Lung diseases, including COVID-19 and lung cancers, is a huge threat to human health. However, for the treatment and diagnosis of various lung diseases, such as pneumonia, asthma, cancer, and pulmonary tuberculosis, are becoming increasingly challenging. Currently, several types of treatments and/or diagnostic methods are used to treat lung diseases; however, the occurrence of adverse reactions to chemotherapy, drug-resistant bacteria, side effects that can be significantly toxic, and poor drug delivery necessitates the development of more promising treatments. Nanotechnology, as an emerging technology, has been extensively studied in medicine. Several studies have shown that nano-delivery systems can significantly enhance the targeting of drug delivery. When compared to traditional delivery methods, several nanoparticle delivery strategies are used to improve the detection methods and drug treatment efficacy. Transporting nanoparticles to the lungs, loading appropriate therapeutic drugs, and the incorporation of intelligent functions to overcome various lung barriers have broad prospects as they can aid in locating target tissues and can enhance the therapeutic effect while minimizing systemic side effects. In addition, as a new and highly contagious respiratory infection disease, COVID-19 is spreading worldwide. However, there is no specific drug for COVID-19. Clinical trials are being conducted in several countries to develop antiviral drugs or vaccines. In recent years, nanotechnology has provided a feasible platform for improving the diagnosis and treatment of diseases, nanotechnology-based strategies may have broad prospects in the diagnosis and treatment of COVID-19. This article reviews the latest developments in nanotechnology drug delivery strategies in the lungs in recent years and studies the clinical application value of nanomedicine in the drug delivery strategy pertaining to the lung.

Small molecular inhibitors or drugs targeting specific molecular alterations are widely used in clinic cancer therapy. Despite the success of targeted therapy, the development of drug resistance remains a challenging problem. Identifying drug resistance mechanisms for targeted therapy is an area of intense investigation, and recent evidence indicates that cellular polyploidy may be involved. Here, we demonstrate that the cell cycle kinase inhibitor, Oxindole-1 (Ox-1), induces mitotic slippage, causing resistant polyploidy in acute myeloid leukemia (AML) cells. Indeed, Ox-1 decreases the kinase activity of CDK1 (CDC2)/cyclin B1, leading to inhibition of Bcl-xL phosphorylation and subsequent resistance to apoptosis. Addition of ABT-263, a Bcl-2 family inhibitor, to Ox-1, or the other polyploidy-inducer, ZM447439 (ZM), produces a synergistic loss of cell viability with greater sustained tumor growth inhibition in AML cell lines and primary AML blasts. Furthermore, genetic knockdown of Bcl-xL, but not Bcl-2, exhibited synergistic inhibition of cell growth in combination with Ox-1 or ZM. These data demonstrate that Bcl-xL is a key factor in polyploidization resistance in AML, and that suppression of Bcl-xL by ABT-263, or siRNAs, may hold therapeutic utility in drug-resistant polyploid AML cells.

The hypoxic microenvironment is presumed to be a sanctuary for myeloid leukemia cells that causes relapse following chemotherapy, but the underlying mechanism remains elusive. Using a zebrafish xenograft model, we observed that the hypoxic hematopoietic tissue preserved most of the chemoresistant leukemic cells following the doxorubicin (Dox) treatment. And hypoxia upregulated TFEB, a master regulator of lysosomal biogenesis, and increased lysosomes in leukemic cells. Specimens from relapsed myeloid leukemia patients also harbored excessive lysosomes, which trapped Dox and prevented drug nuclear influx leading to leukemia chemoresistance. Pharmaceutical inhibition of lysosomes enhanced Dox-induced cytotoxicity against leukemic cells under hypoxia circumstance. To overcome lysosome associated chemoresistance, we developed a pH-sensitive dextran-doxorubicin nanomedicine (Dex-Dox) that efficiently released Dox from lysosomes and increased drug nuclear influx. More importantly, Dex-Dox treatment significantly improved the chemotherapy outcome in the zebrafish xenografts transplanted with cultured leukemic cells or relapsed patient specimens. Overall, we developed a novel lysosome targeting nanomedicine that is promising to overcome the myeloid leukemia chemoresistance.

