Deoxypodophyllotoxin

Glucose-regulated protein 78 (GRP78), as a chaperone protein, can protect the endoplasmic reticulum of cells and is expressed to influence chemoresistance and prognosis in cancer. Deoxypodophyllotoxin (DPT) is a compound with antitumor effects on cancers. DPT inhibits the proliferation of osteosarcoma by inducing apoptosis, necrosis, or cell cycle arrest.

This study was performed to demonstrate the molecular mechanism by which DPT attenuates osteosarcoma progression through GRP78.

Natural compound libraries and western blot (WB) were used to screen the inhibitors of osteosarcoma GRP78. The expression of mitochondria-related genes in cancer cells of the treatment group was detected by quantitative real-time PCR (qPCR) and WB. 3-(4,5)- Dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and 5-ethynyl-2'- deoxyuridine (EDU) were used to discover the activity and proliferation of osteosarcoma cells treated with DPT. We constructed an in vivo mouse model of DPT drug therapy and carried out immunohistochemical detection of xenografts. The treated osteosarcoma cells were analyzed using bioinformatics and electron microscopy. The data were analyzed finally

DPT inhibited osteosarcoma cell survival and the growth of tumor xenografts. It promoted up-regulation of BCL2-associated X protein (Bax) and B-cell CLL/lymphoma 2 (Bcl-2), which serves to mediate and attenuate, respectively, the killing activities of DPT through mitochondria dysfunction. The effect of DPT against cancer cells could be attenuated by the overexpression of GRP78, characterized by the inactivation of the caspase cascade. The loss of GRP78 in osteosarcoma cells negatively mediated the basal level of autophagyassociated genes. DPT stimulated autophagy via the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT), a mechanistic target of rapamycin (mTOR) axis. The autophagy caused by DPT played an active role in the osteosarcoma of humans and blocked the apoptotic cascade.

Combination treatment with the GRP78 inhibitor DPT and pharmacological autophagy inhibitors will be a meaningful method of obviating osteosarcoma cells.

Not receiving a DPT-containing vaccine in early childhood indicates an absence of routine immunization, which puts children at an elevated risk of mortality, morbidity, and worse human development over the life course. We estimated the percentage of children 12-35 months who did not receive a dose of DPT-containing vaccine (termed zero-dose children) using household surveys from 81 low- and middle-income countries conducted between 2014 and 2023. For 68 countries with more than one survey (with the earlier survey conducted 2000-2013), we estimated the average annual percentage point change in prevalence of zero-dose children between the earliest and latest surveys. We also explored the association of zero-dose prevalence with postneonatal and child mortality, health expenditure, and Gavi-eligibility. Overall, 16% of children in our pooled sample had not received a dose of DPT-containing vaccine. There was a 0.8% point decline in zero-dose prevalence per year on average across the period studied. A single percentage point average annual decline in zero-dose prevalence was associated with an average annual decrease of 1.4 deaths in the postneonatal and childhood period per 1000 live births. Gavi-eligible countries had a much faster decline in zero-dose prevalence than other countries. Large gains have been made in reducing the percentage of children who did not receive a DPT-containing vaccine. Efforts to reduce the number of zero-dose children should focus on countries with high prevalence to achieve the Immunization Agenda 2030. Healthcare spending could be prioritized so that the prevalence of zero-dose children is reduced.