Combinatorial Chemistry & High Throughput Screening - Current Issue

Immune Checkpoint Inhibitors (ICIs) are becoming a new treatment approach for patients with unresectable hepatocellular carcinoma (uHCC). However, the results regarding its efficacy compared with the standard regimen of targeted therapy are not consistent.

Our aim was to conduct a meta-analysis of existing studies to reveal the differences in the efficacy and safety of the two systems of treatment.

The related studies were searched in PubMed, Web of Science, the Cochrane Library, and Embase from inception to June 30^th, 2022. Data on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and rate of treatment-related adverse events (TrAEs) with their 95% confidence intervals (CI) were pooled and analyzed by Stata 12.0 software.

A total of ten high-quality controlled clinical studies with 5,539 patients with uHCC were included. The hazard ratio (HR) of the OS and PFS were 0.80 (95% CI, 0.74-0.86) and 0.72 (95% CI, 0.58-0.89), respectively. In addition, the odds ratio (OR) of the ORR and DCR were 3.39 (95% CI, 2.75-4.17) and 1.20 (95% CI, 0.84-1.73), respectively. The ORR of ICIs monotherapy, ICIs plus anti-vascular endothelial growth factor (VEGF) and ICIs plus ICIs were 16% (95% CI, 0.13-0.18), 17% (95% CI, 0.10-0.27), and 20% (95% CI, 0.16-0.24), respectively. For all included studies, the OR of the overall TrAEs was 0.51(95% CI, 0.22-1.18), and grade ≥ 3 TrAEs was 0.78 (95% CI, 0.53-1.14).

ICIs were more effective than targeted drugs concerning survival periods and ORR in patients with uHCC while maintaining a stable safety profile.

Sevoflurane and propofol are the most commonly used anesthetics in surgery. In this study, we aim to explore and clarify the function of sevoflurane and propofol in colorectal cancer.

Cell counting kit-8, colony formation, western blot, and transwell assays were performed to determine cell proliferation, apoptosis, ferroptosis, invasion, and migration. We performed overexpression experiments to detect the underlying molecular mechanism of sevoflurane and propofol. The genes related to epithelial-mesenchymal transition were measured by western blot.

We discovered that sevoflurane and propofol co-treatment exerted more anti-tumor activities than just sevoflurane or propofol treatment in colorectal cancer cells in vitro. Mechanistically, our data showed that sevoflurane and propofol-induced apoptosis and ferroptosis and inhibited cell proliferation, invasion, and migration. Additionally, TM2D1 was considered a target of sevoflurane and propofol, and TM2D1 overexpression reversed the effect of sevoflurane and propofol on colorectal cancer cell biology behaviors.

Our results showed a novel anti-tumor mechanism of sevoflurane and propofol in colorectal cancer cells, and TM2D1 might be an underlying therapeutic target for treating colorectal cancer patients.

Acute pancreatitis (AP) is a common digestive tract disease, often accompanied by severe metabolic disorders, but there are no specific markers and treatment methods, and the potential metabolic pathways behind it remain to be explored.

Establish mild acute pancreatitis and severe acute pancreatitis models in rats and intervene with antioxidant NAC. Analyze serum oxidative stress indicators and pathological changes in pancreatic tissue. In addition, non-targeted metabolomics analysis of serum differential metabolites between groups was conducted based on the LC/MS system.

The pathological score of the model group rats increased, and the levels of oxidative stress factors ROS and MDA significantly increased, while the activity of the antioxidant enzyme SOD decreased. After NAC intervention, oxidative stress damage in rats was alleviated. Non-targeted metabolomics experiments suggest significant differences in serum metabolic profiles among different groups of rats.

Metabolomics results show that the obtained differential metabolites are expected to become serum biomarkers for AP.

QiShenYiQi (QSYQ) has shown promise in the treatment of blood-brain barrier (BBB) damage following stroke. However, the identification of its bioactive components and the underlying molecular mechanisms of action remain unknown. This study aimed to investigate the active ingredients and mechanisms involved in the inhibitory effects of QSYQ on BBB damage after ischemic stroke based on network pharmacology and experimental verification.

The chemical composition and target information of QSYQ were obtained from the Traditional Chinese Medicine Systems Pharmacology and Analysis Platform. BBB injury-related targets were identified by screening databases, and the overlapping targets with QSYQ were collected. Cytoscape software was utilized to construct protein-protein interaction (PPI) networks. Molecular docking analysis was conducted using AutoDock software. Animal experiments were carried out to verify the protective effect of QSYQ on BBB and explore potential molecular mechanisms.

