Modulating the Release Kinetics of Natural Product Actinomycin from Bacterial Nanocellulose Films and Their Antimicrobial Activity.

The present study aimed to create a more sustainable and controlled delivery system based on natural biopolymer bacterial nanocellulose (BNC) and bacterial natural product actinomycin (Act), with the applicative potential in the biomedical field. In order to provide improved interaction between BNC and the active compound, and thus to modulate the release kinetics, the TEMPO oxidation of BNC support was carried out. A mix of actinomycins from bacterial fermentation (ActX) were used as natural antimicrobial agents with an established bioactivity profile and clinical use. BNC and TEMPO-oxidized BNC films with incorporated active compounds were obtained and analyzed by FTIR, SEM, XPS, and XRD. The ActX release profiles were determined in phosphate-buffer solution, PBS, at 37 °C over time. FTIR analysis confirmed the improved incorporation and efficiency of ActX adsorption on oxidized BNC due to the availability of more active sites provided by oxidation. SEM analysis indicated the incorporation of ActX into the less-dense morphology of the TEMPO-oxidized BNC in comparison to pure BNC. The release kinetics of ActX were significantly affected by the BNC structure, and the activated BNC sample indicated the sustained release of active compounds over time, corresponding to the Fickian diffusion mechanism. Antimicrobial tests using Staphylococcus aureus NCTC 6571 confirmed the potency of this BNC-based system for biomedical applications, taking advantage of the capacity of modified BNC to control and modulate the release of bioactive compounds.

Characterization of Antibiotic Actinomycin D Isolated from Streptomyces parvulus Collected from Marine Sponge of Barrang Lompo Island, Makassar, Indonesia.

BACKGROUND: Microorganisms associated with sea sponges have proven to be good natural product resources that are biologically active and pharmaceutically important. OBJECTIVE: This research aimed to identify actinomycetes related to a sponge from Bar-ranglompo Island Makassar and the antibacterial compounds. METHODS: Identification of actinomycetes was based on molecular characterization of sequence gen16S rRNA. The antibacterial compound was separated using vacuum liquid chromatog-raphy and preparative Thin Layer Chromatography (TLC). The structure determination was done based on spectroscopy 1H-NMR, 13C-NMR, 2D NMR, and mass spectra. RESULTS: Molecular characterization showed that actinomycetes strain BLP 20 had the closest relationship with Streptomyces parvulus and Uncultured Streptomyces sp. with a similarity value of 83%. The results obtained from the characterization of antibacterial compounds based on spectroscopic data indicate that these compounds lead to Actinomycin D. CONCLUSION: Characterization and identification of Strain 20 / BLP by molecular phylogenetic analysis of 16S rRNA sequences revealed the closest relationship with Uncultured Streptomy-ces sp and S. parvulus with a similarity value of 83 %, which indicated a new species. The structure of the active compound isolated from actinomycetes strain 20 / BLP leads to Actino-mycin D.

Myosin VI in the nucleolus of neurosecretory PC12 cells: its involvement in the maintenance of nucleolar structure and ribosome organization.

We have previously shown that unconventional myosin VI (MVI), a unique actin-based motor protein, shuttles between the cytoplasm and nucleus in neurosecretory PC12 cells in a stimulation-dependent manner and interacts with numerous proteins involved in nuclear processes. Among the identified potential MVI partners was nucleolin, a major nucleolar protein implicated in rRNA processing and ribosome assembly. Several other nucleolar proteins such as fibrillarin, UBF (upstream binding factor), and B23 (also termed nucleophosmin) have been shown to interact with MVI. A bioinformatics tool predicted the presence of the nucleolar localization signal (NoLS) within the MVI globular tail domain, and immunostaining confirmed the presence of MVI within the nucleolus. Depletion of MVI, previously shown to impair PC12 cell proliferation and motility, caused disorganization of the nucleolus and rough endoplasmic reticulum (rER). However, lack of MVI does not affect nucleolar transcription. In light of these data, we propose that MVI is important for nucleolar and ribosome maintenance but not for RNA polymerase 1-related transcription.

Noradrenaline enhances Na-K ATPase subunit expression by HuR-induced mRNA stabilization and their transportation to the cell surface through PLC and PKC mediated pathway: Implications with REMS-loss associated disorders.

