Research Progress on the Mechanism of the Antitumor Effects of Cannabidiol.

Cannabidiol (CBD), a non-psychoactive ingredient extracted from the hemp plant, has shown therapeutic effects in a variety of diseases, including anxiety, nervous system disorders, inflammation, and tumors. CBD can exert its antitumor effect by regulating the cell cycle, inducing tumor cell apoptosis and autophagy, and inhibiting tumor cell invasion, migration, and angiogenesis. This article reviews the proposed antitumor mechanisms of CBD, aiming to provide references for the clinical treatment of tumor diseases and the rational use of CBD.

Biological characteristics of Cordyceps militaris single mating-type strains.

Cordyceps militaris has been extensively cultivated as a model cordyceps species for commercial purposes. Nevertheless, the problems related to strain degeneration and breeding technologies remain unresolved. This study assessed the physiology and fertility traits of six C. militaris strains with distinct origins and characteristics, focusing on single mating-type strains. The results demonstrated that the three identified strains (CMDB01, CMSY01, and CMJB02) were single mating-type possessing only one mating-type gene (MAT1-1). In contrast, the other three strains (CMXF07, CMXF09, and CMMS05) were the dual mating type. The MAT1-1 strains sourced from CMDB01, CMSY01, and CMJB02 consistently produced sporocarps but failed to generate ascospores. However, when paired with MAT1-2 strains, the MAT1-1 strains with slender fruiting bodies and normal morphology were fertile. The hyphal growth rate of single mating-type strains (CMDB01, CMSY01, and CMJB02) typically surpassed that of dual mating-type strains (CMXF07, CMXF09, and CMMS05). The growth rates of MAT1-2 and MAT1-1 strains were proportional to their ratios, such that a single mating-type strain with a higher ratio exhibited an increased growth rate. As C. militaris matured, the adenosine content decreased. In summary, the C. militaris strains that consistently produce sporocarps and have a single mating type are highly promising for production and breeding.

Biomaterials combined with ADSCs for bone tissue engineering: current advances and applications.

In recent decades, bone tissue engineering, which is supported by scaffold, seed cells and bioactive molecules (BMs), has provided new hope and direction for treating bone defects. In terms of seed cells, compared to bone marrow mesenchymal stem cells, which were widely utilized in previous years, adipose-derived stem cells (ADSCs) are becoming increasingly favored by researchers due to their abundant sources, easy availability and multi-differentiation potentials. However, there is no systematic theoretical basis for selecting appropriate biomaterials loaded with ADSCs. In this review, the regulatory effects of various biomaterials on the behavior of ADSCs are summarized from four perspectives, including biocompatibility, inflammation regulation, angiogenesis and osteogenesis, to illustrate the potential of combining various materials with ADSCs for the treatment of bone defects. In addition, we conclude the influence of additional application of various BMs on the bone repair effect of ADSCs, in order to provide more evidences and support for the selection or preparation of suitable biomaterials and BMs to work with ADSCs. More importantly, the associated clinical case reports and experiments are generalized to provide additional ideas for the clinical transformation and application of bone tissue engineering loaded with ADSCs.

Integrating physicomechanical and biological strategies for BTE: biomaterials-induced osteogenic differentiation of MSCs.

