Conjugated linoleic acid (CLA) is a nutrient substance that exists in humans and animals. It has anti-tumor, anti-atherosclerosis, and immune-regulating functions, but its oral bioavailability is low. Conjugated linoleic acid dry powder inhalers (CDPIs) were prepared and intratracheally administered to the rats that suffered from primary lung cancer. Conjugated linoleic acid nanoemulsions were prepared first and CDPIs were with 10% mannitol after lyophilization. CDPIs are loose white powders with the aerodynamic median diameter (D_a) of 3.10 μm, which were suitable for pulmonary delivery. Rats lung cancer models were established after 45 days by instilling 3-methylcholanthrene (MCA) and N, N-dimethylnitrosamine (DEN) into the rats lung once. The animal experiments were approved by the Ethics Committee of Academy of Military Medical Sciences and conducted in accordance with the relevant guidelines and regulations. The CDPIs, gefitinib suspension and blank DPIs were sprayed into the lungs of rats with lung cancer through the trachea. Compared with the model group, both the gefitinib suspension group and the CDPIs group showed significantly fewer tumor nodules and inflammatory cells, and the CDPIs group was better than the gefitinib suspension group. The inhibition efficiency of CDPIs on CD31 and NF-κB p65 was better than that of the gefitinib suspension group. The vascular endothelial growth factor (VEGF) level in the CDPIs group was significantly reduced, which was equivalent to that of the gefitinib suspension group. The apoptosis in the CDPIs group by Tunel tests showed a significant increase, which was significantly better than the gefitinib suspension group. Therefore, CDPIs had excellent pharmacological activity on lung cancer, which provided a model for the efficient delivery of oil therapeutic agents.

This article systematically reviews the background and regulatory requirements of bioequivalence of orally inhaled and nasal drug products (OINDPs), as well as the basic regulatory requirements for the assessment by the guidelines and guidance issued in China, the United States, and the European Union. Detailed statistical evaluation method considerations and calculations of the US FDA population bioequivalence (PBE) method were presented for the evaluation of in vitro bioequivalence (IVBE) for OINDPs. Using the example described in the FDA Draft Guidance for budesonide inhalation suspension, the PBE analysis statistical parameters were calculated via the R programming, and the results were compared with that in the guidelines. Moreover, pseudo-code for the PBE calculation program was provided. This paper aims to provide guidance and references for the research and development of new drug, as well as pharmaceutical quality control, and development of generic medicinal products for OINDPs.

Most small molecule drugs bind to enzymes, receptors or ion channels, which possess binding pocket for drug occupation. However, the study of drugs that interfere with protein-protein interactions has always been a challenging subject. The discovery of molecular glues and degraders has opened an avenue to tackle this issue. With the structural features of bifunctional ligand molecular glues mediate the recognition and binding of two proteins. As a useful tool for chemical biology molecular glue can not only help to find probes to undruggable targets, but also can be developed into drugs through structure optimization in medicinal chemistry. This minireview concisely describes the features of molecular glue using a few existing drugs or active compounds.

Bacterial pneumonia is a common clinical disease and the abuse of antibacterial leads to the production and prevalence of resistant bacteria. Novel antibacterial active ingredients can be found from natural products for the treatment of bacterial pneumonia. Pulmonary delivery systems can directly deliver drugs to infected lung tissues, favoring the treatment of bacterial pneumonia. Cinnamon oil (CO) is a volatile oil extracted from cinnamon, which has antibacterial and anti-inflammation functions. However, the preparation of its pulmonary delivery systems is difficult because of its oil and volatile properties. Here, CO-β-cyclodextrin inclusion complex (CO-β-CD) was prepared. Its dry powder inhalers (DPIs) were obtained by lyophilization. The DPIs had the aerodynamic diameter of 1.34 μm and the fine particle fraction (FPF) of 30.90%, which was suitable for pulmonary delivery. The minimal bactericidal concentration of CO-β-CD was 2 mg·mL^-1 against Staphylococcus aureus (SA). The animal experiments were approved by the Ethics Committee of Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. A high intratracheal (i.t.) dose (100 mg·kg^-1) of CO-β-CD did not show significant toxicity to the mice. Bacterial pneumonia mice models were established after intraperitoneal injection of dexamethasone and then i.t. administration of SA. CO-β-CD and penicillin were separately i.t. administered to the mice. Both of them alleviated the lung injury of mice and remarkably increased the survival rates. Compared to penicillin, CO-β-CD significantly reduced the infiltration of inflammatory cells and the numbers of leukocytes and neutrophils in the blood, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the lung tissues were similar to those of the healthy mice, indicating that CO-β-CD had the capability of anti-inflammation besides antibacterial effect in vivo. CO-β-CD dry powder inhalers are a potential pulmonary delivery system for the treatment of bacterial pneumonia.

Growth differentiation factor 15 (GDF15) is an endocrine hormone that belongs to the transforming growth factor β (TGFβ) superfamily, which plays a role by binding to the glial cell line derived neurotrophic factor (GDNF)-family receptor α-like (GFRAL)-rearranged during transfection (RET) heterodimer receptor. A number of studies have confirmed that GDF15, as a biomarker for obesity, diabetes, tumors, non-alcoholic fatty liver disease, ischemic diseases, and so on, has become a new target for new drug discovery. At present, pharmaceutical companies around the world are carrying out drug discovery with GDF15 as a new therapeutic target involving many therapeutic areas such as anti-obesity, anti-tumor, and treatment of anorexia syndrome. Comprehensive analysis of the advantages and disadvantages of the GDF15 target, discussion, and objective evaluation of research and development of new drugs based on GDF15 will provide a scientific basis for the discovery of innovative drugs that could relieve the human suffering from illness.