Rapid eye movement sleep (REMS) maintains brain excitability at least by regulating Na-K ATPase activity. Although REMS deprivation (REMSD)-associated elevated noradrenaline (NA) increases Na-K ATPase protein expression, its mRNA transcription did not increase. We hypothesized and confirmed both in vivo as well as in vitro that elevated mRNA stability explains the apparent puzzle. The mRNA stability was measured in control and REMSD rat brain with or without in vivo treatment with α1-adrenoceptor (AR) antagonist, prazosin (PRZ). Upon REMSD, Na-K ATPase α1-, and α2-mRNA stability increased significantly, which was prevented by PRZ. To decipher the molecular mechanism of action, we estimated NA-induced Na-K ATPase mRNA stability in Neuro-2a cells under controlled conditions and by transcription blockage using Actinomycin D (Act-D). NA increased Na-K ATPase mRNA stability, which was prevented by PRZ and propranolol (PRP, ß-AR antagonist). The knockdown assay confirmed that the increased mRNA stabilization was induced by elevated cytoplasmic abundance of Human antigen R (HuR) and involving (Phospholipase C) PLC-mediated activation of Protein Kinase C (PKC). Additionally, using cell-impermeable Enz-link sulfo NHS-SS-Biotin, we observed that NA increased Na-K ATPase α1-subunits on the Neuro-2a cell surface. We conclude that REMSD-associated elevated NA, acting on α1- and ß-AR, increases nucleocytoplasmic translocation of HuR and increases Na-K ATPase mRNA stability, resulting in increased Na-K ATPase protein expression. The latter then gets translocated to the neuronal membrane surface involving both PKC and (Protein Kinase A) PKA-mediated pathways. These findings may be exploited for the amelioration of REMSD-associated chronic disorders and symptoms.

Antibacterial Mechanism, Control Efficiency, and Nontarget Toxicity Evaluation of Actinomycin X2 against Xanthomonas citri Subsp. citri.

The present study investigated the antibacterial mechanism, control efficiency, and nontarget toxicity of actinomycin X2 (Act-X2) against Xanthomonas citri subsp. citri (Xcc) for the first time. Act-X2 almost completely inhibited the proliferation of Xcc in the growth curve assay at a concentration of 0.25 MIC (minimum inhibitory concentration, MIC = 31.25 µg/mL). This inhibitory effect was achieved by increasing the production of reactive oxygen species (ROS), blocking the formation of biofilms, obstructing the synthesis of intracellular proteins, and decreasing the enzymatic activities of malate dehydrogenase (MDH) and succinate dehydrogenase (SDH) of Xcc. Molecular docking and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis results indicated that Act-X2 steadily bonded to the RNA polymerase, ribosome, malate dehydrogenase, and succinate dehydrogenase to inhibit their activities, thus drastically reducing the expression levels of related genes. Act-X2 showed far more effectiveness than the commercially available pesticide Cu2(OH)3Cl in the prevention and therapy of citrus canker disease. Furthermore, the nontarget toxicity evaluation demonstrated that Act-X2 was not phytotoxic to citrus trees and exhibited minimal toxicity to earthworms in both contact and soil toxic assays. This study suggests that Act-X2 has the potential as an effective and environmentally friendly antibacterial agent.

Low-risk gestational trophoblastic neoplasia - 20 years experience of a state registry.

BACKGROUND: Gestational trophoblastic disease (GTD) is an uncommon but highly treatable condition. There is limited local evidence to guide therapy. AIMS: To report the experience of a statewide registry in the treatment of low-risk gestational trophoblastic neoplasia (GTN) over a 20-year period. MATERIALS AND METHODS: A retrospective review of the prospectively maintained GTD registry database was conducted. There were 144 patients identified with low-risk GTN, of which 115 were analysed. Patient demographics, treatment details and outcomes, including development of resistance, toxicity or relapse were reviewed. RESULTS: The incidence of GTD was 2.6/1000 live births. There was 100% survival. The mean time from diagnosis to commencing treatment was 1.9 days (range 0-29 days). Seventy-seven percent of patients treated with methotrexate achieved complete response. Thirteen patients (11.3%) required multi-agent chemotherapy, for the treatment of resistant or relapsed disease. There was a higher rate of treatment resistance in those with World Health Organization (WHO) risk scores 5-6 (odds ratio (OR) 6.56, 95% CI 1.73-24.27, P = 0.005) and those with pre-treatment human chorionic gonadotropin >10 000 (OR 4.00 95% CI 1.73-24.27 P = 0.007). Four patients (3.5%) were diagnosed with choriocarcinoma after commencing treatment. Nine patients (7.8%) had successful surgical treatment for GTN, both alone and in combination with chemotherapy. The relapse rate was 4.3%; all were treated successfully with a combination of chemotherapy and surgery, and 93.9% of patients completed follow up through the registry. CONCLUSIONS: Methotrexate is a highly effective treatment for low-risk GTN, especially with WHO risk score ≤4. The optimal treatment for those with risk scores of 5-6 requires further investigation.