Large bone defects are a major global health concern. Bone tissue engineering (BTE) is the most promising alternative to avoid the drawbacks of autograft and allograft bone. Nevertheless, how to precisely control stem cell osteogenic differentiation has been a long-standing puzzle. Compared with biochemical cues, physicomechanical stimuli have been widely studied for their biosafety and stability. The mechanical properties of various biomaterials (polymers, bioceramics, metal and alloys) become the main source of physicomechanical stimuli. By altering the stiffness, viscoelasticity, and topography of materials, mechanical stimuli with different strengths transmit into precise signals that mediate osteogenic differentiation. In addition, externally mechanical forces also play a critical role in promoting osteogenesis, such as compression stress, tensile stress, fluid shear stress and vibration, etc. When exposed to mechanical forces, mesenchymal stem cells (MSCs) differentiate into osteogenic lineages by sensing mechanical stimuli through mechanical sensors, including integrin and focal adhesions (FAs), cytoskeleton, primary cilium, ions channels, gap junction, and activating osteogenic-related mechanotransduction pathways, such as yes associated proteins (YAP)/TAZ, MAPK, Rho-GTPases, Wnt/ß-catenin, TGFß superfamily, Notch signaling. This review summarizes various biomaterials that transmit mechanical signals, physicomechanical stimuli that directly regulate MSCs differentiation, and the mechanical transduction mechanisms of MSCs. This review provides a deep and broad understanding of mechanical transduction mechanisms and discusses the challenges that remained in clinical translocation as well as the outlook for the future improvements.

Epigenetics: Novel crucial approach for osteogenesis of mesenchymal stem cells.

Bone has a robust regenerative potential, but its capacity to repair critical-sized bone defects is limited. In recent years, stem cells have attracted significant interest for their potential in tissue engineering. Applying mesenchymal stem cells (MSCs) for enhancing bone regeneration is a promising therapeutic strategy. However, maintaining optimal cell efficacy or viability of MSCs is limited by several factors. Epigenetic modification can cause changes in gene expression levels without changing its sequence, mainly including nucleic acids methylation, histone modification, and non-coding RNAs. This modification is believed to be one of the determinants of MSCs fate and differentiation. Understanding the epigenetic modification of MSCs can improve the activity and function of stem cells. This review summarizes recent advances in the epigenetic mechanisms of MSCs differentiation into osteoblast lineages. We expound that epigenetic modification of MSCs can be harnessed to treat bone defects and promote bone regeneration, providing potential therapeutic targets for bone-related diseases.

Transcriptome and metabolome profiling unveils the mechanisms of naphthalene acetic acid in promoting cordycepin synthesis in Cordyceps militaris.

Cordycepin, an important active substance in Cordyceps militaris, possesses antiviral and other beneficial activities. In addition, it has been reported to effectively promote the comprehensive treatment of COVID-19 and thus has become a research hotspot. The addition of naphthalene acetic acid (NAA) is known to significantly improve the yield of cordycepin; however, its related molecular mechanism remains unclear. We conducted a preliminary study on C. militaris with different concentrations of NAA. We found that treatment with different concentrations of NAA inhibited the growth of C. militaris, and an increase in its concentration significantly improved the cordycepin content. In addition, we conducted a transcriptome and metabolomics association analysis on C. militaris treated with NAA to understand the relevant metabolic pathway of cordycepin synthesis under NAA treatment and elucidate the relevant regulatory network of cordycepin synthesis. Weighted gene co-expression network analysis (WGCNA), transcriptome, and metabolome association analysis revealed that genes and metabolites encoding cordycepin synthesis in the purine metabolic pathway varied significantly with the concentration of NAA. Finally, we proposed a metabolic pathway by analyzing the relationship between gene-gene and gene-metabolite regulatory networks, including the interaction of cordycepin synthesis key genes; key metabolites; purine metabolism; TCA cycle; pentose phosphate pathway; alanine, aspartate, and glutamate metabolism; and histidine metabolism. In addition, we found the ABC transporter pathway to be significantly enriched. The ABC transporters are known to transport numerous amino acids, such as L-glutamate, and participate in the amino acid metabolism that affects the synthesis of cordycepin. Altogether, multiple channels work together to double the cordycepin yield, thereby providing an important reference for the molecular network relationship between the transcription and metabolism of cordycepin synthesis.

