The effect of high doses of vitamin C for the treatment of cancer has been controversial. Our previous studies, and studies by others, have reported that vitamin C at concentrations of 0.25-1.0 mM ...induced a dose- and time-dependent inhibition of proliferation in acute myeloid leukemia (AML) cell lines and in leukemic cells from peripheral blood specimens obtained from patients with AML. Treatment of cells with high doses of vitamin C resulted in an immediate increase in intracellular total glutathione content and glutathione-S transferase activity that was accompanied by the uptake of cysteine. These results suggest a new role for high concentrations of vitamin C in modulation of intracellular sulfur containing compounds, such as glutathione and cysteine. This review, discussing biochemical pharmacologic studies, including pharmacogenomic and pharmacoproteomic studies, presents the different pharmacological effects of vitamin C currently under investigation.
Diverse flavonoids are abundant in dietary food constituents and possess useful biological activities. However, some flavonoids have limited bioavailability due to their low solubility in water. As ...an important approach to enhance aqueous solubility, inclusion of hydrophobic guest molecules in hydrophilic hosts such as cyclic glucans has been used. This review summarizes applications of β-cyclodextrin, synthetic β-cyclodextrin derivatives, and newly synthesized derivatives of cyclosophoraoses as complexing agents to enhance the bioavailability of flavonoids such as baicalein, kaempferol, and naphthoflavones.
A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most ...biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).
Gene therapy would benefit from a miniature CRISPR system that fits into the small adeno-associated virus (AAV) genome and has high cleavage activity and specificity in eukaryotic cells. One of the ...most compact CRISPR-associated nucleases yet discovered is the archaeal Un1Cas12f1. However, Un1Cas12f1 and its variants have very low activity in eukaryotic cells. In the present study, we redesigned the natural guide RNA of Un1Cas12f1 at five sites: the 5' terminus of the trans-activating CRISPR RNA (tracrRNA), the tracrRNA-crRNA complementary region, a penta(uridinylate) sequence, the 3' terminus of the crRNA and a disordered stem 2 region in the tracrRNA. These optimizations synergistically increased the average indel frequency by 867-fold. The optimized Un1Cas12f1 system enabled efficient, specific genome editing in human cells when delivered by plasmid vectors, PCR amplicons and AAV. As Un1Cas12f1 cleaves outside the protospacer, it can be used to create large deletions efficiently. The engineered Un1Cas12f1 system showed efficiency comparable to that of SpCas9 and specificity similar to that of AsCas12a.
Abstract
Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (
EGFR
) mutations exhibit an unfavorable response to PD-1 inhibitor through unclear mechanisms. ...Hypothesizing that
EGFR
mutations alter tumor-immune interactions, we compare tumor-infiltrating lymphocytes between EGFR mutant (EGFR-MT) and wild type (EGFR-WT) tumors through single-cell transcriptomic analysis. We find that B cells, CXCL13-producing follicular helper CD4
+
T (T
FH
)-like cells, and tissue-resident memory CD8
+
T (T
RM
)-like cells decreased in EGFR-MT tumors. The NOTCH-RBPJ regulatory network, which is vital for persistence of T
RM
state, is perturbed, and the interactions between T
FH
and B cells through the CXCL13-CXCR5 axis disappear in EGFR-MT tumors. Notably, the proportion of T
RM
-like cells is predictive for anti-PD-1 response in NSCLC. Our findings suggest that the impairment of T
FH
-B-T
RM
cooperation in tertiary lymphoid structure formation, accompanied by the dysregulation of T
RM
homeostasis and the loss of T
FH
-B crosstalk, underlies unfavorable anti-PD-1 response in EGFR-MT lung tumors.
A large number of people suffer from alopecia or hair loss worldwide. Drug-based therapies using minoxidil and finasteride for the treatment of alopecia are available, but they have shown various ...side effects in patients. Thus, the use of new therapeutic approaches using bioactive products to reduce the risk of anti-hair-loss medications has been emphasized. Natural products have been used since ancient times and have been proven safe, with few side effects. Several studies have demonstrated the use of plants and their extracts to promote hair growth. Moreover, commercial products based on these natural ingredients have been developed for the treatment of alopecia. Several clinical, animal, and cell-based studies have been conducted to determine the anti-alopecia effects of plant-derived biochemicals. This review is a collective study of phytochemicals with anti-alopecia effects, focusing mainly on the mechanisms underlying their hair-growth-promoting effects.