Discovery of a new highly pathogenic toxin involved in insect sepsis.

IMPORTANCE: As a current biocontrol resource, entomopathogenic nematodes and their symbiotic bacterium can produce many toxin factors to trigger insect sepsis, having the potential to promote sustainable pest management. In this study, we found Steinernema feltiae and Xenorhabdus bovienii were highly virulent against the insects. After infective juvenile injection, Galleria mellonella quickly turned black and softened with increasing esterase activity. Simultaneously, X. bovienii attacked hemocytes and released toxic components, resulting in extensive hemolysis and sepsis. Then, we applied high-resolution mass spectrometry-based metabolomics and found multiple substances were upregulated in the host hemolymph. We found extremely hazardous actinomycin D produced via 3-hydroxyanthranilic acid metabolites. Moreover, a combined transcriptomic analysis revealed that gene expression of proteins associated with actinomycin D was upregulated. Our research revealed actinomycin D might be responsible for the infestation activity of X. bovienii, indicating a new direction for exploring the sepsis mechanism and developing novel biotic pesticides.

circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor worldwide. Circular RNA (circRNA) is of great value in tumorigenesis progression. However, the mechanism of circFNDC3B in ESCC remains to be clarified. METHODS: Firstly, the circular characteristics of circFNDC3B were evaluated by Actinomycin D and RNase R measurements. The functions of circFNDC3B in ESCC cells were examined by CCK-8, EdU and flow cytometry. Subsequently, the molecular mechanism of circFNDC3B was explained using luciferase reporter gene detection. Finally, we constructed xenograft model to prove the role of circFNDC3B in vivo. RESULTS: Our study revealed that circFNDC3B was more stable than its linear RNA and prominently upregulated in ESCC. Functional findings suggested that silencing of circFNDC3B reduced the proliferation and enhanced apoptosis of ESCC cells in vitro. Meanwhile, knockdown of circFNDC3B attenuated tumor progression in vivo. Next, miR-370-3p/miR-136-5p was discovered to bind circFNDC3B. miR-370-3p/miR-136-5p reversed the promotive effect on cell proliferation and the inhibitory effect on cell apoptosis of circFNDC3B. MYO5A was a downstream target of miR-370-3p/miR-136-5p. CircFNDC3B served as a sponge for miR-370-3p/miR-136-5p and alleviated the prohibitory effect of miR-370-3p/miR-136-5p on MYO5A, which accelerated ESCC progression. CONCLUSION: circFNDC3B positively adjusted the MYO5A expression via spongy miR-370-3p/miR-136-5p, hence achieving the cancer-promoting effect on ESCC. circFNDC3B was a prospective diagnosis marker for ESCC.

Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.

BACKGROUND: Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens. METHODS: We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m2) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life. DISCUSSION: Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).

Actinomycins produced by endophyte Streptomyces sp. GLL-9 from navel orange plant exhibit high antimicrobial effect against Xanthomonas citri susp. citri and Penicillium italicum.

BACKGROUND: Citrus canker and citrus blue mold are two severe diseases in citrus plants, which are mainly caused by Xanthomonas citri susp. citri (Xcc) and Penicillium italicum, respectively. The currently widely used pesticides for these two diseases are harmful to human health and the environment. Therefore, searching for novel antimicrobial agents, especially from natural resources, is getting increasing interest. RESULTS: In this study, the crude extract of Streptomyces sp. GLL-9, an endophyte from a navel orange tree, was found to exhibit excellent antimicrobial effects against Xcc and P. italicum. Bioassay-guided isolation led to the discovery of three actinomycins (Acts), actinomycin X2 (Act-X2 ), actinomycin D (ActD), and actinomycin XOß (Act-XOß ). The MIC (minimum inhibitory concentration) values of Act-X2 , ActD, and Act-XOß were 31.25, 62.50, and 62.50 µg mL-1 against Xcc, respectively, while 62.50 (Act-X2 ) and 125.00 µg mL-1 (ActD) against P. italicum, being better or comparable to the positive controls. The highest yield of Acts was obtained by solid-state fermentation with rice containing 1% L-tryptophan as a culture medium, being 6.03, 3.07, and 1.02 mg g-1 , for Act-X2 , ActD, and Act-XOß , respectively. The ethyl acetate extract of Streptomyces sp. GLL-9 cultivated under the optimal fermentation conditions (EAE-1) can efficiently control these two citrus diseases by excessively producing reactive oxygen species (ROS) in both pathogens, damaging the cell membranes of P. italicum, and inhibiting the growth of Xcc. In addition, Act-X2 , ActD, and EAE-1 displayed broad-spectrum antifungal activity. CONCLUSION: EAE-1 and Acts produced by Streptomyces sp. GLL-9 have high potential as novel antimicrobial agents against plant pathogens. © 2023 Society of Chemical Industry.