A total of 131 active ingredients in QSYQ and 154 common targets related to QSYQ and BBB damage were identified. Analysis of the PPI network revealed key targets including ALB, INS, ACTB, TP53, and CASP3 against BBB injury. Molecular docking analysis indicated favorable binding interactions between dihydrotanshinlactone, tanshinone IIA, salviolone, and their respective target proteins, such as FOS, INS, CASP3, and JUN. In animal experiments, QSYQ demonstrated effective inhibition of BBB damage, and this effect may be attributed to the regulation of ALB, INS, TP53, and CASP3.

This study provides intriguing insights into the mechanisms by which QSYQ protects against BBB injury following ischemic stroke. Key targets, including ALB, INS, TP53, and CASP3, could be potentially involved in the beneficial effects of QSYQ.

Most COVID-19 survivors are troubled with chronic persistent symptoms, which have currently no definitive treatments. Bufei Huoxue (BFHX) capsule exerts clinical benefit, while the material basis and molecular mechanism remain unclear.

The study aimed to elucidate the protective mechanisms of BFHX capsule against COVID-19 convalescence.

UHPLC-HRMS and various databases were employed to explore potential compounds and targets. PPI, MCODE, transcription factor (TF), and miRNA analyses were conducted to receive hub targets and corresponding upstream regulators. Molecular docking was applied to verify the binding activity of compound and target. Further, GO, KEGG, WIKI, and Reactome analyses were performed, and compound-target-symptom and gene-disease networks were constructed.

A total of 127 compounds and 313 targets were acquired. A sum of 10 hub targets were screened and molecular docking results suggested that the top 3 compounds had good binding affinities with the top 3 target proteins. MLLT1, CBFB, and EZH2 were identified as key TFs, and hsa-mir-146a-5p, hsa-mir-26b-5p, and hsa-mir-24-3p were predicted to be important miRNAs. BFHX capsule may alleviate the symptoms by targeting TNF, IL-6, IFNG, and TGF-β1. Besides, BFHX capsule may exert a therapeutic effect on respiratory disease (especially pulmonary fibrosis and lung infection) and multi-system damage during COVID-19 convalescence by regulating cytokine-cytokine receptor interaction, as well as TGF-β, TNF, and Toll-like receptor signaling pathways.

In summary, BFHX capsule may exert a therapeutic effect on multi-system damages during COVID-19 convalescence through multiple compounds (such as albiflorin, isopsoralen, and neobavaisoflavone), multiple targets (such as TNF, IL-6, and EGF) and multiple pathways (TGF-β, TNF, and Toll-like receptor signaling pathways).

This study entailed the creation of a new variation of pyrroloimidazoles with exceptional efficacy through chemical synthesis. The synthesis was accomplished by tricomponent reactions utilizing ninhydrins, diamines, and activated acetylenic compounds in an aqueous setting, leading to significant yields. The antioxidant properties of recently synthesized Pyrroloimidazoles derivatives have been ascribed to the existence of NH and OH groups, which were evaluated using two techniques. The antimicrobial effectiveness of recently developed pyrroloimidazoles was evaluated using a disk diffusion technique against both Gram-negative and Gram-positive bacteria.

The study team utilized high-quality starting chemicals, solvents, and reagents with consistent chemical and physical properties. The Shimadzu IR-460 spectrometer was used in a KBr medium to get the Ft-IR spectra of the synthesized nanocatalyst. Furthermore, we employed a Bruker DRX-400 AVANCE spectrometer to acquire ¹H-NMR and ¹³C-NMR spectra of the synthesized compounds. The spectrometer utilized in this investigation functions at a frequency of 400 MHz. The solvent employed for the spectra of produced compounds was CDCl3, with TMS serving as the internal standard. The mass spectra of the produced compounds, which have an ionization potential of 70 eV, were obtained using the Finnigan MAT 8430 spectrometer. Elements of produced compounds were subjected to elemental analysis using the Heraeus CHN-O-Rapid analyzer.

This work investigated the three-component reaction involving ninhydrins 1, diamines 2, and electron-deficient acetylenic compounds 3 for the eco-friendly production of pyrroloimidazoles derivatives 4 in water-based solutions at normal temperature. The results indicated that these molecules displayed noteworthy efficacy, similar to that of conventional antioxidants. Also, the results indicated that the synthesized pyrroloimidazoles have bacteriostatic properties.

