Nutrient vitamins enabled metabolic regulation of ferroptosis via reactive oxygen species biology.

Vitamins are dietary components necessary for cellular metabolic balance, especially redox homeostasis; deficient or excessive supply may give rise to symptoms of psychiatric disorders. Exploring the nutritional and metabolic pathways of vitamins could contribute to uncovering the underlying pathogenesis of ferroptosis-associated diseases. This mini-review aims to provide insights into vitamins closely linked to the regulation of ferroptosis from the perspective of cellular reactive oxygen species biology. The mainstream reprogramming mechanisms of ferroptosis are overviewed, focusing on unique biological processes of iron metabolism, lipid metabolism, and amino acid metabolism. Moreover, recent breakthroughs in therapeutic interventions targeting ferroptosis via fully utilizing vitamin-based pharmacological tools were overviewed, covering vitamins (B, C, E, and K). Finally, mechanism insight related to vitamin-associated nutrient signaling was provided, highlighting the pharmacological benefits of metabolically reprogramming ferroptosis-associated diseases.

Systemic Therapy and Its Surgical Implications in Patients with Resectable Liver Colorectal Cancer Metastases. A Report from the Western Canadian Gastrointestinal Cancer Consensus Conference.

The Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) convened virtually on 4 November 2021. The WCGCCC is an interactive multi-disciplinary conference attended by health care professionals, including surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals from across four Western Canadian provinces, British Columbia, Alberta, Saskatchewan, and Manitoba, who are involved in the care of patients with gastrointestinal cancer. They participated in presentation and discussion sessions for the purpose of developing recommendations on the role of systemic therapy and its optimal sequence in patients with resectable metastatic colorectal cancer.

A Case of an Adult Wilms Tumour in a Patient With Velocardiofacial Syndrome.

Adult Wilms tumors (nephroblastomas) are exceedingly rare with less than 500 cases reported in the literature. To our knowledge, ours is the first reported case of a patient with velocardiofacial syndrome (Shprintzen syndrome) acquiring an adult Wilms tumor. The case highlights the possible role of chromosome 22q aberrations toward the pathogenesis of a subset of Wilms tumors.

Cp*Co(III)-Catalyzed C-H Acylmethylation of Arenes by Employing Sulfoxonium Ylides as Carbene Precursors.

A Cp*Co(III)-catalyzed C-H bond functionalization of a range of arenes by employing sulfoxonium ylides as carbene precursors instead of diazo compounds and other carbene precursors has been established. This reaction is highly efficient without any additive, possesses high step and atom economies, and tolerates a range of functional groups.

Post-marketing safety surveillance and reevaluation of Motherwort injection: A clinical study of 10 094 cases.

OBJECTIVE: To investigate the safety profiles of Motherwort injection (MI). METHODS: A multi-center, prospective and drug- derived hospital intensive monitoring method was conducted to assess the safety of MI in real world applications. This study was based on a very large population after the injection was approved and marketed in China. All patients using the injection in participating hospitals were monitored to determine the incidence, pattern, severity and outcome of associated adverse events. RESULTS: The post-marketing surveillance was performed in 10 094 female patients from April to December, 2015. The incidence of adverse drug reactions (ADRs) was 0.79¡ë(8/10 094). Among the 8 patients, the reported adverse events mainly included systemic abnormalities, such as fever, chills and eyelid edema; skin and appendages disorders, such as pruritus and rash; gastrointestinal disorders, such as nausea, abdominal distension and pain; heart rate and rhythm disorders, such as palpitation and increased heart rate. All of these ADRs were mild in severity. CONCLUSION: In this study the ADRs incidence rate of MI is very low, which supports that it is generally safe for use in obstetric and gynecological diseases. However, the total number of 8 ADRs recorded over a relatively short time span seems limited, and the low number of reports could not represent an absolute guarantee of safety.

Investigation of factors affecting the stability of lysozyme spray dried from ethanol-water solutions.

Formulation composition and processing conditions can be adjusted to enhance the structural integrity as well as the bioactivity of proteins in the spray drying process. In this study, lysozyme was chosen as a model pharmaceutical protein to study these aspects when spray drying from water-ethanol mixtures. The effect of formulation additives (trehalose, Tween 20 and phosphate-buffered saline) and processing conditions (inlet temperature and storage time of lysozyme in the feed solution before the spray drying process) on the protein bioactivity was investigated. The results showed that the bioactivities of spray dried lysozyme with these additives were about 5-10% higher than that without additives. The bioactivity of the spray dried lysozyme was found to increase with a decrease in the inlet temperature from 130°C to 80°C, with similar findings when shortening the storage time of the feed solutions prior to spray drying. Fourier Transform Infrared (FTIR) and Circular Dichroism (CD) results showed that the native structures of lysozyme were largely restored upon reconstitution of the spray dried powder in water after the spray drying process. This suggests that the bioactivity of lysozyme could be preserved adequately by optimization of both the formulation composition and process conditions even when spray drying from a water-ethanol mixture.