Pyridine Derivative of Succinic Acid Hydroxylamide Enhances the Cytotoxic Effect of Cisplatin and Actinomycin D.

We studied the possibility of inhibition of histone deacetylases (HDAC) in the nuclear extract of HeLa cells by N1-hydroxy-N4-(pyridin-4-yl)succinamide (compound 1). Compound 1 inhibits HDAC and showed low toxicity for A-172, HepG2, HeLa, MCF-7, and Vero cells. HeLa cells were most sensitive to the compound. Increasing the interval between administration of compound 1 and the chemotherapeutic agent to 8 h led to an increase in the cytotoxic effect of cisplatin (actinomycin D) on HeLa cells. The combination of compound 1 with cisplatin (actinomycin D) reduced the cytotoxic effect of these drugs for non-tumor Vero cells.

tRNATyr has an unusually short half-life in Trypanosoma brucei.

Following transcription, tRNAs undergo a series of processing and modification events to become functional adaptors in protein synthesis. Eukaryotes have also evolved intracellular transport systems whereby nucleus-encoded tRNAs may travel out and into the nucleus. In trypanosomes, nearly all tRNAs are also imported from the cytoplasm into the mitochondrion, which lacks tRNA genes. Differential subcellular localization of the cytoplasmic splicing machinery and a nuclear enzyme responsible for queuosine modification at the anticodon "wobble" position appear to be important quality control mechanisms for tRNATyr, the only intron-containing tRNA in T. brucei Since tRNA-guanine transglycosylase (TGT), the enzyme responsible for Q formation, cannot act on an intron-containing tRNA, retrograde nuclear transport is an essential step in maturation. Unlike maturation/processing pathways, the general mechanisms of tRNA stabilization and degradation in T. brucei are poorly understood. Using a combination of cellular and molecular approaches, we show that tRNATyr has an unusually short half-life. tRNATyr, and in addition tRNAAsp, also show the presence of slow-migrating bands during electrophoresis; we term these conformers: alt-tRNATyr and alt-tRNAAsp, respectively. Although we do not know the chemical or structural nature of these conformers, alt-tRNATyr has a short half-life resembling that of tRNATyr; the same is not true for alt-tRNAAsp We also show that RRP44, which is usually an exosome subunit in other organisms, is involved in tRNA degradation of the only intron-containing tRNA in T. brucei and is partly responsible for its unusually short half-life.

Preparation and Characterization of a Silk Fibroin/Polyurethane Fiber Blend Membrane Containing Actinomycin X2 with Excellent Mechanical Properties and Enhanced Antibacterial Activities.

Development of suitable antimicrobial biomaterials for hygienic wound dressing and healing is an important requirement for medical application. Durable mechanical properties increase the application range of biomaterial in different environmental and biological conditions. Due to the inherent brittleness of silk fibroin (SF), polyurethane fiber (PUF) was used to modify SF containing actinomycin X2 (Ac.X2) to prepare silk fibroin@actinomycin X2 /polyurethane fiber (ASF/PUF) blend membranes. The ASF/PUF blend membrane was developed by solution casting method. Incorporation of PUF improved the flexibility of material and introduction of Ac.X2 has increased antibacterial activity of materials. Excellent mechanical properties (tensile strength up to 25.7 MPa and elongation at break up to 946.5 %) of 50 % SF+50 % PUF blend membrane were proved by tensile testing machine. FT-IR spectra, TGA, contact angle and DMA were tested to prove the blend membrane's physico-chemical characteristics. ASF/PUF blend membrane displayed satisfactory antibacterial activity against S. aureus, and the cytotoxicity tests showed that the blend membrane has better biosafety compared to directly applied Ac.X2 in soluble form. These results suggest that the modification of SF through PUF for development of flexible antibacterial membranes has great potential application value in the field of silk-like material fabrication.

Actinomycin-X2-Immobilized Silk Fibroin Film with Enhanced Antimicrobial and Wound Healing Activities.