A novel mechanism of cannabidiol in suppressing ovarian cancer through LAIR-1 mediated mitochondrial dysfunction and apoptosis.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid compound. It has been shown that CBD can inhibit the proliferation of ovarian cancer cells, but the underlying specific mechanism is unclear. We previously presented the first evidence for the expression of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), a member of the immunosuppressive receptor family, in ovarian cancer cells. In the present study, we investigated the mechanism by which CBD inhibits the growth of SKOV3 and CAOV3 ovarian cancer cells, and we sought to understand the concurrent role of LAIR-1. In addition to inducing ovarian cancer cell cycle arrest and promoting cell apoptosis, CBD treatment significantly affected the expression of LAIR-1 and inhibited the PI3K/AKT/mTOR signaling axis and mitochondrial respiration in ovarian cancer cells. These changes were accompanied by an increase in ROS, loss of mitochondrial membrane potential, and suppression of mitochondrial respiration and aerobic glycolysis, thereby inducing abnormal or disturbed metabolism and reducing ATP production. A combined treatment with N-acetyl-l-cysteine and CBD indicated that a reduction in ROS production would restore PI3K/AKT/mTOR pathway signaling and ovarian cancer cell proliferation. We subsequently confirmed that the inhibitory effect of CBD on the PI3K/AKT/mTOR signal axis and mitochondrial bioenergy metabolism was attenuated by knockdown of LAIR-1. Our animal studies further support the in vivo anti-tumor activity of CBD and suggest its mechanism of action. In summary, the present findings confirm that CBD inhibits ovarian cancer cell growth by disrupting the LAIR-1-mediated interference with mitochondrial bioenergy metabolism and the PI3K/AKT/mTOR pathway. These results provide a new experimental basis for research into ovarian cancer treatment based on targeting LAIR-1 with CBD.

The efficacy of cell-assisted versus conventional lipotransfer: A systematic review and meta-analysis.

Autologous lipotransfer is an essential component of soft tissue reconstruction. However, it is not widely applied or accepted by surgeons due to its unstable survival rate and uncertain efficacy. The cell-assisted fat transfer (CAL) is a promising technique that increases the fat survival rate. However, it is controversial based on various clinical studies. Here, we assessed the fat survival and complication rates of CAL, compared to the conventional autologous lipotransfer. To conduct our research, two reviewers independently screened related articles published in Medicine (via PubMed), EMBASE, Cochrane Library, and Web of Science. The combined effect estimates for efficacy evaluation was performed by the Review Manager software (RevMan 5.4.1). In total, 14 articles were included in our analysis (n = 722). Based on our analysis, the survival rate of the fat graft in CAL was significantly higher than the conventional fat grafting group (non-CAL group) (SMD = 2.81, 95%CI [1.54, 4.08], P < 0.01). In the subgroup, the fat retention of CAL in the facial filling was higher than the conventional one (SMD = 3.01, 95%CI [1.68, 4.33], P < 0.01). After breast augmentation, however, the difference between the experimental and control group was not statistically significant (SMD = 1.80, 95%CI [-0.31, 3.91], P = 0.09). Moreover, the CAL group exhibited comparable complications as the non-CAL group. Based on our analysis, the CAL group was significantly better than the conventional lipotransfer in terms of fat survival, particularly, during facial filling. However, it failed to reduce the complication rate, compared to the non-CAL group.

3D printed oral solid dosage form: Modified release and improved solubility.

Oral solid dosage form is currently the most common used form of drug. 3D Printing, also known as additive manufacturing (AM), can quickly print customized and individualized oral solid dosage form on demand. Compared with the traditional tablet manufacturing process, 3D Printing has many advantages. By rationally selecting the formulation composition and cleverly designing the printing structure, 3D printing can improve the solubility of the drug and achieve precise modify of the drug release. 3D printed oral solid dosage form, however, still has problems such as limitations in formulation selection. And the selection process of the formulation lacks scientificity and standardization. Structural design of some 3D printing approaches is relatively scarce. This article reviews the formulation selection and structure design of 3D printed oral solid dosage form, providing more ideas for achieving modified drug release and solubility improvement of 3D printed oral solid dosage form through more scientific and extensive formulation selection and more sophisticated structural design.

