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Gastroenterology Mar 2022Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular...
BACKGROUND & AIMS
Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis.
METHODS
To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis.
RESULTS
Our lineage-tracing studies revealed that in CRC, many ACTA2 CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr) cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis.
CONCLUSIONS
In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.
Topics: Actins; Adult; Aged; Aged, 80 and over; Animals; CD146 Antigen; Cancer-Associated Fibroblasts; Carcinogenesis; Cell Differentiation; Cell Lineage; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Female; Humans; Intestinal Mucosa; Ki-67 Antigen; Male; Mesenchymal Stem Cells; Mice; Mice, Transgenic; Middle Aged; Organoids; Prognosis; Receptors, Leptin; Sequence Analysis, RNA; Survival Rate; Tumor Microenvironment
PubMed: 34883119
DOI: 10.1053/j.gastro.2021.11.037 -
Military Medical Research Feb 2021Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic...
BACKGROUND
Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aimed to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration.
METHODS
We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice, as a model of liver regeneration. Bacterial flagellin content was measured with ELISA, and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, we analyzed bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression with immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels, and with Western blotting analysis of hepatic NF-κB and STAT3 activation. Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.
RESULTS
The bacterial flagellin content in the serum and liver increased, and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx. TLR5-deficient mice exhibited diminished numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokine and growth factor production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5 mice, as compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation, which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Furthermore, Tlr5 mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx.
CONCLUSION
We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.
Topics: Animals; Disease Models, Animal; Liver Regeneration; Mice; Mice, Inbred C57BL; Signal Transduction; Statistics, Nonparametric; Toll-Like Receptor 5
PubMed: 33622404
DOI: 10.1186/s40779-021-00309-4 -
Chinese Medical Journal Dec 2023Posttraumatic stress disorder (PTSD) and depression are highly comorbid. Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity....
BACKGROUND
Posttraumatic stress disorder (PTSD) and depression are highly comorbid. Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity. Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD. We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.
METHODS
First, we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning (FC) and fear extinction paradigm in mice. Psilocybin was administered 30 min before extinction training. Fear extinction testing was performed on the first day; fear extinction retrieval and fear renewal were tested on the sixth and seventh days, respectively. Furthermore, we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density, Western blotting for the protein levels of brain derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR), and immunofluorescence staining for the numbers of doublecortin (DCX)- and bromodeoxyuridine (BrdU)-positive cells.
RESULTS
A single dose of psilocybin (2.5 mg/kg, i.p.) reduced the increase in the percentage of freezing time induced by FC at 24 h, 6th day and 7th day after administration. In terms of structural neuroplasticity, psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC; in terms of neuroplasticity related proteins, psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC; in terms of neurogenesis, psilocybin rescued the decrease in the numbers of DCX- and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.
CONCLUSIONS
A single dose of psilocybin facilitated rapid and sustained fear extinction; this effect might be partially mediated by the promotion of hippocampal neuroplasticity. This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characterized by failure of fear extinction.
Topics: Humans; Mice; Animals; Psilocybin; Fear; Extinction, Psychological; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Hippocampus; Neuronal Plasticity; TOR Serine-Threonine Kinases
PubMed: 37000971
DOI: 10.1097/CM9.0000000000002647 -
Autophagy Mar 2020Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals....
Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA: bafilomycin A; BrdU: Bromodeoxyuridine/5-bromo-2'-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3'-diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.
Topics: Animals; Anxiety; Apoptosis; Autophagy; Autophagy-Related Protein 7; Cognition Disorders; Corticosterone; Depression; Doublecortin Protein; Gene Deletion; Gene Silencing; Hippocampus; Immediate-Early Proteins; Mice, Knockout; Necroptosis; Neural Stem Cells; Neurogenesis; Protein Serine-Threonine Kinases; Stress, Physiological
PubMed: 31234698
DOI: 10.1080/15548627.2019.1630222 -
Hepatology (Baltimore, Md.) Oct 2019Activation of hepatic stellate cells (HSCs) represents the primary driving force to promote the progression of chronic cholestatic liver diseases. We previously reported...