Actinomycin is a family of chromogenic lactone peptides that differ in their peptide portions of the molecule. An antimicrobial peptide, actinomycin X2 (Ac.X2), was produced through the fermentation of a Streptomyces cyaneofuscatus strain. Immobilization of Ac.X2 onto a prepared silk fibroin (SF) film was done through a carbodiimide reaction. The physical properties of immobilized Ac.X2 (antimicrobial films, AMFs) were analyzed by ATR-FTIR, SEM, AFM, and WCA. The findings from an in vitro study showed that AMFs had a more broad-spectrum antibacterial activity against both S. aureus and E. coli compared with free Ac.X2, which showed no apparent strong effect against E. coli. These AMFs showed a suitable degradation rate, good hemocompatibility, and reduced cytotoxicity in the biocompatibility assay. The results of in vivo bacterially infected wound healing experiments indicated that wound inflammation was prevented by AMFs, which promoted wound repair and improved the wound microenvironment. This study revealed that Ac.X2 transformation is a potential candidate for skin wound healing.

In vitro and in silico evaluations of actinomycin X2and actinomycin D as potent anti-tuberculosis agents.

Background: Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR-Mycobacterium tuberculosis (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, in vitro and in silico studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X2 (act-X2) and actinomycin-D (act-D), from the Streptomyces smyrnaeus strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia). Methods: The anti-TB activity of the isolated actinomycins was assessed in vitro using the Mtb H37Ra, Mycobacterium bovis (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. In silico molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands. Results: In vitro results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X2 had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The in silico molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-X2and act-D respectively. The molecular dynamics (MD) results demonstrated that act-X2 and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X2 was more potent than act-D. Conclusion: In conclusion, our results suggest that both actinomycins X2 and D are highly potent anti-TB drug candidates. We show that act-X2is better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.

Polypeptide antibiotic actinomycin D induces Mcl-1 uncanonical downregulation in lung cancer cell apoptosis.

AIMS: Actinomycin (Act) D, a polypeptide antibiotic, is used clinically to inhibit the growth of malignant tumors. Act D binds to DNA at the transcription initiation complex to prevent the elongation of RNA. Act D causes DNA damage, growth inhibition, and cell death. Myeloid cell leukemia (Mcl-1) is an anti-apoptotic Bcl-2 family member protein, and the present study explored the effects and molecular mechanism of Act D-induced Mcl-1 downregulation. MAIN METHODS: Human adenocarcinoma A549 cells were used to check the cytotoxic signaling pathways of Act D, particularly in apoptotic mechanism, in a cell-based study approach. Specific blockers targeting the apoptotic factors were examined for their possible roles. KEY FINDINGS: We found that Act D caused cell growth inhibition and apoptosis. Propidium iodide-based flow cytometric analysis and immunostaining confirmed cell apoptosis. Treatment with Act D caused DNA damage, followed by p53-independent cell death. Western blotting showed a significant decrease in Mcl-1 expression, mitochondrial transmembrane potential loss, and caspase-9/caspase-3 cascade activation. The proteasome inhibitor MG132 reversed Act D-induced Mcl-1 downregulation. However, pharmacological inhibition of glycogen synthase kinase-3, p53 expression, ER stress, autophagy, and vesicle acidification, which are Mcl-1-regulating signaling pathways, did not rescue these effects. Notably, Cullin-Ring E3 ligase partially mediated Mcl-1 downregulation. Administration of transforming growth factor-ß induced mesenchymal cell differentiation, but Act D still decreased Mcl-1 and caused cell apoptosis. SIGNIFICANCE: All of these data show a potential pro-apoptotic effect for Act D by facilitating Mcl-1 uncanonical downregulation.

Synthetic, biological and optoelectronic properties of phenoxazine and its derivatives: a state of the art review.

Phenoxazines have sparked a lot of interest owing to their numerous applications in material science, organic light-emitting diodes, photoredox catalyst, dye-sensitized solar cells and chemotherapy. Among other things, they have antioxidant, antidiabetic, antimalarial, anti-alzheimer, antiviral, anti-inflammatory and antibiotic properties. Actinomycin D, which contains a phenoxazine moiety, functions both as an antibiotic and anticancer agent. Several research groups have worked on various structural modifications over the years in order to develop new phenoxazines with improved properties. Both phenothiazines and phenoxazines have gained prominence in medicine as pharmacological lead structures from their traditional uses as dyes and pigments. Organoelectronics and material sciences have recently found these compounds and their derivatives to be quite useful. Due to this, organic synthesis has been used in an unprecedented amount of exploratory alteration of the parent structures in an effort to create novel derivatives with enhanced biological and material capabilities. As a result, it is critical to conduct more frequent reviews of the work done in this area. Various stages of the synthetic transformation of phenoxazine scaffolds have been depicted in this article. This article aims to provide a state of the art review for the better understanding of the phenoxazine derivatives highlighting the progress and prospects of the same in medicinal and material applications.

