Glioblastoma is the most aggressive malignant brain tumor characterized by rapid development, poor prognosis and high mortality. The purpose of this in vitro study was to assess cytotoxic and anti-proliferative effects of arvanil, olvanil and LY2183240 (three cannabinoid receptor ligands), when used alone and in combination with cisplatin and temozolomide in various neuroblastoma (CHP-134 and KELLY) and glioblastoma (U87MG, C6, and T98G) cell lines in the MTT assay. Results indicate that arvanil, olvanil and LY2183240 considerably affected the viability of neuroblastoma and glioblastoma cell lines with selectivity index values ranging from 0.50 to 17.48 for arvanil; from 0.93 to 24.06 for olvanil; and from 1.68 to 14.52 for LY2183240. With isobolographic analysis we found that the combination of LY2183240 with cisplatin produced three different types of interactions: a synergy in CHP-134; an antagonism in T98G; and additivity in KELLY, C6 and U87MG cell lines in the MTT assay. The combinations of arvanil and olvanil with cisplatin exerted additive interaction in all the tested cell lines in the MTT assay. Similarly, the combinations of temozolomide with arvanil, olvanil and LY 2183240 produced the additive interaction in all the tested glioblastoma and neuroblastoma cell lines. In conclusion, the combinations of temozolomide with the three cannabinoids, due to their additive interactions, can be considered as a promising therapeutic direction in glioblastoma. Favorable combinations of cisplatin with arvanil, olvanil and LY2183240 can also be recommended, except for a combination of cisplatin with LY2183240 in glioblastoma T98G cell line in the MTT assay.

Extreme heat and traffic-related air pollution (TRAP) have been linked to worsening chronic health disorders, however, their combined effects on diabetic nephropathy (DN) are little understood. Type II diabetic mice were exposed to heat (40 °C) and NO2 (5 ppm) separately for 4 h per day over 6 weeks to investigate the synergistic effects on the progression of DN. We found that exposure to high temperature and NO2 elevated blood glucose levels and exacerbated histopathological changes. Additionally, there were increased oxidation indicators (ROS, MDA, 8-OHdG) and decreased antioxidant indicators (CAT, SOD, GSH-PX), along with elevated inflammation markers (TNF-α, IL-1β, IL-6). The expressions of transient receptor potential (TRP) ion channels (TRPV1, TRPV4, TRPA1, TRPM2) were also upregulated. Our findings suggest that simultaneous exposure to high temperature and NO2 impairs metabolic and autophagy pathways. Exposure to both high temperature and NO2 produces a synergistic effect, leading to more severe damage than exposure to either factor individually. This resulted in increased expression of APOA1, P62, and p-mTOR/mTOR while decreasing the expression of p-AMPKα/AMPKα and LC3-II/I. This disruption promoted the progression of DN. In contrast, capsazepine (CZP) reduced TRP expression, inflammatory markers, oxidative stress, metabolic and autophagy disorders, thereby mitigating renal damage and alleviating the progression of diabetic nephropathy. Our study provides some potential strategies for early prevention and effective reduction of DN.

Mitochondria represent a fundamental structure for cellular homeostasis, controlling multiple conditions regarding energetic functions and cellular survival. To maintain these organelles functioning in ideal conditions, their membranes count with ion channels for different inorganic ions, which must be balanced to offer the proper function for both the organelle and the cell. However, studies have shown that other health conditions impair the activities of mitochondrial ion channels, including cancer. In this sense, the altered activities of potassium, calcium, and calcium-activated potassium channels are mainly linked with cancer development and cellular homeostasis alteration, demonstrating their role as pharmacological targets. With that in mind, scientists have found significant mitochondrial and cellular responses related to apoptosis and reduction of cellular survival from cells with modulated ion channels, indicating the potential of this possible therapy in carcinogenic contexts. Nonetheless, few studies still evaluate mitochondrial ion channel modulation as a treatment against cancer. Hence, more research must be conducted on this subject.

Cannabinoids have attracted increasing attention in cancer research in recent decades. A major focus of current preclinical and clinical studies is on the interactions and potential risks when combined with chemotherapeutic agents, targeted therapies and other anticancer strategies. Given the extensive preclinical data on additive, synergistic and, in some cases, antagonistic tumor cell killing effects of chemotherapeutic agents and cannabinoids when co-administered, a critical analysis of these data seems essential. The available data mainly relate to combination treatments for glioblastoma, hematological malignancies and breast cancer, but also for other cancer types. Such an analysis also appears necessary because cannabinoids are used as an option to treat nausea and vomiting caused by chemotherapy, as well as tumor-related pain, and cancer patients sometimes take cannabinoids without a medical prescription. In addition, numerous recent preclinical studies also suggest cannabinoid-mediated relief of other chemotherapy-related side effects such as peripheral neuropathy, nephrotoxicity, cardiotoxicity, cystitis, bladder complications and mucositis. To summarize, the data available to date raise the prospect that cannabinoids may increase the efficacy of chemotherapeutic agents while reducing their side effects. However, preclinical studies on anticancer interactions are mostly limited to cytotoxicity analyses. An equally thorough investigation of the effects of such combinations on the immune system and on the tumorigenic levels of angiogenesis, invasion and metastasis is still pending. On this basis, a comprehensive understanding for the evaluation of a targeted additional treatment of various cancers with cannabinoids could be established.

Glioblastoma (GBM) is an aggressive primary brain tumor with high lethality. The typical treatment regimen includes post-surgical radiotherapy and temozolomide (TMZ) chemotherapy, which helps extend survival. Nevertheless, TMZ resistance occurs in approximately 50% of patients. This resistance is primarily associated with the expression of O6-methylguanine-DNA methyltransferase (MGMT), which repairs O6-methylguanine lesions generated by TMZ and is thought to be the major mechanism of drug resistance. Additionally, the mismatch repair and base excision repair pathways play crucial roles in TMZ resistance. Emerging studies also point to drug transport mechanisms, glioma stem cells, and the heterogeneous tumor microenvironment as additional influences on TMZ resistance in gliomas. A better understanding of these mechanisms is vital for developing new treatments to improve TMZ effectiveness, such as DNA repair inhibitors, inhibitors of multidrug transporting proteins, TMZ analogs, and combination therapies targeting multiple pathways. This article discusses the main resistance mechanisms and potential strategies to counteract resistance in GBM patients, aiming to broaden the understanding of these mechanisms for future research and to explore the therapeutic effects of traditional Chinese medicines and their active components in overcoming TMZ resistance.