In summary, this study aimed to examine the environmentally friendly characteristics of ninhydrins, diamines, and electron-deficient acetylenic compounds when dissolved in water at normal room temperature. The research resulted in the successful production of new pyrroloimidazole derivatives with a high rate of success. This study conducted a more in-depth analysis of the antioxidant properties of the synthesized pyrroloimidazoles 4a-4d by the utilization of two techniques: DPPH radical scavenging and FRAP assays. The results indicated that these molecules displayed noteworthy efficacy, similar to that of conventional antioxidants. Furthermore, we utilized both Gram-positive and Gram-negative bacteria to showcase the antibacterial effectiveness of the synthesized pyrroloimidazoles by the disk diffusion technique. The results indicated that the synthesized pyrroloimidazoles have bacteriostatic properties. These reactions provide benefits, such as efficient utilization of atoms, generation of large quantities of products, and straightforwardness of the reaction.

Intervertebral disc degeneration (IVDD), a key contributor to degenerative spinal diseases such as cervical spondylosis, significantly influences the quality of life of patients. Tuina, historically employed in the clinical management of cervical spondylosis, has demonstrated positive therapeutic outcomes; however, the mechanism of Tuina remains unclear.

This study examined the efficacy of Tuina in correcting the imbalanced structure of the cervical spine and its impact on apoptotic chondrocytes within the cervical disc. The underlying mechanisms were explored using a rabbit model of IVDD induced by dynamic and static imbalances.

The IVDD rabbit model was established by restraining the head in a downward position for 12 weeks (Model group). In the Tuina1 group, treatment was performed on the posterior cervical trapezius muscle daily for 2 weeks, whereas in the Tuina2 group, treatment was performed on both the posterior cervical trapezius and anterior sternocleidomastoid muscles daily for 2 weeks. After treatment, X-ray, micro-computed tomography (CT), histological staining, qRT-PCR, and western blotting were used to evaluate the mechanism by which Tuina inhibits chondrocyte apoptosis.

The results demonstrated that Tuina treatment inhibited chondrocyte apoptosis in cervical discs by adjusting the neck structure balance, and a more significant therapeutic effect was observed in the Tuina2 group. Lateral cervical spine X-ray and CT scans in rabbits revealed notable improvements in cervical spine curvature and vertebral structure in the treatment groups compared with those in the Model group. Hematoxylin and eosin staining and TUNEL staining further confirmed the positive impact of Tuina treatment on intervertebral disc tissue morphology and chondrocyte apoptosis. Additionally, western blotting and immunohistochemical analysis showed that Tuina treatment suppressed chondrocyte apoptosis by downregulating Bax and caspase-3 while upregulating Bcl-2. Western blotting results further indicated that Tuina could activate the FAK/PI3K/Akt signaling pathway by mediating integrin-β1.

Tuina treatment inhibited chondrocyte apoptosis in cervical discs by activating the FAK/PI3K/Akt signaling pathway, providing convincing evidence to support Tuina treatment as a promising method for IVDD.

Sodium-dependent glucose transporter (SGLT2) inhibitors (SGLT2i) have been found to have anti-atherosclerotic effects in clinical treatment.

The aim of this study was to explore whether angiotensin II (Ang II) induces changes in the expression of Na+/H+ exchanger of cytoplasmic membrane channel proteins (NHE1) and SGLT2 in macrophages and whether dapagliflozin (DAPA), an SGLT2i, protects against Ang II induced macrophage senescence by inhibiting NHE1 activation to alleviate Atherosclerosis (AS).

After intervention with DAPA plus gavage or feeding them a high-fat diet, the mice's aortas were dissected, and oil red O staining was performed. Cell proliferation and toxicity detection, western blot, immunofluorescence, and β-galactosidase staining methods were adopted to detect cell activity, expressions of senescence-related genes, and number of senescent cells after different concentrations of Ang II or DAPA or plasmid NHE1 were treated with RAW264.7 cells.

(1) The formation of AS plaques in ApoE -/- mice showed a downward trend under DAPA. (2) After the intervention of Ang II, the cell activity of RAW264.7 decreased, and the expression of senescent cells and related genes increased. (3) Under the Ang II condition, the expression of SGLT2 and NHE1 increased, and SGLT2, NHE1, and senescence-related genes decreased with the addition of DAPA. (4) The expression of NHE1, senescent cells and related genes decreased in RAW264.7 cells after DAPA treatment with plasmid NHE1 intervention.

SGLT2i alleviates atherosclerosis by inhibiting NHE1 activation to protect against macrophage senescence induced by Ang II.

