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Frontiers in Pharmacology 2024Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential... (Review)
Review
Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential therapeutic tools throughout the long history due to their different structures of biologically active substances with high affinity to the human body. Here, we focus on the effects and the mechanism of action of animal-derived natural products against HCC, which were searched in databases encompassing Web of Science, PubMed, Embase, Science Direct, Springer Link, and EBSCO. A total of 24 natural products from 12 animals were summarized. Our study found that these natural products have potent anti-hepatocellular carcinoma effects. The mechanism of action involving apoptosis induction, autophagy induction, anti-proliferation, anti-migration, and anti-drug resistance via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Ras/extracellular signal regulated kinases (ERK)/mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Huachansu injection and sodium cantharidate have been used in clinical applications with good efficacy. We review the potential of animal-derived natural products and their derivatives in the treatment of HCC to date and summarize their application prospect and toxic side effects, hoping to provide a reference for drug development for HCC.
PubMed: 38803433
DOI: 10.3389/fphar.2024.1399882 -
Tofacitinib for the treatment of refractory immune checkpoint inhibitor-associated immune nephritis.Clinical Kidney Journal May 2024Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines...
Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines recommend treatment of ICI-associated AIN with steroids, then TNF-alpha inhibitor infliximab. However, some cases are refractory to these therapies, potentially due to insufficient cytokine blockade. This is the first case where a 65-year-old female with metastatic lung adenocarcinoma, requiring high maintenance doses of steroids for immune nephritis was treated with tofacitinib, an oral Janus kinase (JAK) inhibitor. Tofacitinib enabled successful steroid tapering and might be a therapy option for refractory immune nephritis.
PubMed: 38803394
DOI: 10.1093/ckj/sfae127 -
Nature Communications May 2024Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we...
Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.
Topics: Humans; HEK293 Cells; Interferon Type I; Interferon-Stimulated Gene Factor 3, gamma Subunit; Janus Kinase 1; Phosphorylation; Proteome; Receptor, Interferon alpha-beta; Signal Transduction; STAT1 Transcription Factor; STAT2 Transcription Factor; TYK2 Kinase; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 38802340
DOI: 10.1038/s41467-024-48800-5 -
Clinical Case Reports Jun 2024Generalized lichen planus pigmentosus significantly improved with the daily administration of Tofacitinib at a dosage of 15 mg.
Generalized lichen planus pigmentosus significantly improved with the daily administration of Tofacitinib at a dosage of 15 mg.
PubMed: 38799517
DOI: 10.1002/ccr3.8829 -
Frontiers in Pharmacology 2024Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal...
Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal if untreated. In AML, mutations in tyrosine kinases (TKs) lead to enhanced tumor cell survival. The most frequent mutations in TKs are reported in -like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), and KIT (tyrosine-protein kinase KIT), making these TKs potential targets for TK inhibitor (TKI) therapies in AML. With 30% of the mutations in TKs, mutated FLT3 is associated with poor overall survival and an increased chance of resistance to therapy. FLT3 inhibitors are used in FLT3-mutant AML, and the combination with hypomethylating agents displayed promising results. Midostaurin (MDS) is the first targeted therapy in FLT3-mutant AML, and its combination with chemotherapy showed good results. However, chemotherapies induce several side effects, and an alternative to chemotherapy might be the use of nanoparticles for better drug delivery, improved bioavailability, reduced drug resistance and induced toxicity. The herein study presents MDS-loaded gold nanoparticles and compares its efficacy with MDS alone, on both and models, using the FLT3-ITD-mutated AML cell line transfected to express luciferin. Our preclinical study suggests that MDS-loaded nanoparticles have a better tumor inhibitory effect than free drugs on models by controlling tumor growth in the first half of the treatment, while in the second part of the therapy, the tumor size was comparable to the cohort that was treatment-free.
PubMed: 38799169
DOI: 10.3389/fphar.2024.1382399 -
Journal of Clinical Biochemistry and... May 2024Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the...
Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone α-klotho. Immunofluorescent staining of α-klotho was observed in the renal distal tubules and pituitary glands of somatostatin- and GH-positive cells in wild-type (WT) mice. Treatment of 4-week-old WT mice with GH increased IGF1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased α-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased α-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of α-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and α-klotho supplementation in HEK293 cells transfected with GHR increased Janus kinase 2 mRNA (a GH downstream signal) expression compared to supplementation with GH alone. In conclusion, we suggest that 1) the kidney is the main source of secreted α-klotho, which is detected in blood by the downstream action of GH, 2) α-klotho induction by GH is resistant in kidney disease, and 3) α-klotho might be an enhanced regulator of GH signaling.
PubMed: 38799134
DOI: 10.3164/jcbn.23-127 -
The Korean Journal of Internal Medicine May 2024The aim of this study was to compare the short- and long-term retention rates of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in...
BACKGROUND/AIMS
The aim of this study was to compare the short- and long-term retention rates of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in Korean patients with seropositive rheumatoid arthritis.
METHODS
This study was conducted with 1,538 treatment courses of 1,063 patients, including adalimumab (n = 332), etanercept (n = 369), infliximab (n = 146), abatacept (n = 152), tocilizumab (n = 299), tofacitinib (n = 136), and baricitinib (n = 104), in patients with seropositive rheumatoid arthritis who started b/tsDMARD treatment between 2008 and 2020 at Seoul St. Mary's Hospital. Discontinuation 1 and 3 years after the first prescription of each drug was investigated. Kaplan- Meier estimates of time to discontinuation were calculated to compare the difference in drug retention rate for each drug. Patient-level predictors of drug discontinuation were evaluated using a Cox proportional hazards model.
RESULTS
The overall 1-year drug retention rate was from 60.1% for adalimumab to 90.0% for tofacitinib in the b/tsDMARD-naïve group, and from 55.2% for infliximab to 84.8% for tofacitinib in the b/tsDMARD-experienced group. The 3-year drug retention rate was from 36.9% for infliximab to 86.5% for tofacitinib in the b/tsDMARD-naïve group, and from 31.0% for infliximab to 65.4% for tocilizumab in the b/tsDMARD-experienced group. Drug discontinuation appeared to be affected by specific types of b/tsDMARDs.
CONCLUSIONS
Tocilizumab and tofacitinib are less commonly discontinued compared to tumor necrosis factor-α inhibitors at 1 and 3 years. Specifically, tofacitinib in the b/tsDMARD-naïve group and tocilizumab in the b/tsDMARD-experienced group showed the highest 3-year retention rates.
PubMed: 38798047
DOI: 10.3904/kjim.2023.297 -
Cell Transplantation 2024Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid...
Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid first-line treatment could not satisfy therapeutic needs due to limited efficacy. As a highly selective Janus kinase (JAK) 1 inhibitor, SHR0302 exhibits a reduced inhibition effect on JAK2 and might have less effect on hematopoiesis. This phase I clinical trial investigated the tolerability and safety of SHR0302 in combination with prednisone, and its early efficacy evidence as a potential first-line treatment to moderate/severe cGVHD. The standard 3 + 3 dose escalation was implemented to find the optimal dose of SHR0302. And prednisone was concurrently administrated with a dose of 1 mg/kg/d and then gradually tapered after 2 weeks. Eighteen patients were enrolled into the study. Grade ≥ 3 treatment-related adverse events were observed in 38.9% of patients. Only one patient developed DLT (grade ≥ 3 hypercholesterolemia) in the highest dose-level group who had pre-existing hypercholesterolemia. The maximum tolerated dose was not reached. No patient discontinued treatment due to AEs. Sixteen out of 18 patients were evaluable for responses, the ORR at week 4 and week 24 were 94.4 and 87.5%, respectively. Overall, the treatment of SHR0302 combined with prednisone was safe and well-tolerated, preliminary clinical results presented a high response for previously untreated cGVHD and a significant reduction in prednisone use in this study. A phase II trial will be conducted to further investigate its therapeutic effects clinically.
Topics: Humans; Graft vs Host Disease; Prednisone; Male; Female; Adult; Middle Aged; Janus Kinase 1; Chronic Disease; Young Adult; Hematopoietic Stem Cell Transplantation; Aged; Drug Therapy, Combination; Bronchiolitis Obliterans Syndrome
PubMed: 38798038
DOI: 10.1177/09636897241254678 -
Journal of Autoimmunity May 2024- Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi...
OBJECTIVES
- Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment.
METHODS
- We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology.
RESULTS
- 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment.
CONCLUSION
- JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.
PubMed: 38797048
DOI: 10.1016/j.jaut.2024.103248 -
RMD Open May 2024Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19.
METHODS
A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m, 25-30 kg/m and >30 kg/m) and age <65 years and ≥65 years.
RESULTS
In the high BMI group (>25 kg/m), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05).
CONCLUSION
The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.
Topics: Humans; Purines; Sulfonamides; Azetidines; Obesity; Male; Middle Aged; COVID-19; Pyrazoles; Female; Aged; SARS-CoV-2; Body Mass Index; Double-Blind Method; Janus Kinase Inhibitors; COVID-19 Drug Treatment; Pneumonia, Viral; Treatment Outcome; Betacoronavirus; Coronavirus Infections; Pandemics
PubMed: 38796180
DOI: 10.1136/rmdopen-2023-004045