Study on Characteristics of Triterpenoids and Hepatoprotective Effects of Fruit Body of Stout Camphor Mushroom, Taiwanofungus camphoratus (Agaricomycetes), Cultivated with Apple-Wood.

Taiwanofungus camphoratus is a parasite medicinal fungus with significant hepatoprotective activity that grows in Cinnamomum camphora, a class II protected tree species in Taiwan. Currently, commercial cultivation of T. camphoratus is limited by the resources of C. camphora. To broaden the range of substrates, this study investigated the feasibility of using apple-wood as a substrate for T. camphoratus cultivation and examined the content of fruit body triterpenoids and liver-protective activity as quality indicators. The triterpenoids were determined by ultra-performance liquid chromatography-mass spectrometry and compared with T. camphoratus cultivated in C. camphora. The ICR mouse acute alcoholic liver injury model was used to explore the hepatoprotective effects of the apple-wood cultivated fungus. T. camphoratus grew on apple-wood medium within 7 months; a total of 62 fungal triterpenoid components were detected, including the seven characteristic triterpenoids. Only three were higher in T. camphoratus cultured on C. camphora. The medium-dose fungal extracts (150 mg/kg) produced significant protective effects against acute alcoholic liver injury in mice. These results indicate that apple-wood cultivation is a feasible method compared to C. camphora for commercial cultivation of T. camphoratus.

Study on Exosomes Promoting the Osteogenic Differentiation of ADSCs in Graphene Porous Titanium Alloy Scaffolds.

Titanium and titanium alloys (Ti6Al4V and Ti) have been widely used in bone tissue engineering to repair maxillofacial bone defects caused by traumas and tumors. However, such materials are also bio-inert, which does not match the elastic modulus of bone. Therefore, different surface modifications have been proposed for clinical application. Based on the use of traditional titanium alloy in the field of bone repair defects, we prepared a compound Gr-Ti scaffold with ADSC-derived Exos. The results showed that Gr-Ti scaffolds have low toxicity and good biocompatibility, which can promote the adhesion and osteogenic differentiation of ADSCs. Exos played a role in promoting osteogenic differentiation of ADSCs: the mRNA levels of RUNX2, ALP, and Osterix in the Gr-Ti/Exos group were significantly higher than those in the Gr-Ti group, which process related to the Wnt signaling pathway. Gr-Ti scaffolds with ADSCs and ADSC-derived Exos successfully repaired rabbit mandibular defects. The bone mineral density and the bending strength of the Gr-Ti/Exos group was significantly higher than that of the Gr-Ti group. This study provides a theoretical basis for the research and development of new clinical bone repair materials.

Mg-, Zn-, and Fe-Based Alloys With Antibacterial Properties as Orthopedic Implant Materials.

Implant-associated infection (IAI) is one of the major challenges in orthopedic surgery. The development of implants with inherent antibacterial properties is an effective strategy to resolve this issue. In recent years, biodegradable alloy materials have received considerable attention because of their superior comprehensive performance in the field of orthopedic implants. Studies on biodegradable alloy orthopedic implants with antibacterial properties have gradually increased. This review summarizes the recent advances in biodegradable magnesium- (Mg-), iron- (Fe-), and zinc- (Zn-) based alloys with antibacterial properties as orthopedic implant materials. The antibacterial mechanisms of these alloy materials are also outlined, thus providing more basis and insights on the design and application of biodegradable alloys with antibacterial properties as orthopedic implants.

Skin cutaneous melanoma properties of immune-related lncRNAs identifying potential prognostic biomarkers.

