Current Pharmaceutical Design - Online First

Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC), but its clinical efficacy is often compromised by the acquisition of drug resistance. Various cancers, including HCC, are affected by long non-coding RNA (lncRNA), but the mechanisms underlying HCC sorafenib resistance have not been extensively studied. This article aims to summarize the recently reported pathways associated with sorafenib resistance and discusses potential applications for the treatment of HCC.

Relevant studies on the resistance of HCC to anti-tumor drugs were retrieved from PubMed. Given the compelling evidence that sorafenib is an effective treatment for advanced HCC, we analyzed the research papers on lncRNA and sorafenib resistance in HCC in the PubMed system in the past decade and found that lncRNA may be involved in sorafenib resistance in HCC through multiple pathways.

lncRNA is widely involved in the resistance mechanism of HCC to sorafenib. Recent studies have revealed that numerous lncRNAs, such as NEAT1, affect the sensitivity of HCC to sorafenib through various mechanisms, including autophagy and AKT signaling pathways.

lncRNAs play a pivotal role in modulating HCC resistance to sorafenib. And lncRNA is expected to become a new solution to the resistance of sorafenib and other targeted drugs.

Bear bile powder (BBP) has been traditionally used in Chinese medicine for calming the liver, pacifying the mind, and relieving convulsions, as recorded in Ben Jing Feng Yuan and Yu Qiu Yao Jie. Although the antidepressant effects of BBP have been previously reported, the underlying neurological mechanisms have yet to be fully elucidated. This study aimed to investigate the antidepressant effects of BBP on corticosterone (CORT)-induced depression-like behaviors in female mice and to explore the involvement of the BDNF/TrkB/CREB signaling pathway.

Female mice received subcutaneous CORT injections to induce depression-like behaviors, followed by oral administration of BBP at doses of 50, 100, and 200 mg/kg. Behavioral assessments, biochemical analyses, UPLC-MS/MS, immunohistochemistry, and Western blotting were conducted to evaluate antidepressant effects. Additionally, a CORT-induced HT22 cell injury model was established to assess the neuroprotective mechanisms of BBP, with or without the TrkB antagonist K252a, focusing on the BDNF/TrkB/CREB pathway.

BBP significantly alleviated depression-like behaviors in CORT-treated female mice. It restored neurotransmitter levels, reduced neuronal necrosis in the hippocampal CA3 region, increased DCX-positive cells in the dentate gyrus, and activated hippocampal BDNF/TrkB/CREB signaling. In vitro, BBP attenuated CORT-induced apoptosis and promoted proliferation in HT22 cells. Applying K252a confirmed that BBP’s neuroprotective and antidepressant effects were mediated via the BDNF/TrkB/CREB pathway.

These findings suggest that BBP exerts notable antidepressant and neuroprotective effects in female depression models by modulating neurotransmitters and enhancing neurogenesis through the BDNF/TrkB/CREB pathway. Using both in vivo and in vitro models strengthens the evidence for BBP’s mechanism of action. However, further studies involving additional brain regions and upstream regulatory mechanisms are warranted.

BBP effectively alleviates CORT-induced depressive-like behaviors in female mice by restoring neurotransmitter balance, protecting hippocampal neurons, and promoting neurogenesis via the BDNF/TrkB/CREB pathway. These results provide a theoretical basis for the potential application of BBP in managing female depression.

The autoimmune inflammatory disease known as rheumatoid arthritis (RA) has a complicated and poorly understood etiology. Fibroblast-like synoviocytes (FLSs) have tumor-like characteristics in RA, including aggressive growth and heightened activation that leads to the release of pro-inflammatory factors. These processes are essential for the gradual deterioration of joint tissues. Kaempferol, with the chemical formula 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one, is found in many different types of plants and plant families. The pharmacological effects of this substance have been well-documented. The benefits of this substance encompass protection for the heart and brain, as well as fighting inflammation, bacteria, cancer, osteoporosis, and allergies. It also has properties that can help with anxiety, pain relief, and hormonal balance. However, its precise function in the management of RA is still unclear.