This study aimed to look at emotions perceived about the attributes, prevention, diagnosis, and treatment of infectious diseases related to coronavirus disease (COVID-19) that were widespread across ...the world and identify their relevance to knowledge about infectious diseases and preventative behaviors.
Texts to measure emotional cognition were selected through a pre-test, and 282 people were chosen as participants based on the survey conducted for 20 days from August 19 to August 29, 2020, created with Google Forms. IBM SPSS Statistics 25.0 was used for the primary analysis, and the SNA package in R (version 4.0.2) was utilized to conduct the network analysis.
It was found that universal negative emotions such as feeling "anxious" (65.5%), "afraid" (46.1%), and "scared" (32.7%) commonly appeared among most people. Also, they were found to be feeling both positive ("caring" 42.3% and "strict" 28.2%) and negative ("frustrating" 39.1% and "isolated" 31.0%) emotions about efforts to prevent and curb the spread of COVID-19. In terms of emotional cognition for the diagnosis and treatment of such diseases, "reliable" (43.3%) took the biggest ratio among the replies. The level of understanding about infectious diseases showed differences in emotional cognition, thereby affecting people's emotions. However, no differences were found in the practice of preventative behaviors.
Emotions associated with cognition in the context of pandemic infectious diseases have been found to be mixed. Furthermore, it can be seen that feelings vary depending on the degree of understanding of the infectious disease.
The present study compared the effects of pectoral nerve block II
(
PECS II) and erector spinae plane (ESP) block for postoperative analgesia in patients who underwent modified radical mastectomy by ...performing a network meta-analysis (NMA) using indirect comparison with systemic analgesia. Studies comparing the analgesic effects of PECS II and ESP block were searched on MEDLINE, PubMed, EMBASE and the Cochrane Library. The primary outcome of this study was cumulative opioid consumption for 24 h postoperatively. Pain score during this period was also assessed. NMA was performed to compare the postoperative analgesic effects of plane blocks and systemic analgesia. A search of databases identified 17 studies, with a total of 1069 patients, comparing the analgesic efficacies of PECS II block, ESP block, and systemic analgesia. Compared with systemic analgesia, mean difference of opioid consumption was − 10 mg (95% credible interval CrI − 15.0 to − 5.6 mg) with PECS II block and − 5.7 mg (95% CrI − 11.0 to − 0.7 mg) with ESP block. Relative to systemic analgesia, PECS II block showed lower pain scores over the first postoperative 24 h, whereas ESP block did not. PECS II block showed the highest surface under the cumulative ranking curves for both opioid consumption and pain score. Both PECS II and ESP blocks were shown to be more effective than systemic analgesia regarding postoperative analgesia following modified radical mastectomy, and between the two blocks, PECS II appeared to have favorable analgesic effects compared to ESP block.
A target-based approach has been used to develop novel drugs in many therapeutic fields. However, this approach remains suboptimal for drug discovery in brain disorders because the target ...identification in a brain disorder requires a hierarchical integration from in vitro cellular and functional tissue studies to animal models that sustain neuronal and glial complexity. Although glial cells comprise over half of the brain and play important roles in brain function and disease, the intracellular signaling of glial cells remains essentially unexplored. This is because the lack of optimal strategy to selectively activate or deactivate glial signaling has made it difficult to study glial roles. The recent development of approaches using mouse models and enabling the selective activation of cell signaling could be used to assess the role of glial cells in physiology and disease. This review presents how glial G- protein signaling contributes to brain disorders and how the role of glia is investigated.
T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which ...suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy.
We analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8
T cell population based on PDCD1 (PD-1) levels, i.e., PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8
T cells was confirmed by single-cell trajectory and flow cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses.
We retrieved many known factors for regulating T cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8
T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8
T cells become more exhausted. Flow cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T cell exhaustion. TOX knockdown in the human TI CD8
T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC.
We predicted the regulatory factors involved in T cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8
T cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.
PDF
