylic Acid/metabolism , Purines/pharmacology , Benzyl Compounds/pharmacology , Gene Expression Regulation, Plant/drug effects , Plant Growth Regulators/pharmacology , Plant Growth Regulators/metabolism , Oxylipins/pharmacology , Cytokinins/metabolism , Cytokinins/pharmacology , Seeds/drug effects , Seeds/growth & development , Seeds/genetics , Gene Expression Profiling , Signal Transduction/drug effects , Indoleacetic Acids/pharmacology , Indoleacetic Acids/metabolism , Cyclopentanes/pharmacology
10.
BMC Microbiol ; 24(1): 229, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38943061

ABSTRACT

BACKGROUND: Lactobacillus plantarum has been found to play a significant role in maintaining the balance of intestinal flora in the human gut. However, it is sensitive to commonly used antibiotics and is often incidentally killed during treatment. We attempted to identify a means to protect L. plantarum ATCC14917 from the metabolic changes caused by two commonly used antibiotics, ampicillin, and doxycycline. We examined the metabolic changes under ampicillin and doxycycline treatment and assessed the protective effects of adding key exogenous metabolites. RESULTS: Using metabolomics, we found that under the stress of ampicillin or doxycycline, L. plantarum ATCC14917 exhibited reduced metabolic activity, with purine metabolism a key metabolic pathway involved in this change. We then screened the key biomarkers in this metabolic pathway, guanine and adenosine diphosphate (ADP). The exogenous addition of each of these two metabolites significantly reduced the lethality of ampicillin and doxycycline on L. plantarum ATCC14917. Because purine metabolism is closely related to the production of reactive oxygen species (ROS), the results showed that the addition of guanine or ADP reduced intracellular ROS levels in L. plantarum ATCC14917. Moreover, the killing effects of ampicillin and doxycycline on L. plantarum ATCC14917 were restored by the addition of a ROS accelerator in the presence of guanine or ADP. CONCLUSIONS: The metabolic changes of L. plantarum ATCC14917 under antibiotic treatments were determined. Moreover, the metabolome information that was elucidated can be used to help L. plantarum cope with adverse stress, which will help probiotics become less vulnerable to antibiotics during clinical treatment.


Subject(s)
Ampicillin , Anti-Bacterial Agents , Doxycycline , Lactobacillus plantarum , Metabolomics , Lactobacillus plantarum/metabolism , Lactobacillus plantarum/drug effects , Anti-Bacterial Agents/pharmacology , Ampicillin/pharmacology , Doxycycline/pharmacology , Reactive Oxygen Species/metabolism , Purines/metabolism , Stress, Physiological/drug effects , Metabolic Networks and Pathways/drug effects , Adenosine Diphosphate/metabolism , Humans
11.
Expert Opin Drug Deliv ; 21(5): 797-807, 2024 May.
Article in English | MEDLINE | ID: mdl-38881261

ABSTRACT

BACKGROUND: Regadenoson, an agonist of adenosine A2 receptors, enables transient blood-brain barrier (BBB) disruption. The relevance of regadenoson as a pharmacological strategy for brain delivery was investigated using in vivo PET imaging in rats. RESEARCH DESIGN AND METHODS: Kinetic modeling of brain PET data was performed to estimate the impact of regadenoson (0.05 mg.kg-1, i.v.) on BBB permeation compared with control rats (n = 4-6 per group). Three radiolabeled compounds of different sizes, which do not cross the intact BBB, were tested. RESULTS: Regadenoson significantly increased the BBB penetration (+116 ± 13%, p < 0.001) of [18F]2-deoxy-2-fluoro-D-sorbitol ([18F]FDS, MW = 183 Da), a small-molecule marker of BBB permeability. The magnitude of the effect was different across brain regions, with a maximum increase in the striatum. Recovery of BBB integrity was observed 30 min after regadenoson injection. Regadenoson also increased the brain penetration (+72 ± 45%, p < 0.05) of a radiolabeled nanoparticle [89Zr]AGuIX (MW = 9 kDa). However, the brain kinetics of a monoclonal antibody ([89Zr]mAb, MW = 150 kDa) remained unchanged (p > 0.05). CONCLUSIONS: PET imaging showed the features and limitations of BBB disruption induced by regadenoson in terms of extent, regional distribution, and reversibility. Nevertheless, regadenoson enables the brain delivery of small molecules or nanoparticles in rats.


