Pharmaceuticals

Immune checkpoint blockade (ICB) is currently considered to be an important therapeutic method, which obtained FDA approval for clinical use in gastric cancer in 2017. As a new mechanism, it was found that the effect of αPDL1 could be improved by blocking the TGF-β1 signaling pathway, which converts the tumor immune microenvironment from the “immune-excluded phenotype” to the “immune-inflamed phenotype”. Based on this phenomenon, this project was designed to prepare TGF-β1-siRNA-loaded PEG-PCL nanoparticles conjugated to αPDL1 (siTGF-β1-αPDL1-PEG-PCL) since we have linked similar antibodies to PEG-PCL previously. Therefore, MFC tumor-engrafted mice were established to simulate the biological characteristics of converting the phenotype of the immune microenvironment, and to study the anti-tumor effect and possible molecular mechanism. In this study, αPDL1 antibody conjugates markedly increased the cell uptake of NPs. The produced αPDL1-PEG-PCL NPs efficiently reduced the amounts of TGF-β1 mRNA in MFC cells, converting the immune microenvironment of MFC tumors engrafted mice from the “immune-excluded phenotype” to the “immune-inflamed phenotype”. PDL1-harboring gastric cancer had increased susceptibility to αPDL1. The value of this drug-controlled release system targeting the tumor microenvironment in immune checkpoint therapy of gastric cancer would provide a scientific basis for clinically applying nucleic acid drugs. Full article

In South Brazil, the incidence of pediatric adrenocortical carcinoma (ACC) is higher than in other regions and countries worldwide. The ACC treatment includes therapy with mitotane, the only adrenolytic drug approved by the FDA. The mitotane metabolism occurs via two main reactions: the β-hydroxylation, which yields the final product o,p’-DDA, and the α-hydroxylation, which will give the final product o,p’-DDE. It is speculated that o,p’-DDE may be an active metabolite since it has a cytotoxic effect on adrenocortical carcinoma cells (H295R). No further studies have been conducted to confirm this hypothesis; however, it was found that mitotane and its metabolites are present at significantly different concentrations in the plasma of the patients. Our study aimed to assess the in vitro effects of o,p’-DDE and o,p’-DDD in cell death pathways, oxidative parameters, and interaction with adrenal CYP’s involved in the steroidogenic process in the H295R cell line. It was found that o,p’-DDE had a different effect than the o,p’-DDD on apoptosis, inhibiting this cell death pathway, but it promotes cell necrosis at higher concentrations. In contrast to o,p’-DDD, the o,p’-DDE did not have effects on the different oxidative parameters evaluated, but exhibited stimulatory interactions with steroidogenic CYP’s, at intermediate concentrations. Therefore, we demonstrated important cell effects of o,p’-DDE; its plasma levels during mitotane therapy should be monitored as an important therapeutic parameter. Full article

Kidney fibrosis is a common pathophysiological mechanism of chronic kidney disease (CKD) progression caused by several underlying kidney diseases. Among various contributors to kidney fibrosis, transforming growth factor-β1 (TGF-β1) is the major factor driving fibrosis. TGF-β1 exerts its profibrotic attributes via the activation of canonical and non-canonical signaling pathways, which induce proliferation and activation of myofibroblasts and subsequent accumulation of extracellular matrix. Over the past few decades, studies have determined the TGF-β1 signaling pathway inhibitors and evaluated whether they could ameliorate the progression of CKD by hindering kidney fibrosis. However, therapeutic strategies that block TGF-β1 signaling have usually demonstrated unsatisfactory results. Herein, we discuss the therapeutic concepts of the TGF-β1 signaling pathway and its inhibitors and review the current state of the art regarding regarding TGF-β1 inhibitors in CKD management. Full article

Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyclic covalent fragment library with improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH (L-glutathione) reactivity assay, and thrombin counter screen were also used to demonstrate and explain the improved reactivity and selectivity of the N-methylated heterocycles and to compare the two generations of heterocyclic electrophiles. Full article

