Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66.

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca2+ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca2+ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1-PACS2-PKD2 complex, regulating PKD2-dependent mitochondrial Ca2+ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca2+ uptake and the dramatic increase of the cytosolic Ca2+ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca2+-dependent neurotransmitter release.

Antimicrobial Activity of Depsidones and Macrocyclic Peptides Isolated from Marine Sponge-Derived Fungus Aspergillus nidulans M256.

Chemical study on marine sponge-derivated fungus Aspergillus nidulans resulted in the isolation of seven depsidones (1-7) and two macrocyclic peptides (8 and 9). Their chemical structures were elucidated by extensive analyses of HRESIMS and NMR spectral data, as well as comparison with the literature. Compound 1 was an undescribed depsidone. All compounds exhibited significant antimicrobial activity (MICs: 2-128 µg/mL) towards at least one of seven microbial strains, including Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, and Candida albicans. Of these, chlorinated depsidones (1-3, and 5) displayed potential antimicrobial activity. Nidulin (2) possessed good activity against tested strains except for S. enterica with MIC values in range of 2-16 µg/mL. Interestingly, undescribed depsidone 1 was selectively bioactive on the Gram-positive bacteria (MICs: 2-4 µg/mL) and yeast (MIC: 8 µg/mL) but inactivity on the Gram-negative bacteria (MICs: >256 µg/mL). Macrocyclic peptides, 8 and 9, displayed modest activity against E. faecalis strain with MIC values of 32 and 128 µg/mL, respectively.

Identification and nitric oxide production inhibitory activity of phenolic derivatives from the trunks of Gnetum latifolium.

Phytochemical investigation of the trunks from Gnetum latifolium led to the isolation of a novel phenolic glucoside, 2E-2,4-di-(3,4-dihydroxyphenyl)but-2-en-1-yl-O-ß-D-glucopyranoside (1), along with five known stilbene derivatives (2-6). Their structures were determined mainly using high-resolution electrospray ionisation mass spectrometry and nuclear magnetic resonance spectroscopic analyses, followed by comparisons of observed spectral data with reported values. The novel compound 1 in G. latifolium was found to be useful as a chemotaxonomic marker. Biological evaluation revealed that compound 6 had remarkable inhibitory effects on nitric oxide production, with a half-maximal inhibitory concentration (IC50) value of 4.85 ± 0.20 µM, which was much higher than that of the positive control dexamethasone (IC50 = 14.20 ± 0.54 µM).

Oleanane-type triterpenoid sulphates, two new α-glucosidase inhibitors from Elaeocarpus hainanensis.

In connection with our interest in the phytochemical investigation of Elaeocarpus hainanensis Oliv. (Elaeocarpaceae) growing in Vietnam, two new sulphated oleanane triterpenes were obtained herein and structurally identified. Based on the combination of the extensive 1D-, 2D NMR and HR ESI MS spectroscopic data analysis, their chemical structures have been elucidated as 1α,3ß-dihydroxy-olean-18-ene 1-sulphate (1) and 1α,3ß-dihydroxy-olean-12-ene 1-sulphate (2). Notably, compounds 1 and 2 are corroborating the proposition that triterpenoid sulphates serve as chemosystematic markers of the Elaeocarpus genus. Additionally, all these two new compounds 1 and 2 strongly inhibited α-glucosidase in vitro with the respective IC50 values of 3.81 ± 0.33 µM and 21.27 ± 0.48 µM, which were significantly better than that obtained from positive control, acarbose (IC50 247.73 ± 11.85 µM).

Chemical constituents of Impatiens parvisepala and their α-glucosidase inhibition activity.

The first chemical study of the whole Impatiens parvisepala S. X. Yu & Y. T. Hou led to the isolation of a new triterpene saponin, named Iparvisepala-1 (6) along with ten known compounds, which cover three flavonoid glycosides (1-3), one dihydrochalcone glucoside (4), one triterpenoid saponin (5), one triterpene (7) and four miscellaneous compounds (8-11). Their structures were elucidated by MS, NMR spectroscopic analyses as well as by comparisons of spectra data with those of the related published literatures. Additionally, flavonoid glucoside 2 showed impressive effect on α-glucosidase inhibition with the IC50 value of 12.53 ± 0.39 µM, much better than that of the positive control acabose (IC50 = 197.53 ± 2.68 µM).

Novel trans-caffeate hydrazide derivatives: synthesis, inhibition of nitric oxide (NO) production and molecular docking studies.