Activation of hepatic stellate cells (HSCs) represents the primary driving force to promote the progression of chronic cholestatic liver diseases. We previously reported that cholangiocyte-derived exosomal long noncoding RNA-H19 (lncRNA-H19) plays a critical role in promoting cholestatic liver injury. However, it remains unclear whether cholangiocyte-derived lncRNA-H19 regulates HSC activation, which is the major focus of this study. Both bile duct ligation (BDL) and Mdr2 knockout (Mdr2 ) mouse models were used. Wild-type and H19 (H19KO) mice were subjected to BDL. Mdr2 H19 (DKO) mice were generated. Exosomes isolated from cultured mouse and human cholangiocytes or mouse serum were used for in vivo transplantation and in vitro studies. Fluorescence-labeled exosomes and flow cytometry were used to monitor exosome uptake by hepatic cells. Collagen gel contraction and bromodeoxyuridine assays were used to determine the effect of exosomal-H19 on HSC activation and proliferation. Mouse and human primary sclerosing cholangitis (PSC)/primary biliary cholangitis (PBC) liver samples were analyzed by real-time PCR, western blot analysis, histology, and immunohistochemistry. The results demonstrated that hepatic H19 level was closely correlated with the severity of liver fibrosis in both mouse models and human patients with PSC and PBC. H19 deficiency significantly protected mice from liver fibrosis in BDL and Mdr2 mice. Transplanted cholangiocyte-derived H19-enriched exosomes were rapidly and preferentially taken up by HSCs and HSC-derived fibroblasts, and promoted liver fibrosis in BDL-H19KO mice and DKO mice. H19-enriched exosomes enhanced transdifferentiation of cultured mouse primary HSCs and promoted proliferation and matrix formation in HSC-derived fibroblasts. Conclusion: Cholangiocyte-derived exosomal H19 plays a critical role in the progression of cholestatic liver fibrosis by promoting HSC differentiation and activation and represents a potential diagnostic biomarker and therapeutic target for cholangiopathies.
Topics: Animals; Cell Proliferation; Cells, Cultured; Cholangitis, Sclerosing; Cholestasis; Disease Models, Animal; Exosomes; Flow Cytometry; Gene Expression Regulation; Hepatic Stellate Cells; Hepatocytes; Humans; Liver Cirrhosis; Male; Mice; Mice, Knockout; RNA, Long Noncoding; Random Allocation; Species Specificity
PubMed: 30985008
DOI: 10.1002/hep.30662 -
Cell Communication and Signaling : CCS Jul 2020Progression of Colorectal cancer (CRC) is influenced by single or compounded environmental factors. Accumulating evidence shows that microbiota can influence the outcome...
BACKGROUND
Progression of Colorectal cancer (CRC) is influenced by single or compounded environmental factors. Accumulating evidence shows that microbiota can influence the outcome of cancer immunotherapy. T cell, one of the main populations of effector immune cells in antitumor immunity, has been considered as a double-edged sword during the progression of CRC. Our previous studies indicate that traditional Chinese herbs (TCM) have potential anticancer effects in improving quality of life and therapeutic effect. However, little is known about the mechanism of TCM formula in cancer prevention.
METHODS
Here, we used C57BL/6 J Apc mice, an animal model of human intestinal tumorigenesis, to investigate the gut bacterial diversity and their mechanisms of action in gastrointestinal adenomas, and to evaluate the effects of Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) on of colon carcinogenesis in vivo and in vitro. Through human-into-mice fecal microbiota transplantation (FMT) experiments from YYFZBJS volunteers or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration.
RESULTS
We report herein, YYFZBJS treatment blocked tumor initiation and progression in Apc mice with less change of body weight and increased immune function. Moreover, diversity analysis of fecal samples demonstrated that YYFZBJS regulated animal's natural gut flora, including Bacteroides fragilis, Lachnospiraceae and so on. Intestinal tumors from conventional and germ-free mice fed with stool from YYFZBJS volunteers had been decreased. Some inflammation' expression also have been regulated by the gut microbiota mediated immune cells. Intestinal lymphatic, and mesenteric lymph nodes (MLN), accumulated CD4+ CD25+ Foxp3 positive Treg cells were reduced by YYFZBJS treatment in Apc mice. Although YYFZBJS had no inhibition on CRC cell proliferation by itself, the altered Tregs mediated by YYFZBJS repressed CRC cancer cell growth, along with reduction of the phosphorylation of β-catenin.