Tetrahydroisoquinolines have been widely investigated for the treatment of arrhythmias. 1−(3′−bromophenyl)−heliamine (BH), an anti−arrhythmias agent, is a synthetic tetrahydroisoquinoline. This study focuses on the pharmacokinetic characterization of BH, as well as the identification of its metabolites, both in vitro and in vivo. A UHPLC−MS/MS method was developed and validated to quantify BH in rat plasma with a linear range of 1–1000 ng/mL. The validated method was applied to a pharmacokinetic study in rats. The maximum concentration C_max (568.65 ± 122.14 ng/mL) reached 1.00 ± 0.45 h after oral administration. The main metabolic pathways appeared to be phase-I of demethylation, dehydrogenation, and epoxidation, and phase II of glucuronide and sulfate metabolites. Finally, a total of 18 metabolites were characterized, including 10 phase I metabolites and 8 phase II metabolites. Through the above studies, we have gained a better understanding of the absorption and metabolism of BH in vitro and in vivo, which will provide us with guidance for future in-depth studies on this compound. Full article

Background: Due to the blood–brain barrier and limited antibiotic choices, polymyxin is currently the first-line agent for the treatment of central nervous system infections (CNSIs) caused by multidrug-resistant Gram-negative bacteria (MDR-GNB). Colistin sulfate, as a polymyxin E different from CMS, is used in Chinese clinics, and there are limited reports on its use in the treatment of CNSIs. Case Presentation: This case describes a 76-year-old man who underwent complex neurosurgery for cervical spinal stenosis. Postoperatively, the patient developed a fever and a poorly healed surgical wound. Numerous blood routine tests, inflammatory markers, pathogenic tests of cervical secretions, cerebrospinal fluid (CSF), and sputum were sent for diagnosis. After empirical antimicrobial treatments failed, the CSF and wound pus cultured carbapenem-resistant Klebsiella pneumoniae. The regimen was adjusted to colistin sulfate intravenously and intrathecal injection combined with tigecycline. In addition, the management of infection foci, including continuous lumbar pool drain, cervical 3–5 internal fixation removal with cervical 1–6 spine dilation, CSF leak repair, and right thigh broad fasciotomy, were performed. After treatment, the patient was discharged with multiple sets of negative CSF cultures and the infection under control. Conclusions: For CNSIs caused by MDR-GNB, the selection of colistin sulfate for intravenous and topical combination treatment is a viable choice. Full article

Alzheimer’s disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins was investigated in primary neurons from APP/PS1 transgenic mice. The results showed that BG45 can upregulate the expression of synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons. In vivo, the APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with BG45 (30 mg/kg) daily for 12 days. Behavioral testing of BG45-treated APP/PS1 mice showed improvements in learning and memory. BG45 can alleviate damage to the dendritic spine and reduce the deposition of Aβ. Similar to the in vitro results, synapse-related proteins in the prefrontal cortex were increased after BG45 treatment. Proteomic analysis results highlighted the differences in the biological processes of energy metabolism and calmodulin regulation in APP/PS1 mice with or without BG45 treatment. Further verification demonstrated that the effect of BG45 on synapses and learning and memory may involve the CaMKII/ITPKA/Ca²⁺ pathway. These results suggest that class I HDACI BG45 might be a promising drug for the early clinical treatment of AD. Full article

Vaccines and antiviral drugs are widely used to treat influenza infection. However, they cannot rapidly respond to drug-resistant viruses. Therefore, new anti-influenza virus strategies are required. Naringenin is a flavonoid with potential for new antiviral strategies. In this study, we evaluated the antiviral effects of naringenin derivatives and examined the relationship between their cellular uptake and antiviral effects. Madin–Darby canine kidney (MDCK) cells were infected with the A/PR/8/34 strain and exposed to the compound-containing medium for 24 h. The amount of virus in the supernatant was calculated using focus-forming reduction assay. Antiviral activity was evaluated using IC₅₀ and CC₅₀ values. Cells were exposed to a constant concentration of naringenin or prenylated naringenin, and intracellular uptake and distribution were evaluated using a fluorescence microscope. Prenylated naringenin showed strong anti-influenza virus effects, and the amount of intracellular uptake was revealed by the strong intracellular fluorescence. In addition, intracellular distribution differed depending on the position of the prenyl group. The steric factor of naringenin is deeply involved in influenza A virus activity, and prenyl groups are desirable. Furthermore, the prenyl group affects cellular affinity, and the uptake mechanism differs depending on its position. These results provide important information on antiviral strategies. Full article

