Review on article of effects of tenofovir alafenamide and entecavir in chronic hepatitis B virus patients.

This letter comments on the article which reported that tenofovir alafenamide may increase blood lipid levels compared with entecavir in patients with chronic hepatitis B published on World J Hepatol 2023 August 27. We review the related research content, topic selection, methodology, conclusions, strengths and weaknesses of this article. And evaluate it in relation to other published relevant articles.

Total Synthesis of Dysifragilones A and B and Dysidavarone C.

The concise synthesis of dysifragilones A and B and dysidavarones has been accomplished for the first time in a divergent way from a common intermediate. The synthetic route features an intramolecular reductive Heck reaction to construct the 6/5/6/6/-tetracycle of dysifragilones A and B and an intramolecular palladium-catalyzed α-arylation of a sterically hindered ketone to forge the tetracyclo[7.7.1.02,7.010,15]heptadecane core structure of dysidavarone C. The late-stage introduction of amino and ethoxy groups is effective.

Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands.

Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.

The Mouse Gut Microbial Biobank expands the coverage of cultured bacteria.

Mice are widely used as experimental models for gut microbiome (GM) studies, yet the majority of mouse GM members remain uncharacterized. Here, we report the construction of a mouse gut microbial biobank (mGMB) that contains 126 species, represented by 244 strains that have been deposited in the China General Microorganism Culture Collection. We sequence and phenotypically characterize 77 potential new species and propose their nomenclatures. The mGMB includes 22 and 17 species that are significantly enriched in ob/ob and wild-type C57BL/6J mouse cecal samples, respectively. The genomes of the 126 species in the mGMB cover 52% of the metagenomic nonredundant gene catalog (sequence identity ≥ 60%) and represent 93-95% of the KEGG-Orthology-annotated functions of the sampled mouse GMs. The microbial and genome data assembled in the mGMB enlarges the taxonomic characterization of mouse GMs and represents a useful resource for studies of host-microbe interactions and of GM functions associated with host health and diseases.

Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion.

The scarcity of hematopoietic stem cells (HSCs) significantly hindered their clinical potentials. Umbilical cord blood (UCB) has become the leading source of HSCs for both research and clinical applications. But the low content of HSCs in a single UCB unit limited its use only to pediatric patients. Various cytokines and small molecules have demonstrated strong abilities in promoting HSC ex vivo expansion, of which UM171 is the newest and by far the most potent HSC ex vivo expansion agent. In this study, we synthesized 37 pyrimidoindole analogs and identified 6 compounds to be potent in promoting HSC ex vivo expansion. In particular, analog 11 was found to be the most effective in stimulating ex vivo expansion of UCB CD34+ cells and CD34+CD38- cells. Initial data indicated that compound 11 promoted the absolute number of long term HSCs and inhibited their differentiation. UCB HSCs expanded with 11 retained adequate multi-lineage differentiation capacity. In addition, compound 11 is not cytotoxic at its test concentrations, suggesting that it merits further investigation for potential clinical applications.

Isolation, synthesis, and cytotoxicity evaluation of two impurities in nomegestrol acetate.

Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth-generation progestin. It has been approved in many countries for oral contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very similar last three to five steps toward the conversion of 6-methylene to 6-methyl-6,7-unsaturated structure. Therefore the final product from different processing routes may have similar impurity profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF-7 breast cancer cells, and C33A cervical cancer cells. These three analogs are not cytotoxic to the four cell lines at low concentrations (<20 µM). NOMAc and impurity A showed cytotoxicity to L02, MCF-7, and C33A cells at high concentrations, while impurity B did not show significant cytotoxicity to any of the cell lines tested.

Harnessing microfluidic streak plate technique to investigate the gut microbiome of Reticulitermes chinensis.

The termite gut microbiome is a model system to investigate microbial interactions and their associations with host. For decades, extensive research with molecular tools and conventional cultivation method has been carried out to define the microbial diversity in termite gut. Yet, many bacterial groups of the termite gut microbiome have not been successfully cultivated in laboratory. In this study, we adapted the recently developed microfluidic streak plate (MSP) technique for cultivation of termite gut microbial communities at both aerobic and anaerobic conditions. We found that 99 operational taxonomic units (OTUs) were cultivable by MSP approach and 18 OTUs were documented first time for termite gut microbiota. Further analysis of the bacterial diversities derived by culture-dependent MSP approach and culture-independent 16S rRNA gene typing revealed that both methods have bias in recovery of gut microbiota. In total 396 strains were isolated with MSP technique, and potential new taxa at species and/or genus levels were obtained that were phylogenetically related to Burkholderia, Micrococcus, and Dysgonomonas. Results from this study indicate that MSP technique is applicable for cultivating previously unknown and new microbial groups of termite gut microbiota.

Vallitalea okinawensis sp. nov., isolated from Okinawa Trough sediment and emended description of the genus Vallitalea.

A polyphasic study was conducted to characterize an obligately anaerobic bacterial strain, S15T, that was isolated from Okinawa Trough sediment. Strain S15T was Gram-stain-negative, non-motile and rod-shaped. Spores were not observed. Strain S15T grew anaerobically at 20-35 °C (optimum at 25-30 °C) and at pH range of 6.0-8.5 (optimum at 7.5). Analysis of 16S rRNA gene sequences showed that strain S15T was phylogenetically related to Vallitalea guaymasensis Ra1766G1T (94.0 %) and Vallitalea pronyensis FatNI3T (93.1 %). The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and glycolipids. The predominant fatty acids of strain S15T were iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0 and C16 : 0. The draft genome was 5.86 Mb with a DNA G+C content of 33.9 mol%. A total of 5285 genes were predicted and, of those, 4669 genes were annotated. The genome data supported the result that strain S15T assimilated various carbon sources. On the basis of unique phenotypic, chemotaxonomic and phylogenetic comparisons, strain S15T is proposed to represent a novel species within the genus Vallitalea, and the name Vallitaleaokinawensis sp. nov. is proposed. The type strain is S15T=CGMCC 1.5231T=KCTC 15675T.

Synthesis and pharmacological evaluation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands.

Increasing evidences have implicated that sigma-2 receptor is a biomarker and significantly over-expressed in many proliferative cancer cells with no or low expression in normal cells. Sigma-2 receptor selective ligands have been successfully used as valuable tools to study its pharmacological functions, tumor imaging, and cancer therapeutics or adjuvants. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolinylalkyl benzamides are among a few categories of structures that have demonstrated high affinities and selectivities for sigma-2 receptor and been used extensively as study tools in various tumor imaging and therapy. As a continuous effort, we have synthesized a new series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and evaluated their affinities for both sigma-1 and sigma-2 receptors. Most of these newly developed analogs showed good to excellent binding affinities for sigma-2 receptor with no or low affinities for sigma-1 receptor. In particular, compounds 3b, 3e, 4b, and 4e demonstrated Ki values of 5-6 nM affinities and excellent selectivities for sigma-2 receptor. In addition, these analogs also demonstrated moderate anticancer activities against human liver Huh-7 tumor cells and human esophagus KYSE-140 cancer cells. But their cytotoxicities seem not to be correlated with their sigma-2 receptor affinities.