Many studies have documented the protective effects of regulating macrophage M1/M2 polarization in inflammatory diseases characterized by their imbalance state. In pathological diseases associated with inflammation, mesenchymal stem cells (MSCs) regulate macrophages, thereby having anti-inflammatory and tissue regenerative effects. Exosomes have been suggested as an alternative mechanism that underlies the paracrine function of MSCs. Thus, this study explored the anti-inflammatory impact of human umbilical cord MSCs-secreted exosomes (hucMSCs-EX) by influencing macrophage polarization in normal and inflammatory environments in vitro.

In this study, hucMSCs-conditioned medium (hucMSCs-CM) and hucMSCs-EX were used to treat RAW264.7 macrophages with or without LPS. The expressions of TNF-α, IL-10, IL-6, IL-1β, and Arg-1 were quantified by qPCR. The expressions of IL-6 and IL-10 were evaluated by ELISAs. Western blots (WB) were performed to observe the expressions of CD206, NF-κB P65, NF-κB p-p65, p-STAT3, STAT3, and NF-κB phosphorylation. The number of cells expressing CD206 and the fluorescence intensity were measured via flow cytometry (FC) and immunofluorescence staining. Cell propagation and migration were examined via MTT and transwell assays, respectively.

The inhibition of LPS-induced inflammatory polarization by hucMSCs-EX or hucMSCs-CM led to increases in IL-10 and arginase (Arg) levels and decreases in those of IL-6 and TNF-α. Moreover, hucMSCs-EX enhanced the CD206 expression in RAW264.7 cells and accelerated the propagation and migration of LPS-induced cells. The suppressive impact of hucMSCs-EX on the LPS-induced phenotypic polarization of M1 macrophages was linked with the reduction of NF-κB signaling. They stimulated the transition of M2 macrophages by enhancing the activity of STAT3 in RAW264.7 cells.

This study indicated that hucMSCs-EX enhances the macrophage transition into the M2 phenotype by inhibiting the NF-κB p65 axis and stimulating that of STAT3.

Epilepsy is a serious neurological disorder that affects millions of people each year, often leading to cognitive issues and reduced quality of life. Medication is the main treatment, but many patients experience negative side effects. Male Sprague-Dawley (SD) rats were chosen as experimental animals for this experiment due to their physiological and genetic similarities to humans, cost-effectiveness, and ease of handling in a laboratory setting.

The objective of this study was to assess the neuroprotective properties of baicalin (BA) in relation to its impact on anxiety and depressive-like behaviors in the epilepsy model.

Thirty male Sprague-Dawley (SD) rats were selected for this experiment. Pentylenetetrazol (PTZ) kindling (40 mg/kg; i.p.) was utilized to establish an epilepsy model. The effect of BA (50 mg/kg; gavage) on seizure severity (assessed using the Racine scale), anxiety, and depressive-like behaviors (evaluated through open field experiments and forced swimming tests) was examined. Histological examinations, including hematoxylin and eosin (HE) staining and Nissl staining, were conducted to assess neuronal damage. Furthermore, the neuroprotective properties of BA were examined through the analysis of Doublecortin (DCX), MKI67 (KI67), and Brain-Derived Neurotrophic Factor (BDNF) levels in the hippocampus of rats. The inhibitory impact of BA on neuroinflammation was assessed via dual labeling for NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and the microglial marker ionized calcium-binding adapter molecule 1 (Iba-1). The influence of BA on the expression of P2X7 receptor (P2X7R), NLRP3, and Interleukin-1β (IL-1β) was also assessed by reverse transcription quantitative PCR (RT-qPCR) in the brain. Finally, we employed a molecular docking model to assess the extent of receptor-ligand binding.

Epilepsy models exhibited significant anxiety and depressive-like behaviors, and BA significantly reduced the severity of seizures in these rats while also alleviating their anxiety and depressive-like behaviors. Moreover, neuronal loss and damage were observed in the hippocampus of epileptic rats, but BA was able to effectively counteract this issue by enhancing BDNF expression and promoting neurogenesis within the hippocampus, especially in the DG region. The co-localization of Iba-1 with NLRP3 indicated the activation of NLRP3 inflammasome in microglia. Subsequent RT-PCR revealed that BA may alleviate anxiety and depressive-like behaviors in epileptic rats by activating the P2RX7/NLRP3/ IL-1β signaling pathway. The final molecular docking results indicated that BA had a good binding affinity with proteins, such as P2RX7, NLRP3, and IL-1β.

This study confirmed the effectiveness of BA in improving anxiety and depressive-like behaviors associated with epilepsy. Moreover, it provides theoretical support for the neuroprotective role demonstrated by BA.