In order to explore novel immunomodulatory agents as anti-tumor drugs, we designed and synthesized a series of new pomalidomide derivatives containing urea moieties. Interestingly, in vitro biological experiments performed in several cancer cell lines showed that some of them displayed potent anti-tumor ability. These novel compounds 5a–5e and 6a–6e demonstrated the best cell growth inhibitive activity in human breast cancer cell lines MCF-7, but weaker inhibitive activity in human hepatocellular carcinoma cell lines Huh7. Moreover, compound 5d had the most powerful effects in this study, with an IC₅₀ value of 20.2 μM in MCF-7. Further study indicated that compound 5d could inhibit cell growth and induce cell death in a concentration-dependent manner. Besides, compound 5d increased cellular ROS levels and induced DNA damage, thereby potentially leading to cell apoptosis. These observations suggest that the novel pomalidomide derivatives containing urea moieties may be worth further investigation to generate potential anti-tumor drugs. Full article

Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously “undruggable” proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical needs that covalent inhibitors have not yet addressed. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted covalent inhibitors (TCIs), and expanded TCIs. By reviewing both Food and Drug Administration (FDA)-approved drugs and drug candidates from recent literature, we provide insight into the future direction of covalent inhibitor development. Full article

Gastric cancer (GC) is among the five most common malignancies worldwide. Traditional chemotherapy cannot efficiently treat the disease and faces the problems of side effects and chemoresistance. Polygoni orientalis Fructus (POF), with flavonoids as the main bioactive compounds, exerts anti-cancer potential. In this study, we compared the anti-GC effects of the main flavonoids from POF and investigated the anti-cancer effects of eriodictyol towards GC both in vitro and in vivo. CCK-8 assays were performed to examine the inhibitory effects of common flavonoids from POF on GC cell viability. Colony formation assays were used to determine cell proliferation after eriodictyol treatment. Cell cycle distribution was analyzed using flow cytometry. Induction of apoptosis was assessed with Annexin V/PI staining and measurement of related proteins. Anti-cancer effects in vivo were investigated using a xenograft mouse model. Potential targets of eriodictyol were clarified by network pharmacological analysis, evaluated by molecular docking, and validated with Western blotting. We found that eriodictyol exhibited the most effective inhibitory effect on cell viability of GC cells among the common flavonoids from POF including quercetin, taxifolin, and kaempferol. Eriodictyol suppressed colony formation of GC cells and induced cell apoptosis. The inhibitory effects of eriodictyol on tumor growth were also validated using a xenograft mouse model. Moreover, no obvious toxicity was identified with eriodictyol treatment. Network pharmacology analysis revealed that PI3K/AKT signaling ranked first among the anti-GC targets. The molecular docking model of eriodictyol and PI3K was constructed, and the binding energy was evaluated. Furthermore, efficient inhibition of phosphorylation and activation of PI3K/AKT by eriodictyol was validated in GC cells. Taken together, our results identify eriodictyol as the most effective anti-GC flavonoids from POF and the potential targets of eriodictyol in GC. These findings suggest that eriodictyol has the potential to be a natural source of anti-GC agents. Full article

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a-g), benzyl piperidine (4i), and aryl aminothiazoles (5a-e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model. Full article