Bone marrow mesenchymal stem cells (MSCs) are widely used clinically due to their versatile roles in multipotency, immunomodulation, and hematopoietic stem cell (HSC) niche function. However, cellular heterogeneity limits MSCs in the consistency and efficacy of their clinical applications. Metabolism regulates stem cell function and fate decision; however, how metabolites regulate the functional heterogeneity of MSCs remains elusive. Here, using single-cell RNA sequencing, we discovered that fatty acid pathways are involved in the regulation of lineage commitment and functional heterogeneity of MSCs. Functional assays showed that a fatty acid metabolite, butyrate, suppressed the self-renewal, adipogenesis, and osteogenesis differentiation potential of MSCs with increased apoptosis. Conversely, butyrate supplement significantly promoted HSC niche factor expression in MSCs, which suggests that butyrate supplement may provide a therapeutic approach to enhance their HSC niche function. Overall, our work demonstrates that metabolites are essential to regulate the functional heterogeneity of MSCs.

Caspase1 (CASP1) is a gene that encodes multiple proteins related to cell death. Nevertheless, the function of CASP1 in the pathogenesis of AML is still unclear. In the present study, a detailed analysis of cancer versus normal samples was performed to explore the relationship between CASP1 and leukemia. We used sequencing data from multiple cancer gene databases to analyze the gene expression and regulatory network of CASP1 in leukemia. We discovered that mRNA expression levels of CASP1 are increased in leukemia cell lines, especially in acute myelocytic leukemia (AML). Then, we verified the mRNA expression of CASP1 in AML clinical samples and observed significantly higher expression of CASP1 in relapsed AML patients. High CASP1 expression was associated with poor prognosis and CASP1 inhibition could impair the proliferation of AML cells. Related functional network identification suggests that CASP1 regulates apoptosis, immune and inflammatory response via pathways involving LYN, LCK, and the E2F family. These findings suggest that CASP1 probably contributes to the pathogenesis, and identify CASP1 as a factor for predicting the prognosis and as a therapeutic target of AML patients.

Objectives: Maternal cigarette smoke exposure (SE) causes intrauterine undernutrition, resulting in increased risk for metabolic disorders and type 2 diabetes in the offspring without sex differences. L-leucine supplementation has been shown to reduce body weight and improve glucose metabolism in both obese animals and humans. In this study, we aimed to determine whether postnatal L-leucine supplementation in female offspring can ameliorate the detrimental impact of maternal SE.Methods: Female Balb/c mice (6-week) were exposed to cigarette smoke (SE, 2 cigarettes/day) prior to mating for 5 weeks until the pups weaned. Sham dams were exposed to air during the same period. Half of the female offspring from the SE and SHAM dams were supplied with L-leucine via drinking water (1.5% w/w) after weaning (21-day) for 10 weeks and sacrificed at 13 weeks (adulthood).Results: Maternal SE during pregnancy resulted in smaller body weight and glucose intolerance in the offspring. L-leucine supplement in Sham offspring reduced body weight, fat mass, and fasting blood glucose levels compared with their untreated littermates; however somatic growth was not changed. L-leucine supplement in SE offspring improved glucose tolerance and reduced fat mass compared with untreated littermates.Conclusions: Postnatal L-leucine supplement could reduce fat accumulation and ameliorate glucose metabolic disorder caused by maternal SE. The application of leucine may provide a potential strategy for reducing metabolic disorders in offspring from mothers who continued to smoke during pregnancy.

Objectives: Maternal smoking causes fetal underdevelopment and results in births which are small for gestation age due to intrauterine undernutrition, leading to various metabolic disorders in adulthood. Furthermore, postnatal high fat diet (HFD) consumption is also a potent obesogenic factor, which can interact with maternal smoking. In this study, we aimed to determine whether maternal HFD consumption during pregnancy can reverse the adverse impact of maternal smoking and change the response to postnatal HFD consumption.Methods: Female mice were exposed to cigarette smoke (SE, 2 cigarettes/day) or sham exposed for 5 weeks before mating, with half of the SE dams fed HFD (43% fat, SE+HFD). The same treatment continued throughout gestation and lactation. Male offspring from each maternal group were fed the same HFD or chow after weaning and sacrificed at 13 weeks.Results: Maternal SE alone increased body weight and fat mass in HFD-fed offspring, while SE+HFD offspring showed the highest energy intake and glucose metabolic disorder in adulthood. In addition, postnatal HFD increased the body weight and aggravated the metabolic disorder caused by maternal SE and SE+HFD.Conclusions: Maternal HFD consumption could not ameliorate the adverse effect of maternal SE but exaggerate metabolic disorders in adult offspring. Smoking cessation and a healthy diet are needed during pregnancy to optimize the health outcome in the offspring.

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