Mitochondria are a focus of biomedical research because of their role in apoptosis and diabetic retinopathy (DR) initiation and progression. However, the detailed mechanisms underlying mitochondrial disorders and endothelial dysfunction during DR remain elusive. We identified PDZ domain containing 1 (PDZK1) as a key factor linking endothelial mitochondrial dysfunction and cell apoptosis during DR progression. PDZK1 was downregulated by high concentrations of glucose in human retinal capillary endothelial cells (HRCECs) and decreased in serum from patients with DR. PDZK1 knockout induced endothelial cell apoptosis and an irregular and disordered arrangement of retinal cells, aggravating DR. Moreover, PDZK1 loss impaired endothelial mitochondrial function with accumulated damaged mitochondria, decreased mitochondrial DNA (mtDNA) content, and increased reactive oxygen species (ROS) production. Mechanistically, mRNA sequencing showed that PDZK1 deficiency in endothelial cells interfered with mitochondrial function by increasing ATF4 (Activating Transcription Factor 4) expression. Further studies showed that PDZK1 was inhibited by miR-145-5p. The expression of miR-145-5p was significantly upregulated in the serum of patients with DR and HRCECs with high glucose concentration, leading to endothelial dysfunction and DR progression. Our results suggested that PDZK1 deficiency is crucial in mediating retinal endothelial cell apoptosis and is associated with mitochondrial dysfunction. PDZK1 overexpression by upstream miRNA, or its downstream molecule, ATF4, may represent novel therapeutic approaches for DR treatment.

Glioma, the most prevalent primary tumor of the central nervous system (CNS), is also the most lethal primary malignant tumor. Currently, there are limited chemotherapeutics available for glioma treatment, necessitating further research to identify and develop new chemotherapeutic agents. A significant approach to discovering anti-glioma drugs involves isolating antitumor active ingredients from natural products (NPs) and optimizing their structures. Additionally, targeted drug delivery systems (TDDSs) are employed to enhance drug solubility and stability and overcome the blood-brain barrier (BBB). TDDSs can penetrate deep into the brain, increase drug concentration and retention time in the CNS, and improve the targeting efficiency of NPs, thereby reducing adverse effects and enhancing anti-glioma efficacy. This paper reviews the research progress of anti-glioma activities of NPs, including alkaloids, polyphenols, flavonoids, terpenoids, saponins, quinones, and their synthetic derivatives over the past decade. The review also summarizes anti-glioma mechanisms, such as suppression of related protein expression, regulation of reactive oxygen species (ROS) levels, control of apoptosis signaling pathways, reduction of matrix metalloproteinases (MMPs) expression, blocking of vascular endothelial growth factor (VEGF), and reversal of immunosuppression. Furthermore, the functions and advantages of NP-based TDDSs in anti-glioma therapy are examined. The key information presented in this review will be valuable for the research and development of NP-based anti-glioma drugs and related TDDSs.

Cannabidiol (CBD) holds promise for managing metabolic diseases, yet enhancing its oral bioavailability and efficacy remains challenging. To address this, we developed polymeric nanoparticles (NPs), using poly(lactic-co-glycolic acid) (PLGA), encapsulating CBD using nanoprecipitation, aiming to create an effective CBD-nanoformulation for metabolic disorder treatment. These NPs (135-265 nm) demonstrated high encapsulation efficiency (EE% ≈ 100%) and sustained release kinetics. Their therapeutic potential was evaluated in an in vitro metabolic syndrome model employing sodium palmitate-induced HepG2 cells. Key assessment parameters included cell viability (MTT assay), glucose uptake, lipid accumulation (Oil Red O staining), triglycerides, cholesterol, HDL-c levels, and gene expression of metabolic regulators. Results showed an IC50 of 9.85 μg/mL for free CBD and 11.26 μg/mL for CBD-loaded NPs. CBD-loaded NPs significantly enhanced glucose uptake, reduced lipid content, lowered triglycerides and total cholesterol, and increased HDL-c levels compared to free CBD. Gene analysis indicated reduced gluconeogenesis via downregulation of PPARγ, FOXO-1, PEPCK, and G6Pase and enhanced fatty acid oxidation through CPT-1 upregulation. These findings suggest that CBD-loaded NPs may serve as a novel therapeutic strategy for the management of metabolic disorders, warranting further in vivo studies.

Mitochondrial dysfunction has emerged as a critical factor in the progression and prognosis of low-grade glioma (LGG). In this study, we explored the role of mitochondrial-related genes through consensus clustering analysis using multi-omics data from the TCGA, CGGA, and other independent datasets. Patients were categorized into three clusters (Cluster A, B, and C), with Cluster B consistently associated with poorer prognosis. Mutation landscape analysis revealed distinct genetic alterations and copy number variations among clusters, particularly in Cluster B, which exhibited unique genetic signatures. Immune infiltration analysis showed that Cluster B had higher expression levels of immune checkpoint genes, stronger immune evasion activity, and greater immune cell infiltration, suggesting an immunosuppressive tumor microenvironment. Furthermore, we identified mitochondrial-related prognostic markers and developed a MITscore based on gene expression patterns, which stratified patients into high- and low-risk groups. High MITscore groups displayed stronger stemness characteristics, poorer survival outcomes, and differential responses to chemotherapy and immunotherapy. Cross-validation with drug sensitivity and immunotherapy cohorts indicated that high MITscore patients were more sensitive to certain chemotherapeutic agents and responded better to immunotherapy. Finally, using the SRGA method, we identified novel biomarkers (KDR, LRRK2, SQSTM1) closely associated with mitochondrial function, which may serve as potential targets for therapeutic intervention. These findings highlight the critical role of mitochondrial dysfunction in LGG prognosis, tumor microenvironment regulation, and treatment response, providing new avenues for precision oncology.