Lung cancer is considered the most commonly diagnosed cancer and one of the leading causes of death globally. Despite the responses from small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients to conventional chemo- and radiotherapies, the current outcomes are not satisfactory. Recently, novel advances in DNA sequencing technologies have started to take off which have provided promising tools for studying different tumors for systematic mutation discovery. To date, a limited number of DDR inhibition trials have been conducted for the treatment of SCLC and NSCLC patients. However, strategies to test different DDR inhibitor combinations or to target multiple pathways are yet to be explored. With the various biomarkers that have either been recently discovered or are the subject of ongoing investigations, it is hoped that future trials would be designed to allow for studying targeted treatments in a biomarker-enriched population, which is defensible for the improvement of prognosis for SCLC and NSCLC patients. This review article sheds light on the different DNA repair pathways and some of the inhibitors targeting the proteins involved in the DNA damage response (DDR) machinery, such as ataxia telangiectasia and Rad3-related protein (ATR), DNA-dependent protein kinase (DNA-PK), and poly-ADP-ribose polymerase (PARP). In addition, the current status of DDR inhibitors in clinical settings and future perspectives are discussed. Full article

Brain metastasis predicts a worse clinical outcome in cancer patients. Emerging observational evidence suggests that statin use has a protective role in overall cancer prevention. Whether statin use could also be a supplementary treatment for advanced-stage cancers remains under researched and controversial. Data for cancer patients with brain metastasis were selected from the linked electronic medical care records of the West China Hospital between October 2010 and July 2019. Fisher’s exact chi-square test was used to compare the differences between cohorts. Multivariate Cox analysis was conducted to adjust the potential confounders in evaluating the role of statin use in the overall survival (OS) of cancer patients with brain metastasis. There were 4510 brain metastatic patients included in this retrospective study. The overall statin use rate in our patients was 5.28% (219 cases/4510 cases). Compared with the non-statin use cohort, patients who received statin therapy showed a decreased Karnofsky performance score (KPS, p < 0.001) and lower high-density lipoprotein (HDL, p = 0.020) but higher body mass index (BMI, p = 0.002) and triglyceride (TG, p < 0.001) at admission. There was no association between statin use and the OS of the cancer patients with brain metastasis (Hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.73–1.07, p = 0.213) during the univariate analysis. However, after adjusting for baseline patient characteristics, metabolism indicators, and cancer-specific factors, statin use was shown to have a significant protective role, aiding the survival of the cancer patients with brain metastasis (_adjustHR = 0.82, 95%CI: 0.69–0.99, p = 0.034). Our results highlight that statin use shows significant survival benefits in cancer patients with brain metastasis. However, future research is needed to validate our findings. Full article

Globally, pathogenic microbes have reached a worrisome level of antibiotic resistance. Our work aims to identify and isolate the active components from the bioactive Ficus retusa bark extract and assess the potential synergistic activity of the most major compounds’ constituents with the antibiotic tetracycline against certain pathogenic bacterial strains. The phytochemical screening of an acetone extract of F. retusa bark using column chromatography led to the identification of 10 phenolic components. The synergistic interaction of catechin and chlorogenic acid as the most major compounds with tetracycline was evaluated by checkerboard assay followed by time-kill assay, against Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, and Salmonella typhi with fraction inhibitory concentration index values (FICI) of 0.38, 0.43, 0.38, 0.38, 0.38, and 0.75 for catechin and 0.38, 0.65, 0.38, 0.63, 0.38, and 0.75 for chlorogenic acid. The combination of catechin and chlorogenic acid with tetracycline significantly enhanced antibacterial action against gram-positive and gram-negative microorganisms; therefore, catechin and chlorogenic acid combinations with tetracycline could be employed as innovative and safe antibiotics to combat microbial resistance. Full article