Effect of ethanol as a co-solvent on the aerosol performance and stability of spray-dried lysozyme.

In the spray drying process, organic solvents can be added to facilitate drying, accommodate certain functional excipients, and modify the final particle characteristics. In this study, lysozyme was used as a model pharmaceutical protein to study the effect of ethanol as a co-solvent on the stability and aerosol performance of spray-dried protein. Lysozyme was dissolved in solutions with various ratios of ethanol and water, and subsequently spray-dried. A change from spherical particles into wrinkled and folded particles was observed upon increasing the ratio of ethanol in the feed. The aerosol performance of the spray-dried lysozyme from ethanol-water solution was improved compared to that from pure water. The conformation of lysozyme in the ethanol-water solution and spray dried powder was altered, but the native structure of lysozyme was restored upon reconstitution in water after the spray drying process. The enzymatic activities of the spray-dried lysozyme showed no significant impact of ethanol; however, the lysozyme enzymatic activity was ca. 25% lower compared to the starting material. In conclusion, the addition of ethanol as a co-solvent in the spray drying feed for lysozyme did not compromise the conformation of the protein after drying, while it improved the inhaled aerosol performance.

Investigation of brush-type chiral stationary phases based on O,O'-diaroyl tartardiamide and O,O'-bis-(arylcarbamoyl) tartardiamide.

Four chiral organosilanes based on O,O'-dibenzoyl tartardiamide, O,O'-bis-(3,5-dimethylbenzoyl) tartardiamide, O,O'-bis-(phenylcarbamoyl) tartardiamide and O,O'-bis-[(3,5-dimethylphenyl)carbamoyl] tartardiamide were synthesized and immobilized on silica to afford corresponding brush-type chiral stationary phases (CSPs) with well-defined structures. Using 54 compounds containing a wide variety of structures as analytes, the enantioselectivities of the four CSPs were evaluated under normal-phase modes. 3,5-Dimethyl substituent in the aryl group was found to significantly affect the enantioselectivity of CSPs containing aryl ester moieties. Aryl carbamate moieties in CSPs were observed more beneficial for enantioseparation than aryl ester moieties. The additional hydrogen-bond donors (NH) present in the carbamate groups contributed greatly to the enantioselectivity of CSPs, which is contrary to the results that have been found in network-polymeric CSPs.

Constitutively active PKB/Akt inhibited apoptosis and down-regulated beta1,4-galactosyltransferase 1 in hepatocarcinoma cells.

Beta1,4-galactosyltransferase1 (beta1,4GT1) is localized both in the Golgi complex and on the cell surface. In our previous study, we first reported that beta1,4GT1 was associated with cycloheximide-induced apoptosis in human hepatocarcinoma cells. In this study, we transfected constitutively active protein kinase B (Gag-PKB), a central mediator of anti-apoptotic signals transduced by the PI3-kinase, into SMMC-7721 human hepatocarcinoma cells, and examined its effect on apoptosis and beta1,4GT1 activity. Flow cytometry analysis showed that apoptosis was inhibited in Gag-PKB transfected SMMC-7721 cells. At the same time, beta1,4GT1 mRNA level and enzyme activities were downregulated in these cells, consistent with which, the content of beta1,4 Gal branch in the glycoconjugates was decreased in stably transfected cells. Cotransfection of beta1,4GT1 promoter/luciferase reporter and Gag-PKB decreased the luciferase reporter activity in a dose-dependent manner, indicating that the differences in mRNA levels might be regulated through promoter function. All these findings suggested that changes of beta1,4GT1 activity might be involved in apoptotic pathway in hepatocarcinoma cells.

The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis.

The PITSLRE protein kinases are parts of the large family of p34cdc2-related kinases. During apoptosis induced by some stimuli, specific PITSLRE isoforms are cleaved by caspase to produce a protein that contains the C-terminal kinase domain of the PITSLRE proteins (p110C). The p110C induces apoptosis when it is ectopically expressed in Chinese hamster ovary cells. In our study, similar induction of this p110C was observed during anoikis in NIH3T3 cells. To investigate the molecular mechanism of apoptosis mediated by p110C, we used the yeast two-hybrid system to screen a human fetal liver cDNA library and identified p21-activated kinase 1 (PAK1) as an interacting partner of p110C. The association of p110C with PAK1 was further confirmed by in vitro binding assay, in vivo coimmunoprecipitation, and confocal microscope analysis. The interaction of p110C with PAK1 occurred within the residues 210-332 of PAK1. Neither association between p58PITSLRE or p110PITSLRE and PAK1 nor association between p110C and PAK2 or PAK3 was observed. Anoikis was increased and PAK1 activity was inhibited when NIH3T3 cells were transfected with p110C. Furthermore, the binding of p110C with PAK1 and inhibition of PAK1 activity were also observed during anoikis. Taken together, these data suggested that PAK1 might participate in the apoptotic pathway mediated by p110C.