Cannabinoids play significant roles in the central nervous system (CNS), but cannabinoid-mediated physiopathological functions are not elaborated. Cannabinoid receptors (CBRs) mediate functions that include the regulation of neuroinflammation, oxidative stress, apoptosis, autophagy, and neurogenesis. Microglia are the primary immune cells responsible for mediating neuroinflammation in the CNS. Therefore, this article primarily focuses on microglia to summarize the inflammatory pathways mediated by cannabinoids in the CNS, including nuclear factor-κB (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinase (MAPK), protein kinase B (Akt), and cAMP-dependent protein kinase (PKA) signaling pathways. Additionally, we provide a table summarizing the role of cannabinoids in various brain diseases. Medical use of cannabinoids has protective effects in preventing and treating brain diseases; however, excessive and repeated use can be detrimental to the CNS. We propose that cannabinoids hold significant potential for preventing and treating brain diseases, including ferroptosis, lactate metabolism, and mitophagy, providing new insights for further research on cannabinoids.

A predictive model for long-term survival is needed, and mitochondrial dysfunction is a key feature of cancer metabolism, though its link to glioma is not well understood. The aim of this study was to identify the molecular characteristics associated with glioma prognosis and explore its potential function. We analyzed RNA-seq data from The Cancer Genome Atlas and identified differentially expressed mitochondrial long noncoding RNAs (lncRNAs) using R's 'limma' package. A prognostic model was developed using 10 selected lncRNAs and validated with Cox regression and least absolute shrinkage and selection operator algorithm. The model's efficacy was assessed using Kaplan-Meier and receiver operating characteristic curve analyses, and its correlation with immune cell profiles and drug sensitivity was explored. A 10-mitochondria-related LncRNA signature was generated. The median risk score values are used to classify glioma samples into low-risk and high-risk groups. In breast patients, the signature-based risk score demonstrated a more potent ability to predict survival than conventional clinicopathological features. Furthermore, we noted a substantial disparity in the number of immune cells, including B cells, CD8 + T cells, and macrophages, between the two groups. In addition, the high-risk group exhibited lower half-maximal inhibitory concentration values for specific chemotherapy medications, including bortezomib, luminespib, rapamycin, and 5-fluorouracil. Our study elucidates the diagnostic and prognostic value of mitochondria-related-lncRNAs in the promotion, suppression, and treatment of glioma.

Glioma is a refractory malignant tumor with a powerful capacity for invasiveness and a poor prognosis. This study aims to investigate the role and mechanism of tubulin beta class IVA (TUBB4A) in glioma progression. The differential expression of TUBB4A in humans was obtained from databases and analyzed. Glioma cells U251-MG and U87-MG were intervened by pcDNA3.1(+) and TUBB4A overexpression plasmid. MTT, CCK8, LDH, wound healing, transwell, and western blotting were used to explore whether TUBB4A participates in the development of glioma. Reactive oxygen species (ROS) were detected by the DCFH-DA probe. Mitochondrial membrane potential (MMP) was examined by JC-1. It was found that TUBB4A expression level correlated with tumor grade, IDH1 status, 1p/19q status, and poor survival in glioma patients. In addition, TUBB4A overexpression inhibited the proliferation, migration, and invasion of U251-MG and U87-MG, while increasing the degree of apoptosis. Notably, TUBB4A overexpression promotes ROS generation and MMP depolarization, and induces mitophagy through the PINK1/Parkin pathway. Interestingly, mitochondria-targeted ROS scavenger reversed the effect of TUBB4A overexpression on PINK1/Parkin expression and mitophagy, whereas mitophagy inhibitor did not affect ROS production. And the effect of TUBB4A overexpression on mitophagy and glioma progression was consistent with that of PINK1/Parkin agonist. In conclusion, TUBB4A is a molecular marker for predicting the prognosis of glioma patients and an effective target for inhibiting glioma progression by regulating ROS-PINK1/Parkin-mitophagy pathway.

Reactive astrocytes play a critical role in the initiation and progression of epilepsy, but their molecular subtypes and functional characterization are not fully understood. In this study, we report the existence of neurotoxic reactive astrocytes, a recently identified subtype, that contribute to neuronal death in the epileptic brain. In a kainic acid (KA)-induced mouse model of epilepsy, we show that neurotoxic reactive astrocytes are induced by microglia-secreted cytokines, including IL-1α, TNFα, and C1q, and are detectable as early as 7 days post-KA stimulation. These cells exhibit a distinct molecular signature marked by elevated expression of complement 3 and adenosine 2A receptor. Transcriptomics and metabolomics analyses of human brain tissues from temporal lobe epilepsy (TLE) patients and an epileptic mouse model reveal that neurotoxic reactive astrocytes induce neuronal damage through lipid-related mechanisms. Moreover, our results demonstrate that the anti-seizure medication cannabidiol (CBD) and an adenosine 2A receptor antagonist can both suppress the formation of neurotoxic reactive astrocytes, mitigate gliosis, and reduce neuronal loss in a mouse model of epilepsy. Electrophysiological and behavioral studies indicate that cannabidiol attenuates seizure symptoms and enhances memory capabilities in epileptic mice. Our findings suggest that neurotoxic reactive astrocytes are formed at an early stage in both the KA-induced mouse model of epilepsy and TLE patients and can contribute to neuronal loss through releasing toxic lipids. Importantly, cannabidiol emerges as a promising therapeutic drug for targeted intervention against neurotoxic reactive astrocytes in adult epilepsy.

The endoplasmic reticulum (ER) is crucial in the development of numerous age-related bone disorders. Notably, ER stress can precipitate bone loss by orchestrating inflammatory responses, apoptosis, and autophagy through the activation of the p38 MAPK pathway. Age-related bone loss diseases pose a significant burden on society and healthcare as the global population ages. This review provides a comprehensive analysis of recent research advancements, delving into the critical role of ER stress-activated p38 MAPK in inflammation, apoptosis, and autophagy, as well as its impact on bone formation and bone resorption. This review elucidates the molecular mechanisms underlying the involvement of ER stress-activated p38 MAPK in osteoporosis, rheumatoid arthritis, periodontitis, and osteoarthritis and discusses the therapeutic potential of targeting p38 MAPK. Furthermore, this review provides a scientific foundation for new therapeutic strategies by highlighting prospective research directions.

Local brain tissue can suffer from ischaemia/reperfusion (I/R) injury, which lead to vascular endothelial damage. The peptide δ opioid receptor (δOR) agonist [D-ala2, D-leu5]-Enkephalin (DADLE) can reduce apoptosis caused by acute I/R injury in brain microvascular endothelial cells (BMECs).

This study aims to explore the mechanism by which DADLE enhances the level of mitophagy in BMECs by upregulating the expression of transient receptor potential vanilloid subtype 4 (TRPV4).