Little is known about cardiovascular safety profiles for monoclonal antibody products that received the FDA Emergency Use Authorization for COVID-19. In this study, data from the FDA Adverse Event Reporting System from the first quarter of 2020 to the second quarter of 2022 were used to investigate cardiovascular safety signals associated with seven monoclonal antibody products (casirivimab + imdevimab, bamlanivimab, bamlanivimab + etesevimab, sotrovimab, tocilizumab, bebtelovimab, tixagevimab + cilgavimab) in COVID-19 patients. Disproportionality analyses were conducted using reporting odds ratio and information component to identify safety signals. About 10% of adverse events in COVID-19 patients were cardiovascular adverse events. Four monoclonal antibody products (casirivimab + imdevimab, bamlanivimab, bamlanivimab + etesevimab, and bebtelovimab) were associated with higher reporting of hypertension. Tocilizumab was associated with higher reporting of cardiac failure and embolic and thrombotic event. Casirivimab + imdevimab and bamlanivimab were also associated with higher reporting of ischemic heart disease. No cardiovascular safety signals were identified for sotrovimab and tixagevimab + cilgavimab. The results indicate differential cardiovascular safety profiles in monoclonal antibodies. Careful monitoring of cardiovascular events may be considered for certain COVID-19 patients at risk when they are treated with monoclonal antibodies. Full article

Cancer is a serious threat to human beings and is the second-largest cause of death all over the globe. Chemotherapy is one of the most common treatments for cancer; however, drug resistance and severe adverse effects are major problems associated with anticancer therapy. New compounds with multi-target inhibitory properties are targeted to surmount these challenges. Cyclooxygenase-2 (COX-2) is overexpressed in cancers of the pancreas, breast, colorectal, stomach, and lung carcinoma. Therefore, COX-2 is considered a significant target for the synthesis of new anticancer agents. This review discusses the biological activity of recently prepared dual anticancer and COX-2 inhibitory agents. The most important intermolecular interactions with the COX-2 enzyme have also been presented. Analysis of these agents in the active area of the COX-2 enzyme could guide the introduction of new lead compounds with extreme selectivity and minor side effects. Full article

Temporal lobe epilepsy (TLE) is the most prevalent and treatment-refractory type of epilepsy. Among the different mechanisms associated with epileptogenesis, overstimulation of glutamatergic neurotransmission has been associated with the onset and progression of seizures in TLE. Experimental evidence indicates that blocking the N-methyl-D-aspartate (NMDA) receptor or suppressing the expression of its subunit, mainly GluN1, may be effective in preventing epileptic seizures. Small interfering RNA (siRNA) has received attention as a potential therapeutic tool due to the inhibition of gene expression in some diseases. The present work evaluated the potential silencing effect of intranasal administration of an siRNA conjugate against the GluN1 subunit in animals submitted to the pilocarpine model of epilepsy. The results showed that the siRNA conjugate transfection system silences the GluN1 subunit in the hippocampus of rats when administered intranasally. As demonstrated by the RT-qPCR and Western blotting approaches, the silencing of GluN1 was specific for this subunit without affecting the amount of mRNA for other subunits. Silencing increased the latency time for the first tonic–clonic seizure when compared to controls. The overlapping of findings and the validation of the intranasal route as a pharmacological route of siRNA targeting the GluN1 subunit give the work a significant biotechnological interest. Full article

Plant-derived natural compounds are widely used as alternative medicine in healthcare throughout the world. Ginkgolic acids, the phenolic compounds isolated from the leaves and seeds of Ginkgo biloba, are among the chemicals that have been explored the most. Ginkgolic acids exhibit cytotoxic activity against a vast number of human cancers in various preclinical models in vitro and in vivo. Additionally, the pharmacological activities of ginkgolic acids are also involved in antidiabetic, anti-bacteria, anti-virus, anti-fibrosis, and reno/neuroprotection. Autophagy as a highly conserved self-cleaning process that plays a crucial role in maintaining cellular and tissue homeostasis and has been proven to serve as a protective mechanism in the pathogenesis of many diseases, including neurodegenerative diseases, cancer, and infectious diseases. In this review, we surveyed the pharmacological activities of the major three forms of ginkgolic acids (C13:0, C15:1, and C17:1) that are linked to autophagic activity and the mechanisms to which these compounds may participate. A growing body of studies in last decade suggests that ginkgolic acids may represent promising chemical compounds in future drug development and an alternative remedy in humans. Full article