CONCLUSIONS
In conclusion, we demonstrated that gut microbiota and Treg were involved in CRC development and progression, and we propose YYFZBJS as a new potential drug option for the treatment of CRC. Video abstract.
Topics: Adenomatous Polyposis Coli Protein; Animals; Bacteroides fragilis; Bromodeoxyuridine; Carcinogenesis; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; Drugs, Chinese Herbal; Gastrointestinal Microbiome; HCT116 Cells; Humans; Immunity; Ki-67 Antigen; Leukocytes, Mononuclear; Lymph Nodes; Mice; Mice, Inbred C57BL; Mucous Membrane; Proliferating Cell Nuclear Antigen; RNA, Messenger; Spleen; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory
PubMed: 32677955
DOI: 10.1186/s12964-020-00596-9 -
Acta Pharmaceutica Sinica. B Jan 2021Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration....
Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively. knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress, inhibited cell viability and proliferation, and downregulated CCNA1, CCND1 and CKD4 protein levels. knockdown significantly prevented APAP-induced NRF2 activation, reduced the transcriptional activities of and and the mRNA levels of , , and . Furthermore, SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation (Co-IP) assay. Additionally, the protective effect of P53 against APAP-induced hepatocytes injury was -dependent. The mRNA was significantly down-regulated in mice. activated the transcriptional activity of and exerted interaction with SIRT6. Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation, and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.
PubMed: 33532182
DOI: 10.1016/j.apsb.2020.06.016 -
Phytomedicine : International Journal... Jan 2021Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancers. This cancer lacks the expression of the estrogen receptor, progesterone receptor, and...
Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway.
BACKGROUND
Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancers. This cancer lacks the expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The current therapeutic strategy for patients with this subtype is the use of cytotoxic chemotherapy and surgery. Luteolin is a natural herbal flavonoid and a potential therapeutic candidate for multiple diseases. The use of a treatment that combines Chinese herbal medicine and western medicine is rising in Asia.
PURPOSE
The present study evaluates the effects and molecular mechanisms involved with luteolin treatment and evaluates whether this herb affects androgen receptor-positive breast cancer cell proliferation or metastasis.
STUDY DESIGN
In vitro evaluation of the effect of luteolin on androgen receptor-positive TNBC cell proliferation and metastasis METHODS: Cell viability analysis was used for the cytotoxicity test. Colony formation and Bromodeoxyuridine (BrdU) staining-based proliferation experiments were used for cell proliferation. Wound healing and transwell assays were used for in vitro migration/invasion. The RT-qPCR analysis was used for gene expression. Furthermore, ChIP-qPCR analysis was used for epigenetic modification of gene promoters.
RESULTS
Luteolin significantly inhibited the proliferation and metastasis of androgen receptor-positive TNBC. Furthermore, luteolin inactivated the AKT/mTOR signaling pathway and reversed the epithelial-mesenchymal transition (EMT). The combination of luteolin and inhibitors of AKT/mTOR synergistically repressed an androgen receptor-positive TNBC cell proliferation and metastasis. Luteolin also downregulated MMP9 expression by decreasing the levels of the AKT/mTOR promoting H3K27Ac and H3K56A on the MMP9 promoter region.
CONCLUSION
Our findings indicate that luteolin inhibited the proliferation and metastasis of androgen receptor-positive TNBC by regulating MMP9 expression through a reduction in the levels of AKT/mTOR-inducing H3K27Ac and H3K56Ac.
Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Luteolin; Matrix Metalloproteinase 9; Proto-Oncogene Proteins c-akt; Receptors, Androgen; Signal Transduction; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms
PubMed: 33352494
DOI: 10.1016/j.phymed.2020.153437 -
Journal of Neuroinflammation Nov 2019Endothelin-1 (ET-1) is synthesized and upregulated in astrocytes under stroke. We previously demonstrated that transgenic mice over-expressing astrocytic ET-1 (GET-1)...