To investigate the effect of kaempferol on apoptosis in RA FLSs and elucidate the underlying mechanisms.

We used the CCK-8 assay to assess the effects of different kaempferol concentrations on RA FLSs. We also used flow cytometry with Annexin V-FITC/PI staining to analyse cell cycle distribution and quantify apoptotic cells. To verify apoptosis, the TUNEL test was employed. Important proteins associated with apoptosis were verified to be expressed using western blotting. Finally, network pharmacology analysis was used to identify potential kaempferol targets, and their interactions with AKT1, PIK3R1, and HSP90AA1 proteins were studied using molecular docking and molecular dynamics simulations.

Kaempferol treatment significantly increased apoptosis in RA FLSs, up-regulating the pro-apoptotic protein Bax and down-regulating the anti-apoptotic protein Bcl-2. Specifically, kaempferol at 100 and 200 μM increased the apoptosis index to 29.77 ± 6.02% and 55.63 ± 11.05%, respectively, compared to the control. The induction of caspase-9 and caspase-3 cleavage was observed, indicating the activation of the mitochondrial pathway. Kaempferol also inhibited the phosphorylation of PI3K and Akt, with a significant reduction in their activation. Molecular docking studies demonstrated that kaempferol interacted with AKT1, PIK3R1, and HSP90AA1 proteins, with binding energies of -6.51, -4.26, and -6.51 kcal/mol, respectively, suggesting a strong affinity and potential direct impact on these proteins.

Kaempferol induces apoptosis in RA FLSs by inhibiting phosphorylation of the PI3K/Akt signaling pathway, increasing levels of pro-apoptotic proteins, and decreasing levels of anti-apoptotic proteins. Thus, kaempferol, a naturally occurring flavonoid, has great promise in the management of RA.

This research explored the antimicrobial, antifungal, and in vivo anticandidal activities of two herbal extracts: Ocimum basilicum (HEOB) and Ocimum sanctum (HEOS). Additionally, the study analyzed the phytochemical components of these extracts.

To examine the efficacy of HEOB and HEOS extracts in terms of their antimicrobial, antifungal, and anti-candidal activities and analyze their phytochemical composition, antioxidant potential, and immunomodulatory properties in vivo.

Dried flowers and leaves from Ocimum basilicum and Ocimum sanctum were extracted using a cold maceration process with a 1:1 ethanol-water solution. Phytochemical analysis followed established protocols, and the total phenolic and flavonoid contents were measured using colourimetric methods. HPLC was used to determine the concentrations of specific compounds, including rosmarinic acid, rutin, eugenol, and quercetin. Antioxidant activity, specifically nitric oxide (NO) scavenging and antimicrobial properties, was assessed in vitro using the cup plate method. In vivo studies were conducted on immunocompromised mice with systemic candidiasis, treated with plant extracts at 200 and 400 mg/kg or with ketoconazole as a control. Survival rates, tissue histology, and leukocyte counts were evaluated, and statistical analysis was performed using ANOVA.

HEOB and HEOS extracts possess strong antimicrobial and antioxidant activities, largely due to flavonoids such as rutin, quercetin, rosmarinic acid and eugenol. In vivo experiments revealed that both extracts effectively reduced fungal load, increased survival rates, and alleviated immunosuppression in mice with systemic candidiasis. The extracts also exhibited significant immunomodulatory properties by boosting cell-mediated immune responses. At higher concentrations, the antifungal performance of HEOB and HEOS was similar to that of ketoconazole.

HEOB and HEOS exhibited strong antibacterial, antifungal, and anticandidal properties, showing significant effectiveness in treating systemic candidiasis. Their immunomodulatory effects and ability to boost cell-mediated immunity make these extracts promising options for addressing systemic candidiasis, particularly in individuals with weakened immune systems. This research offers valuable insights and sets the stage for future investigations into the treatment of oral and vaginal candidiasis.