BMECs were extracted and made to undergo oxygen-glucose deprivation/reoxygenation (OGD/R) accompanied by DADLE. RNA-seq analysis revealed that DADLE induced increased TRPV4 expression. The CCK-8 method was used to assess the cellular viability; quantitative PCR (qPCR) was used to determine the mRNA expression of Drp1; western blot was used to determine the expression of TRPV4 and autophagy-related proteins; and calcium imaging was used to detect the calcium influx. Autophagosomes in in the cells' mitochondria were observed by using transmission electron microscopy. ELISA was used to measure ATP content, and a JC-1 fluorescent probe was used to detect mitochondrial membrane potential.

When compared with the OGD/R group, OGD/R+DADLE group showed significantly enhanced cellular viability; increased expression of TRPV4, Beclin-1, LC3-II/I, PINK1 and Parkin; decreased p62 expression; a marked rise in calcium influx; further increases in mitophagy, an increase in ATP synthesis and an elevation of mitochondrial membrane potential. These protective effects of DADLE can be blocked by a TRPV4 inhibitor HC067047 or RNAi of TRPV4.

DADLE can promote mitophagy in BMECs through TRPV4, improving mitochondrial function and relieving I/R injury.

Glioblastoma is the most aggressive brain cancer in humans with very poor prognosis and high mortality rate. Despite advances in treatment, glioblastoma almost always recurs and new therapeutic methods are urgently needed. This study aimed at assessing the cytotoxic and antiproliferative effects of AM 1172 and cannabidiol (two cannabinoid receptor ligands) in vitro, when used alone and in combination with cisplatin (a standard cytotoxic drug), in various human neuroblastoma (CHP-134, KELLY), human glioblastoma (U-87MG and T98G) and rat glioblastoma (C6) cell lines. Our experiments showed that AM 1172 and cannabidiol inhibited cell proliferation with IC50 values in the range of 2.29-17.21 μM (for AM 1172) and 11.61-20.35 μM (for cannabidiol), respectively. The selectivity index for AM 1172 ranged from 0.61 to 4.60 and that for cannabidiol ranged from 1.45 to 2.55 in the studied glioblastoma and neuroblastoma cell lines. With isobolographic analysis, it was found that AM 1172 combined with cisplatin exerted a synergistic interaction in the CHP-134 cell line (p < 0.01). In contrast, AM 1172 when combined with cisplatin produced an antagonistic interaction in the C6 cell line (p < 0.01). The remaining combinations of AM 1172 with cisplatin in the U-87MG, KELLY and T98G cell lines were additive. In case of cannabidiol, its combination with cisplatin produced an antagonistic interaction in the T98G cell line (p < 0.0001), whereas the combinations of cannabidiol with cisplatin in the CHP-134, U-87MG, KELLY, and C6 cell lines were additive in nature. The synergistic and additive interactions for the combination of AM 1172 and cannabidiol with cisplatin seem to be a promising direction in glioblastoma therapy. Unfortunately, the combinations producing antagonistic interactions (AM 1172+cisplatin in C6, and cannabidiol + cisplatin in T98G cell lines) should be avoided due to the antagonistic antiproliferative effect of two-drug mixtures.

Background/Objectives: Cannabidiol (CBD) is known for its anti-cancer properties in preclinical models and is increasingly used alongside conventional chemotherapy in cancer treatment. This study aims to evaluate the anti-cancer activity of CBD from Lebanese Cannabis sativa as a monotherapy and in combination with cisplatin or paclitaxel on human ovarian adenocarcinoma cells. Methods: Cytotoxicity of CBD was tested on OVCAR-3 and SK-OV-3 cell lines using the MTS assay. The Chou-Talalay method and CompuSyn software were used to determine the combination indices (CIs) for predicting interactions between CBD and chemotherapeutic agents. CBD showed dose-dependent tumor growth inhibition at 72 h with comparable IC50 values for both cell lines. Results: The combination of CBD with cisplatin or paclitaxel showed significant antagonistic interaction in SK-OV-3 cells (CI > 1), but mild synergism (CI < 1) at high growth inhibition rates (95% and 97%) was observed in SK-OV-3 cells with CBD/cisplatin. Pure antagonism was found in OVCAR-3 cells with CBD/cisplatin. Priming SK-OV-3 cells with CBD reduced the IC50 values of both drugs significantly, with a similar effect seen when cells were primed with cisplatin or paclitaxel before CBD treatment. Conclusions: Integrating CBD with chemotherapy could improve cancer therapy and address drug resistance. Sequential administration of CBD and chemotherapeutic agents is more beneficial than simultaneous administration. Further in vivo studies are necessary to validate these findings and understand CBD's interactions with other drugs fully.

Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor within the ErbB family that plays a pivotal role in the progression of various aggressive cancers. HER2-positive tumors often develop resistance to standard therapies, necessitating the exploration of innovative treatment options. Cannabinoids, bioactive compounds from Cannabis sativa such as cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN), have gained attention for their potential anticancer properties. This study evaluates the efficacy of CBD, CBG, and CBN in targeting HER2-positive ovarian cancer through kinase inhibition assays, surface plasmon resonance (SPR), molecular docking, and cell viability assessments. SPR analysis revealed that cannabinoids bind strongly to HER2-tyrosine kinase (HER2-TK), with CBD showing the highest affinity (K D = 6.16 μM), significantly better than afatinib (K D = 26.30 μM), and CBG demonstrating moderate affinity (K D = 17.07 μM). In kinase inhibition assays, CBG was the most potent inhibitor (IC50 = 24.7 nM), followed by CBD (IC50 = 38 nM), suggesting their ability to disrupt HER2-mediated signaling pathways. Molecular docking studies highlighted critical interactions between cannabinoids and essential HER2 residues (Leu796, Thr862, Asp863). In cell viability assays, CBD and CBG effectively inhibited the growth of HER2-positive SKOV3 cells (IC50 = 13.8 μM and 16.6 μM, respectively), comparable to traditional tyrosine kinase inhibitors. These findings underscore the therapeutic potential of cannabinoids, particularly CBD and CBG, as alternative or adjunct therapies for HER2-positive cancers, with the promise of mitigating resistance and adverse effects associated with existing treatments.