Subject(s)
Adenosine A2 Receptor Agonists , Blood-Brain Barrier , Brain , Positron-Emission Tomography , Purines , Pyrazoles , Animals , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Purines/pharmacology , Purines/administration & dosage , Purines/pharmacokinetics , Pyrazoles/pharmacology , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Rats , Positron-Emission Tomography/methods , Brain/metabolism , Brain/diagnostic imaging , Brain/drug effects , Male , Adenosine A2 Receptor Agonists/pharmacology , Adenosine A2 Receptor Agonists/administration & dosage , Drug Delivery Systems , Nanoparticles , Rats, Sprague-Dawley , Permeability , Fluorine Radioisotopes , Rats, Wistar
12.
Sci Rep ; 14(1): 14714, 2024 06 26.
Article in English | MEDLINE | ID: mdl-38926419

ABSTRACT

Stevia rebaudiana (stevia) is a plant in the Asteraceae that contains several biologically active compounds including the antidiabetic diterpene glycosides (e.g. stevioside, rebaudioside and dulcoside) that can serve as zero-calorie sugar alternatives. In this study, an elicitation strategy was applied using 5% polyethylene glycol (PEG), sodium chloride (NaCl; 50 and 100 mM) and gibberellic acid (2.0 and 4.0 mg/L GA3) to investigate their effect on shoot morphogenesis, and the production of phenolics, flavonoids, total soluble sugars, proline and stevioside, as well as antioxidant activity, in shoot cultures of S. rebaudiana. Herewith, the media supplemented with 2 mg/L and 4 mg/L GA3 exhibited the highest shooting response (87% and 80%). The augmentation of lower concentrations of GA3 (2 mg/L) in combination with 6-benzylaminopurine (BAP) resulted in the maximum mean shoot length (11.1 cm). The addition of 100 mM NaCl salts to the media led to the highest observed total phenolics content (TPC; 4.11 mg/g-DW compared to the control 0.52 mg/g-DW), total flavonoids content (TFC; 1.26 mg/g-DW) and polyphenolics concentration (5.39 mg/g-DW) in shoots cultured. However, the maximum antioxidant activity (81.8%) was observed in shoots raised in media treated with 50 mM NaCl. The application of 2 mg/L of GA3 resulted in the highest accumulation of proline (0.99 µg/mL) as compared to controls (0.37 µg/mL). Maximum stevioside content (71 µL/mL) was observed in cultures supplemented with 100 mM NaCl and 5% PEG, followed by the 4 mg/L GA3 treatment (70 µL/mL) as compared to control (60 µL/mL). Positive correlation was observed between GA3 and stevioside content. Notably, these two compounds are derived from a shared biochemical pathway. These results suggest that elicitation is an effective option to enhance the accumulation of steviosides and other metabolites and provides the groundwork for future industrial scale production using bioreactors.


Subject(s)
Antioxidants , Diterpenes, Kaurane , Gibberellins , Glucosides , Plant Shoots , Stevia , Stevia/metabolism , Stevia/growth & development , Stevia/drug effects , Diterpenes, Kaurane/metabolism , Glucosides/metabolism , Plant Shoots/metabolism , Plant Shoots/growth & development , Plant Shoots/drug effects , Gibberellins/metabolism , Antioxidants/metabolism , Secondary Metabolism , Flavonoids/metabolism , Flavonoids/analysis , Phenols/metabolism , Sodium Chloride/pharmacology , Purines/metabolism , Proline/metabolism , Polyethylene Glycols/pharmacology , Polyethylene Glycols/chemistry , Benzyl Compounds
13.
J Nat Prod ; 87(6): 1618-1627, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38887968

ABSTRACT

Rogersonins C-F (1-4), four unprecedented adenine-polyketide hybrids featuring a rare 9H-imidazo[2,1-i]purine (1,N6-ethenoadenine) moiety, were isolated from an Ophiocordyceps-associated fungus, Clonostachys rogersoniana. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1-4 were assigned by a combination of the modified Mosher method, chemical degradation, electronic circular dichroism (ECD) calculations, and X-ray crystallography using Cu Kα radiation. Compound 3 downregulated the expression of PD-L1 protein in MDA-MB-231 and A549 cells, but did not show detectable effect on mRNA transcription of the PD-L1-encoding gene CD274.


Subject(s)
Adenine , Hypocreales , Humans , Molecular Structure , Adenine/chemistry , Hypocreales/chemistry , Purines/chemistry , Crystallography, X-Ray , Cell Line, Tumor , Imidazoles/chemistry
14.
PLoS One ; 19(6): e0305621, 2024.
Article in English | MEDLINE | ID: mdl-38905267

ABSTRACT

OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.