Skin cutaneous melanoma (SKCM) is one of the most aggressive and life-threatening cancers with high incidence rate, metastasis rate and mortality. Early detection and stratification of risk assessment are essential to treat SKCM and to improve survival rate. The aim of this study is to construct an immune-related lncRNAs (immlncRNAs) prognosis risk model to identify immune biomarkers for early diagnosis, prognosis assessment and target immunotherapy of SKCM. For this purpose, we identified 46 immlncRNAs significantly correlated with SKCM prognosis to construct the prognostic risk model and patients were stratified into the high- and low-risk subgroups according to the developed model. The predictive efficiency of this model has been proved by K-M survival analysis and receiver operating characteristic curve. Moreover, CIBERSORT algorithms confirmed that there were differences in immune cell infiltration between the high- and low-risk groups. Functional enrichment analysis further indicated that immlncRNAs were related to a variety of immune response process signaling pathways, suggesting that relevant immlncRNAs could play an important role in the immune regulation of SKCM. Finally, subgroup analysis and multiple Cox regression analysis further proved the stability of the model. In summary, we successfully constructed a 46 immlncRNA-related prognostic risk score model with excellent predictive efficacy and provided more possibilities to investigate the immune regulation mechanisms and to develop immunotherapy of SKCM.

Efficient extraction and antioxidant activity of polyphenols from Antrodia cinnamomea.

BACKGROUND: Antrodia cinnamomea, a rare medicinal fungus, has been increasingly studied in recent years because of its abundant secondary metabolites which are beneficial to humans. However, there is a lack of research on its polyphenols which are of good research value due to their antioxidant, anti-inflammatory, hypoglycemic and other activities. RESULTS: In this study, the effects of different extraction conditions on the yield of its polyphenols were investigated. Deep-Eutectic Solvents composed of choline chloride and malonic acid had the best extraction efficiency, with the optimal extraction conditions being as follows: a solid-liquid ratio of 40 mg/mL, an extraction temperature of 55 °C, an extraction time of 70 min and a DES with 20% water content. Under these conditions, the extraction yield of polyphenols reached 22.09 mg/g which was about 2 times that of alcohol-based extraction (10.95 mg/g). In vitro antioxidant test results further showed that polyphenols from A. cinnamomea had strong antioxidant activities. When the concentration of polyphenols reached 0.1 mg/mL of polyphenols, the scavenging activity of free radical basically reached its maximum, with values of 94.10%, 83.34% and 95.42% for DPPH, ABTS+ and ·OH scavenging. In this case, the corresponding IC50 values were 0.01, 0.014 and 0.007 mg/mL, respectively. CONCLUSIONS: This study lays the foundation for the efficient extraction and application of polyphenols from A. cinnamomea.

Protective roles of mesenchymal stem cells on skin photoaging: A narrative review.

Skin is a natural barrier of human body and a visual indicator of aging process. Exposure to ultraviolet (UV) radiation in the sunlight may injure the skin tissues and cause local damage. Besides, it is reported that repetitive or long-term exposure to UV radiation may reduce the collagen production, change the normal skin structure and cause premature skin aging. This is termed "photoaging". The classical symptoms of photoaging include increased roughness, wrinkle formation, mottled pigmentation or even precancerous changes. Mesenchymal stem cells (MSCs) are a kind of cells with the ability of self-renewal and multidirectional differentiation into many types of cells, like adipocytes, osteoblasts and chondrocytes. Researchers have explored diverse pharmacological actions of MSCs because of their migratory activity, paracrine actions and immunoregulation effects. In recent years, the huge potential of MSCs in preventing skin from photoaging has gained wide attention. MSCs exert their beneficial effects on skin photoaging via antioxidant effect, anti-apoptotic/anti-inflammatory effect, reduction of matrix metalloproteinases (MMPs) and activation of dermal fibroblasts proliferation. MSCs and MSC related products have demonstrated huge potential in the treatment of skin photoaging. This narrative review concisely sums up the recent research developments on the roles of MSCs in protection against photoaging and highlights the enormous potential of MSCs in skin photoaging treatment.

Immunomodulatory effects and mechanisms of distraction osteogenesis.