Commonly known as marijuana or hemp, Cannabis sativa L. (Cannabaceae), contains numerous active compounds, particularly cannabinoids, which have been extensively studied for their biological activities. Among these, cannabidiol (CBD) stands out for its therapeutic potential, especially given its non-psychotropic effects. This review evaluates the antitumor properties of CBD, highlighting its various mechanisms of action, including the induction of apoptosis, autophagy, and necrosis. By synthesizing findings from in vitro studies on the cell death mechanisms and signaling pathways activated by CBD in various human tumor cell lines, this literature review emphasizes the therapeutic promise of this natural antineoplastic agent. We conducted a comprehensive search of articles in PubMed, Scopus, Springer, Medline, Lilacs, and Scielo databases from 1984 to February 2022. Of the forty-three articles included, the majority (68.18%) reported that CBD activates apoptosis, while 18.18% observed simultaneous apoptosis and autophagy, 9.09% focused on autophagy alone, and 4.54% indicated necrosis. The antitumor effects of CBD appear to be mediated by transient receptor potential cation channels (TRPVs) in endometrial cancer, glioma, bladder cancer, and myeloma, with TRPV1, TRPV2, and TRPV4 playing key roles in activating apoptosis. This knowledge paves the way for innovative therapeutic strategies that may enhance cancer treatment outcomes while minimizing the toxicity and side effects associated with conventional therapies.

Metal-based drugs have been used in the clinical treatment of tumors for over 30 years. However, no metal-based drugs have been clinically approved to treat glioma. Although metal complexes have excellent cytotoxicity, their most critical problem is crossing the blood-brain barrier. Therefore, to enable metal complexes to cross blood-brain barrier and target glioma therapy, herein, we propose to rationally used the basic structure of diazepam (5-chlorobenzophenone) and thiosemicarbazide to synthesize gold (Au) complexes C1, C2 and C3 with antiglioma activity. The C3 complex with two methyl groups attached to the N3 of thiosemicarbazone exhibited excellent cytotoxicity to glioma cells through its multiaction mechanism against glioma, inducing apoptosis, autophagy death, and deoxyribonucleic acid damage. In addition, the synthesized C3 complex can effectively cross the blood-brain barrier and accumulate in glioma, considerably decreasing the untoward reaction in vivo. Our findings provide a novel strategy for designing metal-based complexes for the treatment of glioma.

Diabetic nephropathy is a severe chronic complication characterized by cytotoxicity, inflammation, and fibrosis, ultimately leading to renal failure. This study systematically investigated the effects of the PARP1 inhibitor PJ-34 on high glucose-induced cytotoxicity, inflammation, and fibrosis in HK-2 cells, as well as its improvement on neuropathic pain response and transforming growth factor β (TGFβ) expression in a type 1 diabetes mellitus diabetic nephropathy mouse model. Through cellular and animal experiments, we observed that PJ-34 significantly enhanced the proliferative capacity of cells damaged by high glucose, reduced apoptosis, and decreased the release of proinflammatory factors TGFα, interleukin-6, and interleukin-1β. In the type 1 diabetes mellitus nephropathy mouse model, the administration of PJ-34 substantially improved parameters of neuropathic pain, alleviated renal tissue damage, reduced indicators of renal functional impairment-inhibited renal fibrosis, and reduced the key protein expression in the epithelial-mesenchymal transition process, acting through the regulation of the TGFβ/Smads signaling pathway. This study elucidated the mechanism of action of the PARP1 inhibitor PJ-34 as a potential therapeutic agent for diabetic nephropathy, offering a novel strategy for its treatment.

Pyroptosis represents a mode of programmed necrotic cell death (PCD), mediated by members of gasdermin family (GSDMs), such as GSDME. It is emerging as a promising approach for combating cancer. Notably, GSDME is the key modulator for the switch between apoptosis and pyroptosis in cells. However, GSDME is often downregulated in many malignancies, including lung adenocarcinoma.

To identify novel pyroptosis inducers in non-small cell lung cancer (NSCLC) and dissect the underlying mechanism.

Pyroptosis was examined by live cell imaging, PI/Hoechst/Annexin V staining, LDH release assay, ELISA, and western blot assays. DARTS, CETSA, molecular docking was used to identify the target of NJH-13. RNA-seq, qPCR, chromatin immunoprecipitation (ChIP), dual luciferase assays were used elucidate the mechanism.

In this study, NJH-13, an N-containing heterocycle, was screened out and identified to possess the ability to activate GSDME, consequently triggering pyroptosis in NSCLC cells. By using the DARTS strategy, transient receptor potential cation channel subfamily V member 5 (TRPV5) was identified as a potential target of NJH-13. NJH-13 increased intracellular calcium level and triggered oxidative stress, both of which are critical events leading to pyroptosis mediated by GSDME. Mechanistically, NJH-13 enhanced the transcription of GSDME via the protein kinase B (AKT)/forkhead box transcription factor O1 (FOXO1) signaling pathway. ChIP revealed that FOXO1 bound directly to the promoter region of GSDME, thus triggering the GSDME-mediated pyroptosis. Pharmacological and genetic activation of AKT or inhibition of FOXO1 partially rescued NJH-13-induced pyroptotic cell death. Moreover, NJH-13 treatment suppressed tumor growth in vivo.

Taken together, our results revealed that TRPV5 is a distinctive target for manipulating pyroptosis and provided evidence that NJH-13 functions as a potential anti-cancer agent capable of triggering pyroptosis in NSCLC cells.

Decades after their initial observation in prion-infected brain tissues, the identities of virus-like dense particles, varicose tubules, and oval bodies containing parallel bands and fibrils have remained elusive. Our recent work revealed that a phenotype of dilation of the endoplasmic reticulum (ER), most notable for the perinuclear space (PNS), contributes to spongiform degeneration. To assess the significance of this phenotype for the etiology of prion diseases, we explored whether it can be functionally linked to other neuropathological hallmarks observed in these diseases, as this would indicate it to be a central event. Having surveyed the neuropathological record and other distant literature niches, we propose a model in which pathogenic forms of the prion protein poison raft domains, including essential Na+, K+-ATPases (NKAs) embedded within them, thereby triggering an ER-centered cellular rescue program coordinated by the unfolded protein response (UPR). The execution of this program stalls general protein synthesis, causing the deterioration of synaptic spines. As the disease progresses, cells selectively increase sterol biosynthesis, along with ribosome and ER biogenesis. These adaptive rescue attempts cause morphological changes to the ER which manifest as ER dilation or ER hypertrophy in a manner that is influenced by Ca2+ influx into the cell. The nuclear-to-cytoplasmic transport of mRNAs and tRNAs interrupts in late stage disease, thereby depriving ribosomes of supplies and inducing them to aggregate into a paracrystalline form. In support of this model, we share previously reported data, whose features are consistent with the interpretation that 1) the phenotype of ER dilation is observed in major prion diseases, 2) varicose tubules and oval bodies represent ER hypertrophy, and 3) virus-like dense particles are paracrystalline aggregates of inactive ribosomes.