Subject(s)
Arthritis, Rheumatoid , Azetidines , Bayes Theorem , Janus Kinase Inhibitors , Network Meta-Analysis , Piperidines , Pyrimidines , Humans , Arthritis, Rheumatoid/drug therapy , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Piperidines/therapeutic use , Piperidines/adverse effects , Azetidines/therapeutic use , Azetidines/adverse effects , Purines/therapeutic use , Purines/adverse effects , Pyrroles/therapeutic use , Pyrroles/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Randomized Controlled Trials as Topic , Treatment Outcome , Heterocyclic Compounds, 2-Ring/therapeutic use , Heterocyclic Compounds, 2-Ring/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Niacinamide/adverse effects , Benzamides/therapeutic use , Benzamides/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Triazoles/therapeutic use , Triazoles/adverse effects , Triazoles/administration & dosage , Adamantane/analogs & derivatives , Pyridines , Valine/analogs & derivatives
15.
J Zhejiang Univ Sci B ; 25(6): 529-540, 2024 Jun 15.
Article in English, Chinese | MEDLINE | ID: mdl-38910497

ABSTRACT

BACKGROUND: Following the short-term outbreak of coronavirus disease 2019 (COVID-19) in December 2022 in China, clinical data on kidney transplant recipients (KTRs) with COVID-19 are lacking. METHODS: We conducted a single-center retrospective study to describe the clinical features, complications, and mortality rates of hospitalized KTRs infected with COVID-19 between Dec. 16, 2022 and Jan. 31, 2023. The patients were followed up until Mar. 31, 2023. RESULTS: A total of 324 KTRs with COVID-19 were included. The median age was 49 years. The median time between the onset of symptoms and admission was 13 d. Molnupiravir, azvudine, and nirmatrelvir/ritonavir were administered to 67 (20.7%), 11 (3.4%), and 148 (45.7%) patients, respectively. Twenty-nine (9.0%) patients were treated with more than one antiviral agent. Forty-eight (14.8%) patients were treated with tocilizumab and 53 (16.4%) patients received baricitinib therapy. The acute kidney injury (AKI) occurred in 81 (25.0%) patients and 39 (12.0%) patients were admitted to intensive care units. Fungal infections were observed in 55 (17.0%) patients. Fifty (15.4%) patients lost their graft. The 28-d mortality rate of patients was 9.0% and 42 (13.0%) patients died by the end of follow-up. Multivariate Cox regression analysis identified that cerebrovascular disease, AKI incidence, interleukin (IL)|-6 level of >6.8 pg/mL, daily dose of corticosteroids of >50 mg, and fungal infection were all associated with an increased risk of death for hospitalized patients. CONCLUSIONS: Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality. The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival, while higher doses of corticosteroids may increase the death risk.


Subject(s)
Antiviral Agents , COVID-19 , Kidney Transplantation , SARS-CoV-2 , Humans , Middle Aged , Male , Female , COVID-19/mortality , COVID-19/complications , COVID-19/epidemiology , Retrospective Studies , China/epidemiology , Antiviral Agents/therapeutic use , Adult , Hospitalization , Transplant Recipients , Aged , COVID-19 Drug Treatment , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines , Purines , Pyrazoles , Sulfonamides
16.
Life Sci ; 351: 122838, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38897347

ABSTRACT

AIMS: Neuroinflammation plays a pivotal role in amyloid ß (Aß) plaques formation which is among the hallmarks of Alzheimer's disease (AD). The present study investigated the potential therapeutic effects of baricitinib (BAR), a selective JAK2/ STAT3 inhibitor, in ovariectomized/ D-galactose (OVX/D-gal) treated rats as a model for AD. MAIN METHODS: To induce AD, adult female rats (130-180 g) underwent bilateral ovariectomy and were injected daily with 150 mg/kg, i.p. D-gal for 8 consecutive weeks. BAR (10 and 50 mg/kg/day) was then given orally for 14 days. KEY FINDINGS: BAR in a dose-dependent effect mitigated OVX/D-gal-induced aberrant activation of JAK2/STAT3 signaling pathway resulting in significant decreases in the expression of p-JAK 2, and p-STAT3 levels, along with deactivating AKT/PI3K/mTOR signaling as evidenced by deceased protein expression of p-AKT, p-PI3K, and p-mTOR. As a result, neuroinflammation was diminished as evidenced by decreased NF-κß, TNF-α, and IL-6 levels. Moreover, oxidative stress biomarkers levels as iNOS, and MDA were reduced, whereas GSH was increased by BAR. BAR administration also succeeded in reverting histopathological alterations caused by OVX/D-gal, increased the number of intact neurons (detected by Nissl stain), and diminished astrocyte hyperactivity assessed as GFAP immunoreactivity. Finally, treatment with BAR diminished the levels of Aß. These changes culminated in enhancing spatial learning and memory in Morris water maze, and novel object recognition test. SIGNIFICANCE: BAR could be an effective therapy against neuroinflammation, astrogliosis and cognitive impairment induced by OVX/ D-gal where inhibiting JAK2/STAT3- AKT/PI3K/mTOR seems to play a crucial role in its beneficial effect.


