Preventive effects of Korean red ginseng on experimentally induced colitis and colon carcinogenesis

© 2020 Center for Food and Biomolecules, National Taiwan UniversityKorean Red Ginseng (KRG) exerts chemopreventive effects on experimentally induced carcinogenesis through multiple mechanisms. In this study, we investigated effects of KRG on dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colon carcinogenesis in mice. Male C57BL/6J mice were fed diet containing 1% KRG or a standard diet throughout the experiment. The mouse colitis was induced by administration of 3% DSS in drinking water for 1 week. DSS caused body weight loss, diarrhea, rectal bleeding and colon length shortening, and all these symptoms were ameliorated by KRG treatment. KRG inhibited DSS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by suppressing activation of nuclear factor-kappa B (NF-κB) and signal transducer and activation of transcription 3 (STAT3). In another experiment, colon carcinogenesis was initiated by single intraperitoneal injection of AOM (10 mg/kg) and promoted by 2% DSS in drinking water. KRG administration relieved the symptoms of colitis and reduced the incidence, the multiplicity and the size of colon tumor. The up-regulation of COX-2, iNOS, c-Myc and Cyclin D1 by AOM plus DSS was attenuated in KRG fed mice which was associated with suppression of NF-κB and STAT3 activation. These results suggest that KRG is a potential candidate for chemoprevention of inflammation-associated cancer in the colon.

Chronic Treatment with Squid Phosphatidylserine Activates Glucose Uptake and Ameliorates TMT-Induced Cognitive Deficit in Rats via Activation of Cholinergic Systems

The present study examined the effects of squid phosphatidylserine (Squid-PS) on the learning and memory function and the neural activity in rats with TMT-induced memory deficits. The rats were administered saline or squid derived Squid-PS (Squid-PS 50 mg kg−1, p.o.) daily for 21 days. The cognitive improving efficacy of Squid-PS on the amnesic rats, which was induced by TMT, was investigated by assessing the passive avoidance task and by performing choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) immunohistochemistry. 18F-Fluorodeoxyglucose and performed a positron emission tomography (PET) scan was also performed. In the passive avoidance test, the control group which were injected with TMT showed a markedly lower latency time than the non-treated normal group (P < 0.05). However, treatment of Squid-PS significantly recovered the impairment of memory compared to the control group (P < 0.05). Consistent with the behavioral data, Squid-PS significantly alleviated the loss of ChAT immunoreactive neurons in the hippocampal CA3 compared to that of the control group (P < 0.01). Also, Squid-PS significantly increased the AchE positive neurons in the hippocampal CA1 and CA3. In the PET analysis, Squid-PS treatment increased the glucose uptake more than twofold in the frontal lobe and the hippocampus (P < 0.05, resp.). These results suggest that Squid-PS may be useful for improving the cognitive function via regulation of cholinergic enzyme activity and neural activity

Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification

The present study was aimed to investigate the effects of curcumin, a representative chemopreventive phytochemical with pronounced antioxidant and anti-inflammatory properties, on activation of Nrf2 and expression of its target protein heme oxygenase-1 (HO-1) in mouse skin in vivo and in cultured murine epidermal cells. Treatment of mouse epidermal JB6 cells with curcumin resulted in the induction of HO-1 expression, and this was abrogated in cells transiently transfected with Nrf2 siRNA. While curcumin treatment increased protein expression of Nrf2, it did not alter the steady-state level of the Nrf2 mRNA transcript. Treatment of cells with curcumin stabilized Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of this transcription factor. Tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the alpha,beta-unsaturated carbonyl group, failed to induce HO-1 expression as well as nuclear translocation of Nrf2 and its binding to the antioxidant/electrophile response elements. Cells transfected with a mutant Keap1 protein in which cysteine 151 (Cys151) is replaced by serine exhibited marked reduction in curcumin-induced Nrf2 transactivation. Mass spectrometric analysis revealed that curcumin binds to Keap1 Cys151, supporting that this amino acid is a critical target for curcumin modification of Keap1, which facilitates the liberation of Nrf2. Thus, it is likely that the alpha,beta-unsaturated carbonyl moiety of curcumin is essential for its binding to Keap1 and stabilization of Nrf2 by hampering ubiquitination and proteasomal degradation.

Prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study

Germline mutations; Homologous recombination repair; Somatic mutationsMutaciones de la línea germinal; Reparación de recombinación homóloga; Mutaciones somáticasMutacions de la línia germinal; Reparació de recombinació homòloga; Mutacions somàtiquesBackground The multinational BREAKOUT study (NCT03078036) sought to determine the prevalence of germline BRCA1/2 (gBRCA1/2) and somatic BRCA1/2 (sBRCA1/2) mutations and mutations in other homologous recombination repair (HRR) genes in women with HER2-negative metastatic breast cancer (MBC) starting first-line chemotherapy. Methods Genetic testing for gBRCA, sBRCA, and HRR gene mutations was performed in patients who started first-line chemotherapy for MBC in the last 90 days (341 patients across 14 countries) who were not selected based on risk factors for gBRCA mutations. We report data from the Asian cohort, which included patients in Japan (7 sites), South Korea (10 sites), and Taiwan (8 sites). Results Of 116 patients screened, 104 patients were enrolled in the Asian cohort. The median age was 53.0 (range 25–87) years. gBRCA1/2, gBRCA1, and gBRCA2 mutations were detected in 10.6% (11/104), 5.8% (6/104), and 4.8% (5/104) of patients, respectively; none had mutations in both gBRCA1 and gBRCA2. gBRCA1/2 mutations were detected in 10.0% (6/60) and 11.6% (5/43) of patients with hormone receptor-positive and triple-negative MBC, respectively. HRR gene mutations were tested in 48 patients without gBRCA mutations, and 5 (10.4%) had at least one HRR mutation in sBRCA, ATM, PALB2, and CHEK2. Conclusion We report for the first time the prevalence of gBRCA and HRR mutations in an Asian cohort of patients with HER2-negative MBC. Our results suggest that BRCA mutation testing is valuable to determine appropriate treatment options for patients with hormone receptor-positive or triple-negative MBC.This study was funded by AstraZeneca, and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Scaling Law for Recommendation Models: Towards General-purpose User Representations

Recent advancement of large-scale pretrained models such as BERT, GPT-3, CLIP, and Gopher, has shown astonishing achievements across various task domains. Unlike vision recognition and language models, studies on general-purpose user representation at scale still remain underexplored. Here we explore the possibility of general-purpose user representation learning by training a universal user encoder at large scales. We demonstrate that the scaling law is present in user representation learning areas, where the training error scales as a power-law with the amount of computation. Our Contrastive Learning User Encoder (CLUE), optimizes task-agnostic objectives, and the resulting user embeddings stretch our expectation of what is possible to do in various downstream tasks. CLUE also shows great transferability to other domains and companies, as performances on an online experiment shows significant improvements in Click-Through-Rate (CTR). Furthermore, we also investigate how the model performance is influenced by the scale factors, such as training data size, model capacity, sequence length, and batch size. Finally, we discuss the broader impacts of CLUE in general.Comment: Accepted at AAAI 2023. This version includes the technical appendi

Cold shock domain proteins and glycine-rich RNA-binding proteins from Arabidopsis thaliana can promote the cold adaptation process in Escherichia coli

Despite the fact that cold shock domain proteins (CSDPs) and glycine-rich RNA-binding proteins (GRPs) have been implicated to play a role during the cold adaptation process, their importance and function in eukaryotes, including plants, are largely unknown. To understand the functional role of plant CSDPs and GRPs in the cold response, two CSDPs (CSDP1 and CSDP2) and three GRPs (GRP2, GRP4 and GRP7) from Arabidopsis thaliana were investigated. Heterologous expression of CSDP1 or GRP7 complemented the cold sensitivity of BX04 mutant Escherichia coli that lack four cold shock proteins (CSPs) and is highly sensitive to cold stress, and resulted in better survival rate than control cells during incubation at low temperature. In contrast, CSDP2 and GRP4 had very little ability. Selective evolution of ligand by exponential enrichment (SELEX) revealed that GRP7 does not recognize specific RNAs but binds preferentially to G-rich RNA sequences. CSDP1 and GRP7 had DNA melting activity, and enhanced RNase activity. In contrast, CSDP2 and GRP4 had no DNA melting activity and did not enhance RNAase activity. Together, these results indicate that CSDPs and GRPs help E.coli grow and survive better during cold shock, and strongly imply that CSDP1 and GRP7 exhibit RNA chaperone activity during the cold adaptation process