MAPKAPK2-centric transcriptome profiling reveals its major role in governing molecular crosstalk of IGFBP2, MUC4, and PRKAR2B during HNSCC pathogenesis.

Transcriptome analysis of head and neck squamous cell carcinoma (HNSCC) has been pivotal to comprehending the convoluted biology of HNSCC tumors. MAPKAPK2 or MK2 is a critical modulator of the mRNA turnover of crucial genes involved in HNSCC progression. However, MK2-centric transcriptome profiles of tumors are not well known. This study delves into HNSCC progression with MK2 at the nexus to delineate the biological relevance and intricate crosstalk of MK2 in the tumor milieu. We performed next-generation sequencing-based transcriptome profiling of HNSCC cells and xenograft tumors to ascertain mRNA expression profiles in MK2-wild type and MK2-knockdown conditions. The findings were validated using gene expression assays, immunohistochemistry, and transcript turnover studies. Here, we identified a pool of crucial MK2-regulated candidate genes by annotation and differential gene expression analyses. Regulatory network and pathway enrichment revealed their significance and involvement in the HNSCC pathogenesis. Additionally, 3'-UTR-based filtering recognized important MK2-regulated downstream target genes and validated them by nCounter gene expression assays. Finally, immunohistochemistry and transcript stability studies revealed the putative role of MK2 in regulating the transcript turnover of IGFBP2, MUC4, and PRKAR2B in HNSCC. Conclusively, MK2-regulated candidate genes were identified in this study, and their plausible involvement in HNSCC pathogenesis was elucidated. These genes possess investigative values as targets for diagnosis and therapeutic interventions for HNSCC.

Single-agent chemotherapy in low-risk gestational trophoblastic neoplasia.

Background: Low-risk gestational trophoblastic neoplasia could be cured in the case of appropriate management with single-agent chemotherapy. This study was carried out to compare the efficacy of single-dose methotrexate versus Actinomycin-D in low-risk gestational trophoblastic neoplasia to analyze the most effective agent. Methods: This retrospective cohort study was conducted on the medical record of 170 cases with the diagnosis of low-risk gestational trophoblastic neoplasia from 2012 to 2019 to evaluate the response rate of single-dose weekly-methotrexate versus biweekly-Actinomycin-D. Results: Single agent chemotherapy was required in 170 patients with final risk score of less than 7. Among the 100 cases under weekly-methotrexate therapy, 29 patients were required second-line chemotherapy with Actinomycin-D and combination therapy which means complete remission of 71% with methotrexate, in comparison with 78.5% in the other group. Resistance was mostly seen in patients with documented choriocarcinoma in histology who had not received timely diagnosis and treatment. Conclusion: Individualized decision in the management of low-risk gestational trophoblastic neoplasia cases, based on histology, HCG, and history is the corn stone in successful treatment.

Bizarre presentation of choriocarcinoma: A case report / Philippine Journal of Obstetrics and Gynecology

@#Choriocarcinoma is a malignant subtype of gestational trophoblastic disease that follows any type of pregnancy. It is characterized by rapid hematogenous spread to multiple organs, associated with high human chorionic gonadotropin levels with good response to chemotherapy. We present the case of a 31‑year‑old Filipina who initially presented with severe headaches and blurring of vision 3 years after an unremarkable term pregnancy. The transvaginal ultrasound was normal. After a series of diagnostic tests, the initial working impression was a primary brain tumor with metastases to the lungs, adrenal, kidney, and vulva. Emergency craniotomy was done due to deteriorating status secondary to an intracranial hemorrhage. The histopathology report showed choriocarcinoma. Chemotherapy using Etoposide‑Methotrexate‑Actinomycin D‑Cyclophosphamide‑Vincristine with high‑dose methotrexate and concomitant whole‑brain irradiation was then instituted with good response. This case highlights the importance of having a high index of suspicion for gestational trophoblastic neoplasia to prevent the performance of unnecessary procedures, leading to a delay in diagnosis and the institution of the appropriate treatment.