Eight new caffeyl hydrazide derivatives (4a-4h) were synthesised via a convenient esterification of caffeic acid with some substituted aryl acid hydrazides. The synthesised caffeyl derivatives were evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages. The fluorobenzoylhydrazide derivatives 4f, 4 g and 4h were found to be the most powerful anti-inflammatory compounds with IC50 values ranging from 11.90 to 24.17 µM, which were more potent than the reference compound L-NMMA (IC50 32.8 µM). Additionally, synthesised compounds have been rationalised by using molecular docking studies which were performed in order to understand insights on the action mechanism of newly synthesised inhibitors against inflammatory mediator (iNOS). Obtained data indicate that compounds 4f, 4h, 4a and 4 g were observed to effectively bind to iNOS receptor with dock score values of -11.62, -10.81, -10.78 and -10.51 kcal/mol, respectively.

Sesquiterpenoids from Tithonia diversifolia (Hemsl.) A. Gray induce apoptosis and inhibit the cell cycle progression of acute myeloid leukemia cells.

Three sesquiterpene lactones (1-3) were isolated from the aerial part of Tithonia diversifolia (Hemsl.) A. Gray grown in the Hoa Binh province in Viet Nam. The structures of these three sesquiterpene lactones were identified as tagitinin A (1), 1ß-hydroxytirotundin 3-O-methyl ether (2), and tagitinin C (3) by analyzing spectroscopic data. For the first time, compound 2 was isolated from T. diversifolia growing in Viet Nam. Furthermore, contrary to existing literature, we determined that compound 1 was the major isolate. Compounds 1 and 3 significantly decreased numbers of acute myeloid leukemia OCI-AML3 cells by promoting apoptosis and causing cell cycle arrest at G0/G1 phase at concentrations as low as 2.5 µg/mL (compound 1) and 0.25 µg/mL (compound 3). Additionally, all three compounds showed cytotoxic activity against five human cancer cell lines (A549, T24, Huh-7, 8505, and SNU-1), with IC50 values ranging from 1.32 ± 0.14 to 46.34 ± 2.74 µM. Overall, our findings suggest that compounds 1 and 3 may be potential anti-cancer therapeutics and thus warrant further study.

New phenolics from Uraria crinita (L.) DC.

Reinvestigation of a methanol extract of Uraria crinita afforded a new 3- hydroxyisoflavanone, 3,5,7,2',4'-pentahydroxyisoflavanone (1), two new monoaryl glucosides, 3,4-dimethoxyphenyl 1-O-(6'-O-acetyl)-ß-D-glucopyranoside (2) and 3,4,5-trimethoxyphenyl 1-O-(6'-O-acetyl)-ß-D-glucopyranoside (3), in addition to three known compounds, 3'-O-methylorobol (4), robusflavone B (5), and apigenin (6). The structural elucidation of these compounds was achieved by analyses of their spectroscopic data (HR-ESI-MS, 1 D- and 2 D-NMR) and acidic hydrolysis. The U. crinita extracts and compounds 1-6 exhibited weak or no cytotoxic activity against KB, HepG2, Lu and MCF7 cell lines.

Alpha-Synuclein PET Tracer Development-An Overview about Current Efforts.

Neurodegenerative diseases such as Parkinson's disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

New phenolics from Dianella ensifolia.

Phytochemical investigation and chromatographic separation of extracts from the aerial parts of Dianella ensifolia (L.) DC. (synonym Dianella nemorosa Lam. Ex. Schiler f.) led to the isolation of 10 compounds, the structures of which were determined by HR-ESI-MS and 1 D- and 2 D-NMR spectroscopies, and by comparisons with published studies. Among the isolated compounds were three flavans, a biflavan, a biflavone, a tetralone, a naphthalen glycoside, an aromatic compound, and two steroids. Six of these were known chemicals, while three were identified as new compounds: 7-acetyl-4R,8-dihydroxy-6-methyl-1-tetralone, 2(S),2',4'-dihydroxy-7-methoxyflavan, and diaensi-biflavan. 2(S),7,4'-dimethoxy flavan was obtained for the first time as a natural product.

Pro-apoptoticeffect of diterpenoids from Fokienia hodginsii on acute myeloid leukemia cells.

Previously, we isolated four known diterpenoids, trans-communic acid (1), 13-oxo-15,16-dinor-labda-8(17), 11E-diene-19-oic acid (2), 3ß-hydroxytotarol (3), and totarolone (4) from Fokienia hodginsii leaves. Further study demonstrated the antiproliferative activity of all four compounds in acute myeloid leukemia (OCI-AML) cells due to impaired cell cycle progression. Interestingly, 3ß-hydroxytotarol (3) had very powerful bioactivity at low concentrations (5 µg/mL).

Biotherapeutic Products, Cellular Factories, and Multiomics Integration in Metabolic Engineering.