Distraction osteogenesis (DO) is widely used for bone tissue engineering technology. Immune regulations play important roles in the process of DO like other bone regeneration mechanisms. Compared with others, the immune regulation processes of DO have their distinct features. In this review, we summarized the immune-related events including changes in and effects of immune cells, immune-related cytokines, and signaling pathways at different periods in the process of DO. We aim to elucidated our understanding and unknowns about the immunomodulatory role of DO. The goal of this is to use the known knowledge to further modify existing methods of DO, and to develop novel DO strategies in our unknown areas through more detailed studies of the work we have done.

Effect of Melatonin for Regulating Mesenchymal Stromal Cells and Derived Extracellular Vesicles.

Melatonin is a hormone, synthesized in the pineal gland, which primarily controls the circadian rhythm of the body. In recent years, melatonin has also been shown to regulate metabolism, provide neuroprotection, and act as an anti-inflammatory, free radical scavenger. There has also been a recent research interest in the role of melatonin in regulating mesenchymal stromal cells (MSCs). MSCs are pivotal for their ability to differentiate into a variety of different tissues. There is also increasing evidence for the therapeutic prospects of MSCs via paracrine signaling. In addition to secreting cytokines and chemokines, MSCs can secrete extracellular vesicles (EVs), allowing them to respond to injury and promote tissue regeneration. While there has been a major research interest in the use of MSCs for regenerative medicine, the clinical application is limited by many risks, including tumorigenicity, senescence, and sensitivity to toxic environments. The use of MSC-derived EVs for cell-free therapy can potentially avoid the disadvantages of MSCs, which makes this an exciting prospect for regenerative medicine. Prior research has shown that MSCs, via paracrine mechanisms, can identify receptor-independent responses to melatonin and then activate a series of downstream pathways, which exert a variety of effects, including anti-tumor and anti-inflammatory effects. Here we review the synthesis of melatonin, its mechanisms of action, and the effect of melatonin on MSCs via paracrine signaling. Furthermore, we summarize the current clinical applications of melatonin and discuss future prospects.

Optimization of Extraction Process and the Antioxidant Activity of Phenolics from Sanghuangporus baumii.

Sanghuangporus baumii, is a widely used medicinal fungus. The polyphenols extracted from this fungus exert antioxidant, anti-inflammatory, and hypoglycemic effects. In this study, polyphenols from the fruiting bodies of S. baumii were obtained using the deep eutectic solvent (DES) extraction method. The factors affecting the extraction yield were investigated at different conditions. Based on the results from single-factor experiments, response surface methodology was used to optimize the extraction conditions. The scavenging ability of the polyphenols on •OH, DPPH, and ABTS+ was determined. The results showed that the DES system composed of choline chloride and malic acid had the best extraction yield (6.37 mg/g). The optimal extraction parameters for response surface methodology were as follows: 42 min, 58 ℃, 1:34 solid-liquid (mg/mL), and water content of 39%. Under these conditions, the yield of polyphenols was the highest (12.58 mg/g). At 0.30 mg/mL, the scavenging ability of the polyphenols on •OH, DPPH, and ABTS+ was 95.71%, 91.08%, and 85.52%, respectively. Thus, the method using DES was more effective than the conventional method of extracting phenolic compounds from the fruiting bodies of S. baumii. Moreover, the extracted polyphenols exhibited potent antioxidant activity.

The miR-204-5p/FOXC1/GDF7 axis regulates the osteogenic differentiation of human adipose-derived stem cells via the AKT and p38 signalling pathways.

BACKGROUND: Human adipose-derived stem cells (hADSCs) are stem cells with the potential to differentiate in multiple directions. miR-204-5p is expressed at low levels during the osteogenic differentiation of hADSCs, and its specific regulatory mechanism remains unclear. Here, we aimed to explore the function and possible molecular mechanism of miR-204-5p in the osteogenic differentiation of hADSCs. METHODS: The expression patterns of miR-204-5p, Runx2, alkaline phosphatase (ALP), osteocalcin (OCN), forkhead box C1 (FOXC1) and growth differentiation factor 7 (GDF7) in hADSCs during osteogenesis were detected by qRT-PCR. