-
Biomedicine & Pharmacotherapy =... May 2024The Plectranthus genus is often cited for its medicinal properties. Plectranthus ornatus Codd. is traditionally used in Africa for the treatment of gastric and liver...
The Plectranthus genus is often cited for its medicinal properties. Plectranthus ornatus Codd. is traditionally used in Africa for the treatment of gastric and liver diseases and their leaves are used for their antibiotic action. The main constituent of P. ornatus is the halimane compound, 11 R-acetoxyhalima-5,13E-dien-15-oic acid (Hal), described for its antimicrobial and anticancer properties. The objective of this work was to improve the activity of the halimane lead molecule. Further physiochemical characterisation was performed on Hal. To the best of our knowledge, this work constitutes the first published data of the absolute configurations by SCXRD and thermal stability of Hal. Using Hal, reactions with different amines were carried out to afford novel semi-synthetic derivatives and their structural elucidation was completed. The cytotoxicity of the derivatives was assessed against three leukaemia cancer cell lines (CCRF-CEM, K562 and HL-60). The antioxidant activity was investigated using HO-induced HGF-1 cells and their anti-inflammatory activity was studied using RT-PCR and ELISA. Our data showed that amide derivatives of Hal presented moderate cytotoxicity and more potent activity when compared to the parent molecule, giving insight into the SAR of Hal. The derivatives also displayed protection against oxidative damage to DNA. Finally, the derivatives possessed anti-inflammatory properties at the level of gene and protein expression for the cytokines IL-1β, TNF-α and IL-6, induced by LPS in normal HGF-1 cells. Overall, our study provides useful insight into the enhanced biological activities of semi-synthetic Hal derivatives, as a starting point for novel drug formulations in cancer therapy.
Topics: Humans; Plectranthus; Cell Line, Tumor; Antineoplastic Agents, Phytogenic; Diterpenes; Antioxidants; K562 Cells; HL-60 Cells; Antineoplastic Agents; Anti-Inflammatory Agents; Plant Extracts; Cell Survival
PubMed: 38583339
DOI: 10.1016/j.biopha.2024.116516 -
Epigenetics Dec 2024Deregulation of ten-eleven Translocation protein 1 (TET1) is commonly reported to induce imbalances in gene expression and subsequently to colorectal cancer development...
Deregulation of ten-eleven Translocation protein 1 (TET1) is commonly reported to induce imbalances in gene expression and subsequently to colorectal cancer development (CRC). On the other hand, vitamin C (VitC) improves the prognosis of colorectal cancer by reprogramming the cancer epigenome and limiting chemotherapeutic drug resistance events. In this study, we aimed to characterize TET1-specific subcellular compartments and evaluate the effect of VitC on TET1 compartmentalization in colonic tumour cells. We demonstrated that TET1 is concentrated in coarse nuclear bodies (NB) and 5-hydroxymethylcytosine (5hmC) in foci in colorectal cancer cells (HCT116, Caco-2, and HT-29). To our knowledge, this is the first report of a novel intracellular localization profile of TET1 and its demethylation marker, 5hmC, in CRC cells. Interestingly, we found that TET1-NBs frequently interacted with Cajal bodies, but not with promyelocytic leukaemia (PML) bodies. In addition, we report that VitC treatment of HCT116 cells induces 5hmC foci biogenesis and triggers 5hmC marks to form active complexes with nuclear body components, including both Cajal and PML proteins. Our data highlight novel NB-concentrating TET1 in CRC cells and demonstrate that VitC modulates TET1-NBs' interactions with other nuclear structures. These findings reveal novel TET1-dependent cellular functions and potentially provide new insights for CRC management.
Topics: Humans; Caco-2 Cells; Ascorbic Acid; Promyelocytic Leukemia Nuclear Bodies; DNA Methylation; Nuclear Bodies; Vitamins; Colorectal Neoplasms; Mixed Function Oxygenases; Proto-Oncogene Proteins
PubMed: 38583183
DOI: 10.1080/15592294.2024.2337142 -
Hematology, Transfusion and Cell Therapy Mar 2024Early Death (ED) remains challenging in newly diagnosed acute promyelocytic leukemia (APL), especially in developing countries. The clinical and laboratory profile at...
INTRODUCTION
Early Death (ED) remains challenging in newly diagnosed acute promyelocytic leukemia (APL), especially in developing countries. The clinical and laboratory profile at diagnosis were evaluated and causes and risk factors were investigated in adult APL patients.
METHOD
A retrospective real-life analysis of 141 medical records was performed of patients diagnosed with APL between 2007 and 2018, whether they were treated with the IC-APL 2006 protocol or not. Risk factors were assessed by univariate and multivariate analysis.
MAIN RESULTS
Overall, 112 patients were included in the study. ED occurred in 22.3% of cases, surpassing clinical trial reports, with non-protocol-eligible patients presenting notably higher rates (60%), potentially due to their clinical status. Hemorrhage (60%) and infection (33.3%) were the leading causes of ED. Univariate analysis associated ED to the ECOG score; white blood cell (WBC) count; body mass index; levels of hemoglobin, albumin, uric acid, and creatinine, aPTT and INR and FLT3 mutations. Multivariate analysis identified ECOG score ≥2 and elevated WBC count as independent risk factors.
CONCLUSION
ED remains a substantial challenge in APL, especially in real-world settings with hemorrhage and infection being the leading causes. ECOG status and WBC count emerged as independent risk factors, while age and platelet count lacked a 30-day prognostic correlation. Evaluating prognostic enhancement tools in controlled trials and real-life settings is pivotal to improving APL outcomes.
PubMed: 38582745
DOI: 10.1016/j.htct.2024.02.020 -
Cellular Signalling Jul 2024In the seemingly well-researched field of vascular research, there are still many underestimated factors and molecular mechanisms. In recent years, SUMOylation has... (Review)
Review
In the seemingly well-researched field of vascular research, there are still many underestimated factors and molecular mechanisms. In recent years, SUMOylation has become increasingly important. SUMOylation is a post-translational modification in which small ubiquitin-related modifiers (SUMO) are covalently attached to target proteins. Sites where these SUMO modification processes take place in the cell nucleus are PML nuclear bodies (PML-NBs) - multiprotein complexes with their essential main component and organizer, the PML protein. PML and SUMO, either alone or as partners, influence a variety of cellular processes, including regulation of transcription, senescence, DNA damage response and defence against microorganisms, and are involved in innate immunity and inflammatory responses. They also play an important role in maintaining homeostasis in the vascular system and in pathological processes leading to the development and progression of cardiovascular diseases. This review summarizes information about the function of SUMO(ylation) and PML(-NBs) in the human vasculature from angiogenesis to disease and highlights their clinical potential as drug targets.
Topics: Humans; Sumoylation; Promyelocytic Leukemia Protein; Nuclear Proteins; Transcription Factors; Animals; Tumor Suppressor Proteins; Small Ubiquitin-Related Modifier Proteins; Cardiovascular Diseases
PubMed: 38574938
DOI: 10.1016/j.cellsig.2024.111156 -
Journal of Lipid Research May 2024Intestinal epithelial cells convert excess fatty acids into triglyceride (TAG) for storage in cytoplasmic lipid droplets and secretion in chylomicrons. Nuclear lipid...
Intestinal epithelial cells convert excess fatty acids into triglyceride (TAG) for storage in cytoplasmic lipid droplets and secretion in chylomicrons. Nuclear lipid droplets (nLDs) are present in intestinal cells but their origin and relationship to cytoplasmic TAG synthesis and secretion is unknown. nLDs and related lipid-associated promyelocytic leukemia structures (LAPS) were abundant in oleate-treated Caco2 but less frequent in other human colorectal cancer cell lines and mouse intestinal organoids. nLDs and LAPS in undifferentiated oleate-treated Caco2 cells harbored the phosphatidate phosphatase Lipin1, its product diacylglycerol, and CTP:phosphocholine cytidylyltransferase (CCT)α. CCTα knockout Caco2 cells had fewer but larger nLDs, indicating a reliance on de novo PC synthesis for assembly. Differentiation of Caco2 cells caused large nLDs and LAPS to form regardless of oleate treatment or CCTα expression. nLDs and LAPS in Caco2 cells did not associate with apoCIII and apoAI and formed dependently of microsomal triglyceride transfer protein expression and activity, indicating they are not derived from endoplasmic reticulum luminal LDs precursors. Instead, undifferentiated Caco2 cells harbored a constitutive pool of nLDs and LAPS in proximity to the nuclear envelope that expanded in size and number with oleate treatment. Inhibition of TAG synthesis did affect the number of nascent nLDs and LAPS but prevented their association with promyelocytic leukemia protein, Lipin1α, and diacylglycerol, which instead accumulated on the nuclear membranes. Thus, nLD and LAPS biogenesis in Caco2 cells is not linked to lipoprotein secretion but involves biogenesis and/or expansion of nascent nLDs by de novo lipid synthesis.
Topics: Humans; Caco-2 Cells; Nuclear Envelope; Lipid Droplets; Animals; Mice; Cell Differentiation; Choline-Phosphate Cytidylyltransferase; Oleic Acid; Triglycerides
PubMed: 38570093
DOI: 10.1016/j.jlr.2024.100540 -
Microbiology Spectrum May 2024The key to a curative treatment of hepatitis B virus (HBV) infection is the eradication of the intranuclear episomal covalently closed circular DNA (cccDNA), the stable...
UNLABELLED
The key to a curative treatment of hepatitis B virus (HBV) infection is the eradication of the intranuclear episomal covalently closed circular DNA (cccDNA), the stable persistence reservoir of HBV. Currently, established therapies can only limit HBV replication but fail to tackle the cccDNA. Thus, novel therapeutic approaches toward curative treatment are urgently needed. Recent publications indicated a strong association between the HBV core protein SUMOylation and the association with promyelocytic leukemia nuclear bodies (PML-NBs) on relaxed circular DNA to cccDNA conversion. We propose that interference with the cellular SUMOylation system and PML-NB integrity using arsenic trioxide provides a useful tool in the treatment of HBV infection. Our study showed a significant reduction in HBV-infected cells, core protein levels, HBV mRNA, and total DNA. Additionally, a reduction, albeit to a limited extent, of HBV cccDNA could be observed. Furthermore, this interference was also applied for the treatment of an established HBV infection, characterized by a stably present nuclear pool of cccDNA. Arsenic trioxide (ATO) treatment not only changed the amount of expressed HBV core protein but also induced a distinct relocalization to an extranuclear phenotype during infection. Moreover, ATO treatment resulted in the redistribution of transfected HBV core protein away from PML-NBs, a phenotype similar to that previously observed with SUMOylation-deficient HBV core. Taken together, these findings revealed the inhibition of HBV replication by ATO treatment during several steps of the viral replication cycle, including viral entry into the nucleus as well as cccDNA formation and maintenance. We propose ATO as a novel prospective treatment option for further pre-clinical and clinical studies against HBV infection.
IMPORTANCE
The main challenge for the achievement of a functional cure for hepatitis B virus (HBV) is the covalently closed circular DNA (cccDNA), the highly stable persistence reservoir of HBV, which is maintained by further rounds of infection with newly generated progeny viruses or by intracellular recycling of mature nucleocapsids. Eradication of the cccDNA is considered to be the holy grail for HBV curative treatment; however, current therapeutic approaches fail to directly tackle this HBV persistence reservoir. The molecular effect of arsenic trioxide (ATO) on HBV infection, protein expression, and cccDNA formation and maintenance, however, has not been characterized and understood until now. In this study, we reveal ATO treatment as a novel and innovative therapeutic approach against HBV infections, repressing viral gene expression and replication as well as the stable cccDNA pool at low micromolar concentrations by affecting the cellular function of promyelocytic leukemia nuclear bodies.
Topics: Arsenic Trioxide; Hepatitis B virus; Humans; Virus Replication; Hepatitis B; Sumoylation; DNA, Circular; Cell Nucleus; DNA, Viral; Antiviral Agents; Viral Core Proteins; Hep G2 Cells
PubMed: 38567974
DOI: 10.1128/spectrum.03788-23 -
Frontiers in Oncology 2024Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia. About 2% of APL is characterized by atypical rearrangements. Here we reported one APL case with...
Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia. About 2% of APL is characterized by atypical rearrangements. Here we reported one APL case with atypical manifestations and morphology. A 35-year-old woman patient, mainly due to fatigue, poor appetite for over 10 days and intermittent fever for 3 days. combined with the results of flow cytometry, fusion gene and chromosome, the patient was diagnosed as AML-M3 with atypical morphology. Double induction therapy with retinoic acid and arsenous acid was immediately administrated. Idarubicin was administrated on the 18th day. A re-examination was performed in the 5th week, both the blood routine test and myelogram showed normal results, and the fusion gene turned negative, indicating complete remission. When atypical morphology occurs, peripheral blood POX staining may be performed to check the abnormal cells. Flow cytometry, chromosome analysis, and fusion gene analysis are also required for further diagnosis.
PubMed: 38567145
DOI: 10.3389/fonc.2024.1341840 -
Chinese Medicine Apr 2024Acute promyelocytic leukemia (APL), which was once considered one of the deadliest types of leukemia, has become a curable malignancy since the introduction of all-trans... (Review)
Review
Acute promyelocytic leukemia (APL), which was once considered one of the deadliest types of leukemia, has become a curable malignancy since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as clinical treatments. ATO, which has become the first-line therapeutic agent for APL, is derived from the natural mineral product arsenic, exemplifying an important role of natural products in the treatment of APL. Many other natural products, ranging from small-molecule compounds to herbal extracts, have also demonstrated great potential for the treatment and adjuvant therapy of APL. In this review, we summarize the natural products and representative components that have demonstrated biological activity for the treatment of APL. We also discuss future directions in better exploring their medicinal value, which may provide a reference for subsequent new drug development and combination therapy programs.
PubMed: 38566147
DOI: 10.1186/s13020-024-00928-8 -
Acta Medica Indonesiana Jan 2024Incidents of leukemia in pregnancy are infrequent with only one case found from 75,000 to 100,000 pregnancies. The pathophysiological mechanism of leukemia during...
Incidents of leukemia in pregnancy are infrequent with only one case found from 75,000 to 100,000 pregnancies. The pathophysiological mechanism of leukemia during pregnancy is still unclear. Leukemia which occurs in pregnancy is usually acute and predominantly the myeloid type.A 35-year-old woman in her fourth pregnancy with a gestational age of 38-39 weeks, came to the emergency department (ED) with complaints of contractions since 4.5 hours before admission. The contraction was not accompanied by discharge, mucus, or blood, and fetal movements was still active. She denied complaints of fever, nausea, vomiting, dizziness, shortness of breath, weakness, fatigue, lethargy, and bleeding. Physical examination results, both palpebral conjunctiva were pale. Laboratory examination results of a complete blood count, white blood cell count were 2,930/uL, hemoglobin 8.3 g/dL, Hct 24.10%, erythrocytes 2.78x106/µL, platelets 62,000/µL. Bone Marrow Aspiration (BMA) revealed Acute Promyelocytic Leukemia (APL).APL is a subtype of Acute Myelogenous Leukemia (AML). Persistent fatigue, recurrent infections, and bleeding are common manifestations of APL. The diagnosis of APL is made by bone marrow aspiration examination, and it is safe for pregnancy. APL therapy in pregnancy uses All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO). ATRA and ATO are highly teratogenic, but recent studies have reported no fetal abnormalities.Accuracy and speed in diagnosing and initiating APL therapy in pregnancy are essential in preventing serious complications.
Topics: Adult; Female; Humans; Pregnancy; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Leukemia, Promyelocytic, Acute; Tretinoin
PubMed: 38561886
DOI: No ID Found -
European Journal of Cell Biology Jun 2024We analyzed actin cytoskeleton alterations during NET extrusion by neutrophil-like dHL-60 cells and human neutrophils in the absence of DNase1 containing serum to avoid...
We analyzed actin cytoskeleton alterations during NET extrusion by neutrophil-like dHL-60 cells and human neutrophils in the absence of DNase1 containing serum to avoid chromatin degradation and microfilament disassembly. NET-formation by dHL-60 cells and neutrophils was induced by Ionomycin or phorbol-12-myristat-13-acetate (PMA). Subsequent staining with anti-actin and TRITC-phalloidin showed depolymerization of the cortical F-actin at spatially confined areas, the NET extrusion sites, effected by transient activation of the monooxygenase MICAL-1 supported by the G-actin binding proteins cofilin, profilin, thymosin ß4 and probably the F-actin fragmenting activity of gelsolin and/or its fragments, which also decorated the formed NETs. MICAL-1 itself appeared to be proteolyzed by neutrophil elastase possibly to confine its activity to the NET-extrusion area. The F-actin oxidization activity of MICAL-1 is inhibited by Levosimendan leading to reduced NET-formation. Anti-gasdermin-D immunohistochemistry showed a cytoplasmic distribution in non-stimulated cells. After stimulation the NET-extrusion pore displayed reduced anti-gasdermin-D staining but accumulated underneath the plasma membrane of the remaining cell body. A similar distribution was observed for myosin that concentrated together with cortical F-actin along the periphery of the remaining cell body suggesting force production by acto-myosin interactions supporting NET expulsion as indicated by the inhibitory action of the myosin ATPase inhibitor blebbistatin. Isolated human neutrophils displayed differences in their content of certain cytoskeletal proteins. After stimulation neutrophils with high gelsolin content preferentially formed "cloud"-like NETs, whereas those with low or no gelsolin formed long "filamentous" NETs.
Topics: Humans; Extracellular Traps; Neutrophils; Actin Cytoskeleton; HL-60 Cells; Actins; Gelsolin
PubMed: 38555846
DOI: 10.1016/j.ejcb.2024.151407