This review provides a comprehensive overview of the recent advancements in research on ATF4 (Activating Transcription Factor 4) within the field of oncology. As a crucial transcription factor, ATF4 has garnered increasing attention for its role in cancer research. The review begins with an exploration of the regulatory mechanisms of ATF4, including its transcriptional control, post-translational modifications, and interactions with other transcription factors. It then highlights key research findings on ATF4's involvement in various aspects of tumor biology, such as cell proliferation, differentiation, apoptosis and survival, invasion and metastasis, and the tumor microenvironment. Furthermore, the review discusses the potential of targeting ATF4 as a novel therapeutic strategy for cancer treatment. It also explores how ATF4's interactions with existing anticancer drugs could inform the development of more effective therapeutic agents. By elucidating the role of ATF4 in tumor biology and its potential clinical applications, this review aims to provide new insights and strategies for cancer treatment.

Cannabinoids include both endogenous endocannabinoids and exogenous phytocannabinoids, such as cannabidiol (CBD), and have potential as therapeutic agents in cancer treatment due to their selective anticancer activities. CBD exhibits both antioxidant and pro-oxidant effects depending on its concentration and cell types. These properties allow CBD to influence oxidative stress responses and potentially enhance the efficacy of antitumor therapies. In this study, we treated U87MG glioma cells with low dose (1 μM) CBD and evaluated its molecular effects. Our findings indicate that CBD reduced cell viability by 20% (p < 0.05) through the alteration of mitochondrial membrane potential. The alteration of redox status by CBD caused an attempt to rescue mitochondrial functionality through nuclear localization of the GABP transcription factor involved in mitochondria biogenesis. Moreover, CBD treatment caused an increase in autophagic flux, as supported by the increase in Beclin-1 and the ratio of LC3-II/LC3-I. Due to mitochondria functionality alteration, pro-apoptotic proteins were induced without activating apoptotic effectors Caspase-3 or Caspase-7. The study of the transcription factor NRF2 and the ubiquitin-binding protein p62 expression revealed an increase in their levels in CBD-treated cells. In conclusion, low-dose CBD makes U87MG cells more vulnerable to cytotoxic effects, reducing cell viability and mitochondrial dynamics while increasing autophagic flux and redox systems. This explains the mechanisms by which glioma cells respond to CBD treatment. These findings highlight the therapeutic potential of CBD, suggesting that modulating NRF2 and autophagy pathways could represent a promising strategy for glioblastoma treatment.

Cannabidiol (CBD) is garnering increasing interest due to its significant biological activity. This natural compound is one of the major cannabinoids in Cannabis sativa L. In this work, we describe the encapsulation of CBD in solid and hollow pH-sensitive poly(4-vinylpyridine) (solid@p4VP and hollow@p4VP) nanoparticles, and temperature-sensitive poly(N-isopropylacrylamide) (solid@pNIPAM and hollow@pNIPAM) nanoparticles for transport and release CBD in a controlled manner. The CBD loading into these smart polymeric systems was effective and their release profiles, solubility and resistance to stomach and intestinal conditions were evaluated, showing satisfactory properties and improved bioavailability with respect to free CBD. Finally, the A549 human lung cancer cell line was used as lung adenocarcinoma epithelial cellular model to carry out preliminary assays of the in vitro activity of the vehiculized CBD. For all these studies, synthetic CBD was employed, for which a new efficient and scalable synthesis of cannabinoids has been developed.

Mitochondria, known as the "energy factory" of cells, are essential organelles with a double membrane structure and genetic material found in most eukaryotic cells. They play a crucial role in tumorigenesis and development, with alterations in mitochondrial structure and function in tumor cells leading to characteristics such as rapid proliferation, invasion, and drug resistance. Glioma, the most common brain tumor with a high recurrence rate and limited treatment options, has been linked to changes in mitochondrial structure and function. This review focuses on the bioenergetics, dynamics, metastasis, and autophagy of mitochondria in relation to glioma proliferation, as well as the potential use of mitochondria-targeting drugs in glioma treatment.

Temozolomide (TMZ) is currently the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM). However, the inherent heterogeneity of GBM often results in suboptimal outcomes, particularly due to varying degrees of resistance to TMZ. Over the past several decades, O6-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair pathway has been extensively investigated as a target to overcome TMZ resistance. Nonetheless, the combination of small molecule covalent MGMT inhibitors with TMZ and other chemotherapeutic agents has frequently led to adverse clinical effects. Recently, additional mechanisms contributing to TMZ resistance have been identified, including epidermal growth factor receptor (EGFR) mutations, overactivation of intracellular signalling pathways, energy metabolism reprogramming or survival autophagy, and changes in tumor microenvironment (TME). These findings suggest that novel therapeutic strategies targeting these mechanisms hold promise for overcoming TMZ resistance in GBM patients. In this review, we summarize the latest advancements in understanding the mechanisms underlying intrinsic and acquired TMZ resistance. Additionally, we compile various small-molecule compounds with potential to mitigate chemoresistance in GBM. These mechanism-based compounds may enhance the sensitivity of GBM to TMZ and related chemotherapeutic agents, thereby improving overall survival rates in clinical practice.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and its potential therapeutic effects extend beyond its well-known antiepileptic properties. Exploring CBD and its analogues as anticancer agents has gained significant attention in recent years. In this study, a series of novel ring-annulated analogues of CBD with oxazinyl moiety were synthesized and evaluated for their antiproliferative effect. The analogues 4d and 4h demonstrate promising activity against breast and colorectal cancer. Furthermore, mechanistic insights revealed that the identified candidates arrest the G1 phase of the cell cycle and induce apoptosis via the mitochondrial pathway in breast cancer cell lines. Notably, CBD ring-annulated analogues 4d or 4h exhibit enhanced solubility, better metabolic stability, and lowered cytochrome P450 (CYP) inhibition liability compared to CBD. These multifaceted attributes highlight the potential of cannabinoid-based candidates for further preclinical development.

Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases.

This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential.

In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients.

High dose chemotherapy is one of the therapeutic strategies for breast cancer and doxorubicin (DOX) as a chemotherapy agent is widely used. DOX indication is limited due to its dose-depended cardiotoxicity. Recently, cannabidiol (CBD) shows antitumoral and cardioprotective effects, so we hypothesized that CBD administration with high-dose DOX chemotherapy can improve anticancer activity and reduce cardiotoxic side effects.

Mice breast cancer model established by injecting 4T1 cell lines. One group was not injected by 4T1 cells as a not cancerous group and received normal saline (NS, 0.1 mL). In cancerous groups, first group was considered as cancerous control and received NS (0.1 mL); the second group received CBD (5 mg/kg, IP) on Days 1,7, and 14; in the third group DOX (5 mg/kg, IV) as CBD schedule was administrated; the fourth group treated with CBD 1 day before DOX injection as pretreatment, and the last group was treated with CBD and DOX at same time with previous doses and schedules. On Day 21, all mice were sacrificed, heart and lungs tissues were obtained and histological sections were isolated. SOD2, iNOS, MMP2, MMP9 were evaluated through western blot and TUNEL test preformed for breast tumor.

Tumor size and weight significantly decreased in DOX, pretreatment CBD + DOX and CBD + DOX groups. Administration of CBD with DOX could not prevent weight loss. TUNEL test demonstrated the highest tumor cell apoptosis in pretreatment CBD + DOX and CBD + DOX. In lungs belonged to CBD + DOX, there was not any sign of metastasis. Cardiac histopathological examination of pretreatment CBD + DOX and CBD + DOX did not show any sign of congestion or inflammation. In CBD + DOX SOD2 increased, also iNOS, MMP2, and MMP9 decreased compared to DOX.

This study demonstrated that simultaneous administration of CBD and DOX can increase antitumoral effect and reduce DOX cardiotoxicity. Nevertheless, CBD can induce cardiotoxicity as administrated alone.

Diabetic nephropathy (DN) is a severe complication of prolonged diabetes, impacting millions worldwide with an increasing incidence. This study investigates the role of tribbles pseudokinase 3 (TRIB3), a protein implicated in the progression of DN, focusing on its mechanisms underlying glomerular damage. Through analysis of the Gene Expression Omnibus (GEO) database, we identified TRIB, among differentially expressed genes (DEGs) in streptozotocin (STZ)-treated C57BL/6J mice. Both in vitro and in vivo experiments were conducted to examine the effects of TRIB3 inhibition on high glucose (HG)-induced damage in podocytes and DN mouse models. The results demonstrated that TRIB3 inhibition reduced inflammatory responses and extracellular matrix (ECM) production inMPC5 cells, mediated by the downregulation of DNA damage-inducible transcript 3 (DDIT3) - a critical regulator of proinflammatory cytokine secretion and ECM synthesis. Inhibiting TRIB3 decreased inflammatory factors and ECM deposition in diabetic mice in vivo, confirming its pivotal role in DN pathogenesis. These findings indicate that TRIB3 and its interaction with DDIT3 contribute significantly to DN by promoting inflammatory cascades and ECM accumulation, presenting potential therapeutic targets for managing the disease.

Prostate cancer is one of the leading causes of cancer-related deaths worldwide, even when diagnosed at an early stage in humans and dogs. Dogs have a significant incidence of spontaneous prostate cancer, which is highly similar to human androgen-independent prostate cancer and represents a valuable model for comparative studies. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two main cannabinoids extracted from Cannabis sativa and have demonstrated antiproliferative and anti-invasive properties in different tumor types. In this study, CBD or THC-rich extracts inhibited the proliferation of two canine prostatic carcinoma cell lines, PC1 and PC2, showing an IC50 of 3.43 and 3.57 μM for CBD rich extracts, and 4.90 and 4.48 μM THC rich extracts, respectively. Cell death was also observed with both Annexin V and Propidium iodide staining for the canine cell lines. These results provide new information concerning the use of rich oil in canine PC and open a promising opportunity for further in vitro and in vivo studies to establish the mechanisms of action of these compounds using dogs as a natural model for prostatic carcinoma.

As part of stress-triggered molecules, immediate early response 3 (IER3) dysregulation has been reported to sustain pro-oncogenic pathways and precede malignant transformation. However, the role of IER3 in glioma pathology is ill-defined.

Immunohistochemistry (IHC) assay and publicly available glioma datasets were used to calculate the IER3 expression level in glioma. Wound healing, invasion and cell counting kit-8 (CCK8) assays were applied to measure the cell viability and capacities of migration and invasion of glioma cells in vitro. The immunofluorescence (IF) assay was used to assess the expression associations of IER3 with CCL2 and TGFBI. Cox regression analysis and Kaplan-Meier (K-M) curve were introduced to compute the prognosis-predicting value of IER3. Variations in copy number (CNVs), single nucleotide (SNVs), and methylation profiles were analyzed to illustrate the epigenetic modifications of IER3. Gliomas were divided into two subgroups using the restricted cubic spline (RCS) method. RESULTS IER3: was overexpressed and hypomethylated in gliomas and significantly associated with the dismal prognosis of glioma samples. Samples in the high IER3 subgroup were characterized by increased infiltration of tumor-associated monocytes/macrophages (TAMMs), as well as the elevated sensitivity to Dabrafenib, an inhibitor of BRAF. In addition, this subgroup demonstrated a low mutation rate of IDH, high gain rates of BRAF, ELTD1, and PDGFA. Gliomas with relatively low IER3 expression demonstrated a less invasive subtype and were featured by favorable prognosis, increased response to immunotherapy, and adjuvant chemotherapy plus radiotherapy. The IF assay revealed that IER3 was co-localized and co-expressed with TGFBI. The glioma cells with small interfering RNA (siRNA)-silenced IER3 displayed lower migration, invasion, proliferation, and cell viability than the control group.

In this study, we identified IER3 upregulation as an essential biomarker that could assist in adjuvant therapy and prognosis prediction for gliomas.

Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.

The dynamics of mitochondrial respiratory cristae (MRC) and its impact on oxidative phosphorylation (OXPHOS) play a crucial role in driving the progression of high-grade glioma (HGG). However, the underlying mechanism remains unclear.