The movement and deposition of inhaled particles in the lung tissue have an important influence on the respiratory physiology of human body. The corresponding particle dynamics model plays a vital role in exploring the pathogenic factors and treatment methods of lung diseases. Such as evaluating the optimal design of pulmonary atomization drug delivery and the impact of particulate air pollutants on the lung. According to the different knowledge and modeling methods, this paper classifies, combs and analyzes several representative particle dynamics models in lung airways in recent years. We divided the mechanism models into the biological model, physical model and numerical simulation model. The biological models include in vivo imaging and pharmacokinetic methods; physical models include bionic and microfluidic chip models; the numerical models include respiratory tract model, airflow model and particle model. Moreover, the numerical solution and fluid-structure-interaction models were also reviewed, especially the application prospect of the lattice Boltzmann method.

Protein disulfide isomerase (PDI), also named PDIA1, is an archetype member of protein disulfide isomerase family, which mainly exists in endoplasmic reticulum and plays an important role in pathophysiological progress via enzyme activity and molecular chaperone function helping protein folding correctly. Amyotrophic lateral sclerosis (ALS) is a kind of neurodegenerative diseases characterized by abnormal protein aggregation. Recently, PDI mutants have been found in ALS patients and the important role of PDI protein in the development of ALS has also been confirmed. Here, we focus on the recent studies of PDI in ALS hoping to provide a novel target for the treatment of ALS.

The cyanuric chloride linkers have been used for cyclizing polypeptide, but not used for α-conotoxin, the peptides with rich disulfide bonds and more amino acid residues. In this study, cyclic peptides c[A10L]PnIA-1-4 were synthesized efficiently by lysine assisted cyanuric chloride linkers with 28.92%-52.00% yields. The activity evaluation showed that the IC₅₀ values of c[A10L]PnIA-1 against α7 and α3β2 nAChR subtypes were 5 and 7 times higher than[A10L]PnIA respectively, and the subtype selectivity was maintained. The results of circular dichroism show that this cyclization method had no significant effect on its secondary structure. Compared with the commonly used head-to-tail cyclization in conotoxin cyclization, this method has the advantages of rapid reaction and high yield, which is expected to be further applied to the cyclization study of various α-conotoxins.

The study investigates the mechanism by which Peganum harmala L. (Luotuopeng, LTP) inhibits tube formation in retinal vascular endothelial cells. Tube formation was induced by treatment of retinal vascular endothelial cells with glucose. The cells were divided into a normal group, model group, and an LTP group. The total length of tube formation was measured. The active components, targets, and pathway by which LTP acts in the treatment of diabetic retinopathy was explored by network pharmacology. The mRNA expression levels of targets[extracellular signal-regulated kinase 2 (ERK2), phosphoinositide 3 kinase catalytic alpha polypeptide (PIK3CA), serine/threonine-protein kinase 1 (AKT1)] related to the mitogen-activated protein kinase (MAPK) signaling pathway and vascular endothelial growth factor (VEGF) signaling pathway was measured by real-time PCR. The results of tube formation indicated that compared with the normal group, the total tube length increased in the model group (P < 0.01); after the treatment with LTP, the total tube length decreased compared with the model group (P < 0.01). Network pharmacology revealed that the targets of LTP included PIK3CA, AKT1, and ERK2, and the pathways involved the MAPK signaling pathway and the VEGF signaling pathway. Real-time PCR indicated that compared with the normal group, the mRNA expression levels of ERK2, PIK3CA and AKT1 were elevated in the model group (P < 0.05); after treatment with LTP, the mRNA expression levels of ERK2, PIK3CA and AKT1 decreased compared with the model group (P < 0.05). LTP may inhibit retinal vascular endothelial cell tube formation by regulating the MAPK signaling pathway and the VEGF signaling pathway. This study confirms the multi-targets and multi-pathways of LTP and provides a basis for its use in the treatment of diabetic retinopathy.

Kidney injury and decreased chemosensitivity of tumor cells are obstacles with cisplatin (CDDP) chemotherapy. Down-regulation of the organic cation transporter 2 (OCT2) and multidrug resistance-associated protein 2 (MRP2) is a key means to alleviate CDDP-induced kidney injury and increase chemosensitivity. Astragaloside IV (AS IV) is obtained from the well-known traditional Chinese herb Astragalus membranaceus. This study explored the role of AS IV in preventing kidney injury and enhancing the antitumor effect of CDDP by suppressing OCT2 expression in kidney and MRP2 in tumors. This project was reviewed and approved by the Animal Ethics Committee of the First Hospital of Jilin University. The effects of AS IV on CDDP inhibition of tumor growth and promotion of apoptosis were assessed in Lewis lung tumor (LLC)-bearing mice by H&E and TUNEL staining. Kidney injury was assessed by serum biochemical parameters and H&E staining. We used Western blotting and immunohistochemistry assays to detect OCT2 and MRP2 expression in kidney and tumor. The concentration of CDDP in kidney and tumor was measured by HPLC-MS/MS. AS IV enhanced CDDP chemosensitivity by increasing tumor cell apoptosis and slowing tumor growth, and decreased kidney injury as evidenced by lower blood creatinine (Cr) and blood urea nitrogen (BUN). Co-administration of AS IV suppressed MRP2 overexpression induced by CDDP in tumor tissues and may be an important mechanism for enhancing CDDP chemosensitivity. Moreover, AS IV reduced CDDP-induced kidney injury in mice along with suppression of OCT2 expression in kidney. The concentration of CDDP was increased in tumor but decreased in kidney. In total, AS IV not only enhanced the antitumor effect of CDDP by suppressing MRP2 expression in tumor cells, but also decreased kidney injury induced by CDDP. The results provide new insight into the combined use of a chemotherapy drug and natural ingredients to treat cancer.