Since the introduction of the first monoclonal antibody, biopharmaceuticals and biotherapeutic products manufactured in cellular factories are on the rise in modern medicine and therapeutics. Dynamic and real-time innovation strategies for operational implementation of biotherapeutic production are rapidly emerging. The advances in related fields such as genome editing technology, systems biology, and machine learning/artificial intelligence are expected to introduce innovative solutions in every aspect of the mammalian cell culture-based biotherapeutic production. This conceptual review offers a synthesis of the prospects and challenges of integration of multiomics technologies, and an integrative biology vision to cellular factories and biotherapeutic innovation.

A new oleanane triterpene from the leaves of Ficus hirta.

Repeated column chromatography of the n-hexane extract of Ficus hirta leaves (Moraceae) led to isolation of a new oleanane triterpene, 3ß-hydroxy-11-oxo-olean-12-enyl-3-stearate (1) in addition to three known compounds, taraxerol (2), 3ß-acetoxy-11α-methoxy-12-ursene (3) and 3ß-acetoxy-11α-hydroxy-12-ursene (4). Their structures were elucidated by spectroscopic methods and by comparison with data reported in the literatures.

Anti-proliferative diterpenes from Dacrycarpus imbricatus.

A new diterpene, cassipouryl hexadecanoate (2), in addition to the cassipourol (1) and four terpenes (3-6) were isolated from the twigs and leaves of Dacrycarpus imbricatus (Blume) de Laub. The structures of the two monocyclic diterpenes (1, 2), were elucidated on the basic of 1D and 2D NMR spectroscopic data and compared with the literature. These two monocyclic diterpenes (1, 2) were tested for their anti-proliferative activity on acute myeloid leukemia (OCI-AML) cells. The results showed that 1 had significantly anti-proliferative activity whereas 2 was weakly active.

Chemical constituents of Oldenlandia pinifolia and their antiproliferative activities.

This study describes the chemical constituents of Oldenlandia pinifolia (Wall. Ex G. Don) Kuntze (synonym Hedyotis pinifolia Wall. Ex G. Don) and discusses their anti-proliferative activities. Thirteen compounds were isolated from the n-hexane, ethyl acetate and n-butanol extracts of whole plants O. pinifolia by chromatography method. Their structures were elucidated using MS and NMR analysis and compared with reported data. They are three anthraquinones, a carotenoid, two triterpenes, four iridoid glycosides and three flavonoid glycosides. Among them, 2-methyl-1,4,6-trihydroxy-anthraquinone is a new one, and three compounds were found for the first time in this genus. MTT assay resulted that the n-butanol extract and four isolated compounds inhibited the proliferation of chronic myelogenous leukaemia cells. The results from Hoechst 33343 staining and caspase 3-inducing exhibited that those four tested compounds induced apoptosis and activated caspase 3 (p < 0.05). One of them, isorhamnetin-3-O-ß-rutinoside showed the most activity with IC50 value of 394.68 ± 25.12 µM.

Association of glucose-6-phosphate dehydrogenase deficiency and malaria: a systematic review and meta-analysis.

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency overlaps with malaria endemicity although it predisposes carriers to hemolysis. This fact supports the protection hypothesis against malaria. The aim of this systematic review is to assess the presence and the extent of protective association between G6PD deficiency and malaria. Thirteen databases were searched for papers reporting any G6PD alteration in malaria patients. Twenty-eight of the included 30 studies were eligible for the meta-analysis. Results showed absence of negative association between G6PD deficiency and uncomplicated falciparum malaria (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.59-1.02; p = 0.07). However, this negative association happened in Africa (OR, 0.59; 95% CI, 0.40-0.86; p = 0.007) but not in Asia (OR, 1.24; 95% CI, 0.96-1.61; p = 0.10), and in the heterozygotes (OR, 0.70; 95% CI, 0.57-0.87; p = 0.001) but not the homo/hemizygous (OR, 0.70; 95% CI, 0.46-1.07; p = 0.10). There was no association between G6PD deficiency and total severe malaria (OR, 0.82; 95% CI, 0.61-1.11; p = 0.20). Similarly, there was no association with other malaria species. G6PD deficiency can potentially protect against uncomplicated malaria in African countries, but not severe malaria. Interestingly, this protection was mainly in heterozygous, being x-linked thus related to gender.

Case Report: Postpartum hemorrhage associated with Dengue with warning signs in a term pregnancy and delivery.