In the present study, we employed machine learning-based transmission electron microscopy analysis of 7141 mitochondria from 54 resected glioma patients. Additionally, we conducted bioinformatics analysis and multiplex immunohistochemical (mIHC) staining of clinical glioma microarrays to identify key molecules involved in glioma. Subsequently, we modulated the expression levels of mitochondrial dynamic-1-like protein (DNM1L/DRP1), and its two receptors, mitochondrial fission protein 1 (FIS1) and mitochondrial fission factor (MFF), via lentiviral transfection to further investigate the central role of these molecules in the dynamics of glioblastoma (GBM) cells and glioma stem cells (GSCs). We then evaluated the potential impact of DNM1L/DRP1, FIS1, and MFF on the proliferation and progression of GBM cells and GSCs using a combination of CCK-8 assay, Transwell assay, Wound Healing assay, tumor spheroid formation assay and cell derived xenograft assay employing NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt (NCG) mouse model. Subsequently, we validated the ability of the DNM1L/DRP1-FIS1 axis to remodel MRC structure through mitophagy by utilizing Seahorse XF analysis technology, mitochondrial function detection, MRC abundance detection and monitoring dynamic changes in mitophagy.

Our findings revealed that compared to low-grade glioma (LGG), HGG exhibited more integrated MRC structures. Further research revealed that DNM1L/DRP1, FIS1, and MFF played pivotal roles in governing mitochondrial fission and remodeling MRC in HGG. The subsequent validation demonstrated that DNM1L/DRP1 exerts a positive regulatory effect on FIS1, whereas the interaction between MFF and FIS1 demonstrates a competitive inhibition relationship. The down-regulation of the DNM1L/DRP1-FIS1 axis significantly impaired mitophagy, thereby hindering the remodeling of MRC and inhibiting OXPHOS function in glioma, ultimately leading to the inhibition of its aggressive progression. In contrast, MFF exerts a contrasting effect on MRC integrity, OXPHOS activity, and glioma progression.

This study highlights that the DNM1L/DRP1-FIS1 axis stabilizes MRC structures through mitophagy in HGG cells while driving their OXPHOS activity ultimately leading to robust disease progression. The inhibition of the DNM1L/DRP1-FIS1 axis hinders MRC remodeling and suppresses GBM progression. We propose that down-regulation of the DNM1L/DRP1-FIS1 axis could be a potential therapeutic strategy for treating HGG.

Glioblastoma (GBM) is one of the most lethal malignancies in humans. Even after surgical resection and aggressive radio- or chemotherapies, patients with GBM can survive for less than 14 months. Extreme inter-tumor and intra-tumor heterogeneity of GBM poses a challenge for resolving recalcitrant GBM pathophysiology. GBM tumor microenvironment (TME) exhibits diverse heterogeneity in cellular composition and processes contributing to tumor progression and therapeutic resistance. Autophagy is such a cellular process; that demonstrates a cell-specific and TME context-dependent role in GBM progression, leading to either the promotion or suppression of GBM progression. Autophagy can regulate GBM cell function directly via regulation of survival, migration, and invasion, or indirectly by affecting GBM TME composition such as immune cell population, tumor metabolism, and glioma stem cells. This review comprehensively investigates the role of autophagy in GBM pathophysiology.

Cannabidiol (CBD) is one of the primary cannabinoids present in extracts of the plant Cannabis sativa L. A CBD-based drug, Epidiolex, has been approved by the U.S. FDA for the treatment of seizures in childhood-onset epileptic disorders. Although CBD-associated liver toxicity has been reported in clinical studies, the underlying mechanisms remain unclear. In this study, we demonstrated that CBD causes cytotoxicity in primary human hepatocytes and hepatic HepG2 cells. A 24-h CBD treatment induced cell cycle disturbances, cellular apoptosis, and endoplasmic reticulum (ER) stress in HepG2 cells. A potent ER stress inhibitor, 4-phenylbutyrate, markedly attenuated CBD-induced apoptosis and cell death. Additionally, we investigated the role of cytochrome P450 (CYP)-mediated metabolism in CBD-induced cytotoxicity using HepG2 cell lines engineered to express 14 individual CYPs. We identified CYP2C9, 2C19, 2D6, 2C18, and 3A5 as participants in CBD metabolism. Notably, cells overexpressing CYP2C9, 2C19, and 2C18 produced 7-hydroxy-CBD, while cells overexpressing CYP2C9, 2C19, 2D6, and 2C18 generated 7-carboxy-CBD. Furthermore, CBD-induced cytotoxicity was significantly attenuated in the cells expressing CYP2D6. Taken together, these data suggest that cell cycle disturbances, apoptosis, and ER stress are associated with CBD-induced cytotoxicity, and CYP2D6-mediated metabolism plays a critical role in decreasing the cytotoxicity of CBD.

During oxidative phosphorylation, mitochondria continuously produce reactive oxygen species (ROS), and untimely ROS clearance can subject mitochondria to oxidative stress, ultimately resulting in mitochondrial damage. Mitophagy is essential for maintaining cellular mitochondrial quality control and homeostasis, with activation involving both ubiquitin-dependent and ubiquitin-independent pathways. Over the past decade, numerous studies have indicated that different forms of regulated cell death (RCD) are connected with mitophagy. These diverse forms of RCD have been shown to be regulated by mitophagy and are implicated in the pathogenesis of a variety of diseases, such as tumors, degenerative diseases, and ischemia‒reperfusion injury (IRI). Importantly, targeting mitophagy to regulate RCD has shown excellent therapeutic potential in preclinical trials, and is expected to be an effective strategy for the treatment of related diseases. Here, we present a summary of the role of mitophagy in different forms of RCD, with a focus on potential molecular mechanisms by which mitophagy regulates RCD. We also discuss the implications of mitophagy-related RCD in the context of various diseases.

Glioma is the most common malignant tumor in central nervous system, with significant health burdens to patients. Due to the intrinsic characteristics of glioma and the lack of breakthroughs in treatment modalities, the prognosis for most patients remains poor. This results in a heavy psychological and financial load worldwide. In recent years, cannabidiol (CBD) has garnered widespread attention and research due to its anti-tumoral, anti-inflammatory, and neuroprotective properties. This review comprehensively summarizes the preclinical and clinical research on the use of CBD in glioma therapy, as well as the current status of nanomedicine formulations of CBD, and discusses the potential and challenges of CBD in glioma therapy in the future.