BACKGROUND
Endothelin-1 (ET-1) is synthesized and upregulated in astrocytes under stroke. We previously demonstrated that transgenic mice over-expressing astrocytic ET-1 (GET-1) displayed more severe neurological deficits characterized by a larger infarct after transient middle cerebral artery occlusion (tMCAO). ET-1 is a known vasoconstrictor, mitogenic, and a survival factor. However, it is unclear whether the observed severe brain damage in GET-1 mice post stroke is due to ET-1 dysregulation of neurogenesis by altering the stem cell niche.
METHODS
Non-transgenic (Ntg) and GET-1 mice were subjected to tMCAO with 1 h occlusion followed by long-term reperfusion (from day 1 to day 28). Neurological function was assessed using a four-point scale method. Infarct area and volume were determined by 2,3,5-triphenyltetra-zolium chloride staining. Neural stem cell (NSC) proliferation and migration in subventricular zone (SVZ) were evaluated by immunofluorescence double labeling of bromodeoxyuridine (BrdU), Ki67 and Sox2, Nestin, and Doublecortin (DCX). NSC differentiation in SVZ was evaluated using the following immunofluorescence double immunostaining: BrdU and neuron-specific nuclear protein (NeuN), BrdU and glial fibrillary acidic protein (GFAP). Phospho-Stat3 (p-Stat3) expression detected by Western-blot and immunofluorescence staining.
RESULTS
GET-1 mice displayed a more severe neurological deficit and larger infarct area after tMCAO injury. There was a significant increase of BrdU-labeled progenitor cell proliferation, which co-expressed with GFAP, at SVZ in the ipsilateral side of the GET-1 brain at 28 days after tMCAO. p-Stat3 expression was increased in both Ntg and GET-1 mice in the ischemia brain at 7 days after tMCAO. p-Stat3 expression was significantly upregulated in the ipsilateral side in the GET-1 brain than that in the Ntg brain at 7 days after tMCAO. Furthermore, GET-1 mice treated with AG490 (a JAK2/Stat3 inhibitor) sh owed a significant reduction in neurological deficit along with reduced infarct area and dwarfed astrocytic differentiation in the ipsilateral brain after tMCAO.
CONCLUSIONS
The data indicate that astrocytic endothelin-1 overexpression promotes progenitor stem cell proliferation and astr ocytic differentiation via the Jak2/Stat3 pathway.
Topics: Animals; Astrocytes; Cell Differentiation; Cell Proliferation; Doublecortin Protein; Endothelin-1; Janus Kinase 2; Male; Mice; Mice, Transgenic; Neural Stem Cells; Neurogenesis; STAT3 Transcription Factor; Signal Transduction; Stroke; Up-Regulation
PubMed: 31733648
DOI: 10.1186/s12974-019-1597-y -
Antiviral Chemistry & Chemotherapy 2023Brivudin, (()-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) can be considered the gold standard for the treatment of varicella-zoster virus (VZV) infections, such as herpes... (Review)
Review
Brivudin, (()-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) can be considered the gold standard for the treatment of varicella-zoster virus (VZV) infections, such as herpes zoster (shingles). It is available for clinical use in most European countries (except for the UK) and over the whole world (except for the US and Canada). Besides VZV its activity spectrum also includes various other herpesviruses, such as herpes simplex virus type 1 (HSV-1). Its activity against VZV and HSV-1 depends on phosphorylation by the virus-encoded thymidine kinase (TK). In its active form (BVDU TP or BVDU 5'-triphosphate), it can act as both substrate and inhibitor of the viral (i.e., HSV-1) DNA polymerase. It has proven to be effective against herpes zoster, including post-herpetic neuralgia (PHN). It is contra-indicated in patients concomitantly treated by 5-fluorouracil (FU), since its degradation product, ()-5-(2-bromovinyl)uracil, is inhibitory to the catabolism of FU, which may enhance the toxicity of the latter. A new compound, the bicyclic nucleoside analogue (BCNA) Cf-1743, has been described, which is a more potent inhibitor of VZV replication than BVDU and which does not interfere with the catabolism of FU. It is applicable orally, as its 5'-valine ester FV-100 (Fermavir), but has not (yet) been marketed for clinical use.
Topics: Humans; Antiviral Agents; Bromodeoxyuridine; Herpesvirus 3, Human; Herpes Zoster; Herpesvirus 1, Human; Fluorouracil; Thymidine Kinase
PubMed: 36710501
DOI: 10.1177/20402066231152971