BACKGROUND: Dengue infection during peripartum period, although rare in endemic regions, has challenged clinicians regarding its management, especially if a parturient woman experiences postpartum hemorrhage due to a classical risk factor of maternal bleeding. CASE: A full-term pregnant Vietnamese woman was diagnosed with polyhydramnios and Dengue with warning signs (DWS). She was administered platelet transfusion prior to delivery and then gave birth to a healthy newborn. After active management of the third stage of labor, the patient suffered a postpartum hemorrhage which was caused by uterine atony and accompanied with thrombocytopenia. Therefore, we decided to administer uterotonic drugs and additionally transfuse platelets. CONCLUSION: We describe a case of postpartum hemorrhage caused by uterine atony and coinciding with Dengue infection during delivery period, which is a rare clinical entity. With timely detection and management, the patient was finally discharged without complications.

Case Report: Pre- and postnatal management of an allantoic cyst with patent urachus and single umbilical artery.

Patent urachus is a rare congenital abnormality. Since its first description by Cabriolus in 1550, few cases have been reported. A 26-year-old Vietnamese primigravida presented at 20 weeks of gestation for evaluation of a cystic mass in the umbilical cord, which was first discovered at week 13 of pregnancy by ultrasound scan. The cystic mass originated from the root of the umbilical cord, connected to the urinary bladder, and no intestinal contents were enclosed within. Doppler ultrasound assessment showed that the single umbilical artery existed within the normal range. The progression of the umbilical cyst continued to be screened, but the mass disappeared on ultrasound images at 27 weeks of gestation. This led to the consideration of the cyst's rupture. After 38 gestational weeks, the pregnant woman delivered a 3350g male infant via cesarean section because of an obstructed vaginal labor. The following days, a stream of urine was recorded leaking out from the umbilical mass whenever he cried. Seven weeks after delivery, an open surgical approach was successfully performed. The baby is now 43 months of age, growing and developing normally. Since an allantoic cyst with patent urachus is a rare clinical entity, early discovery, close monitoring and accurate diagnosis through ultrasound in the prenatal period may consequently allow clinicians to have suitable attitudes towards management when the infant is born.

Detection and Characterization of Clade 1 Reassortant H5N1 Viruses Isolated from Human Cases in Vietnam during 2013.

Highly pathogenic avian influenza (HPAI) H5N1 is endemic in Vietnamese poultry and has caused sporadic human infection in Vietnam since 2003. Human infections with HPAI H5N1 are of concern due to a high mortality rate and the potential for the emergence of pandemic viruses with sustained human-to-human transmission. Viruses isolated from humans in southern Vietnam have been classified as clade 1 with a single genome constellation (VN3) since their earliest detection in 2003. This is consistent with detection of this clade/genotype in poultry viruses endemic to the Mekong River Delta and surrounding regions. Comparison of H5N1 viruses detected in humans from southern Vietnamese provinces during 2012 and 2013 revealed the emergence of a 2013 reassortant virus with clade 1.1.2 hemagglutinin (HA) and neuraminidase (NA) surface protein genes but internal genes derived from clade 2.3.2.1a viruses (A/Hubei/1/2010-like; VN12). Closer analysis revealed mutations in multiple genes of this novel genotype (referred to as VN49) previously associated with increased virulence in animal models and other markers of adaptation to mammalian hosts. Despite the changes identified between the 2012 and 2013 genotypes analyzed, their virulence in a ferret model was similar. Antigenically, the 2013 viruses were less cross-reactive with ferret antiserum produced to the clade 1 progenitor virus, A/Vietnam/1203/2004, but reacted with antiserum produced against a new clade 1.1.2 WHO candidate vaccine virus (A/Cambodia/W0526301/2012) with comparable hemagglutination inhibition titers as the homologous antigen. Together, these results indicate changes to both surface and internal protein genes of H5N1 viruses circulating in southern Vietnam compared to 2012 and earlier viruses.

Homoisoflavonoids from Ophiopogon japonicus Ker-Gawler.

From the ethyl acetate extract of the tuberous roots of Ophiopogon japonicus (Liliaceae) eight known and five new homoisoflavonoidal compounds were isolated. The new compounds are 5,7-dihydroxy-8-methoxy-6-methyl-3-(2'-hydroxy-4'-methoxybenzyl)chroman-4-one (1), 7-hydroxy-5,8-dimethoxy-6-methyl-3-(2'-hydroxy-4'-methoxybenzyl)chroman-4-one (2), 5,7-dihydroxy-6,8-dimethyl-3-(4'-hydroxy-3'-methoxybenzyl)chroman-4-one (3), 2,5,7-trihydroxy-6,8-dimethyl-3-(3',4'-methylenedioxybenzyl)chroman-4-one (4) and 2,5,7-trihydroxy-6,8-dimethyl-3-(4'-methoxybenzyl)chroman-4-one (5). Their structures have been elucidated by mass and NMR spectroscopy. Compounds 4 and 5 are the first isolated homoisoflavonoids with a hemiacetal function at position 2.