Subject(s)
Galactose , Janus Kinase 2 , Memory Disorders , Ovariectomy , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Purines , Pyrazoles , STAT3 Transcription Factor , Signal Transduction , Sulfonamides , TOR Serine-Threonine Kinases , Animals , Female , STAT3 Transcription Factor/metabolism , Rats , Janus Kinase 2/metabolism , TOR Serine-Threonine Kinases/metabolism , Signal Transduction/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Sulfonamides/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Pyrazoles/pharmacology , Memory Disorders/drug therapy , Memory Disorders/metabolism , Purines/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Rats, Sprague-Dawley , Azetidines
18.
Int J Mol Sci ; 25(12)2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38928439

ABSTRACT

Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary for growth and proliferation. In fact, cancer cells are characterized by an increased "de novo" synthesis of purine nucleotides. Therefore, it is not surprising that specific enzymes of purine metabolism are the targets of drugs as antineoplastic agents, and a better knowledge of the mechanisms underlying their regulation would be of great help in finding new therapeutic approaches. The mammalian target of the rapamycin (mTOR) signaling pathway, which is often activated in cancer cells, promotes anabolic processes and is a major regulator of cell growth and division. Among the numerous effects exerted by mTOR, noteworthy is its empowerment of the "de novo" synthesis of nucleotides, accomplished by supporting the formation of purinosomes, and by increasing the availability of necessary precursors, such as one-carbon formyl group, bicarbonate and 5-phosphoribosyl-1-pyrophosphate. In this review, we highlight the connection between purine and mitochondrial metabolism, and the bidirectional relation between mTOR signaling and purine synthesis pathways.


Subject(s)
Neoplasms , Purines , Signal Transduction , TOR Serine-Threonine Kinases , Humans , Neoplasms/metabolism , Neoplasms/pathology , TOR Serine-Threonine Kinases/metabolism , Purines/metabolism , Animals , Mitochondria/metabolism
19.
Biomolecules ; 14(6)2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38927104

ABSTRACT

Chemo-enzymatic syntheses of strongly fluorescent nucleoside analogs, potentially applicable in analytical biochemistry and cell biology are reviewed. The syntheses and properties of fluorescent ribofuranosides of several purine, 8-azapurine, and etheno-purine derivatives, obtained using various types of purine nucleoside phosphorylase (PNP) as catalysts, as well as α-ribose-1-phosphate (r1P) as a second substrate, are described. In several instances, the ribosylation sites are different to the canonical purine N9. Some of the obtained ribosides show fluorescence yields close to 100%. Possible applications of the new analogs include assays of PNP, nucleoside hydrolases, and other enzyme activities both in vitro and within living cells using fluorescence microscopy.


Subject(s)
Fluorescent Dyes , Purine-Nucleoside Phosphorylase , Purine-Nucleoside Phosphorylase/metabolism , Purine-Nucleoside Phosphorylase/chemistry , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Humans , Nucleosides/chemistry , Nucleosides/metabolism , Nucleosides/chemical synthesis , Purines/chemistry , Purines/metabolism , Purines/chemical synthesis
20.
Arthritis Res Ther ; 26(1): 116, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38840219

ABSTRACT

BACKGROUND: A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. METHODS: Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. RESULTS: Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. CONCLUSIONS: This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).


Subject(s)
Giant Cell Arteritis , Janus Kinase Inhibitors , Recurrence , Humans , Giant Cell Arteritis/drug therapy , Giant Cell Arteritis/blood , Female , Janus Kinase Inhibitors/therapeutic use , Aged , Male , Retrospective Studies , Treatment Outcome , Pyrimidines/therapeutic use , Piperidines/therapeutic use , Azetidines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Purines/therapeutic use , Aged, 80 and over , Middle Aged , Heterocyclic Compounds, 3-Ring
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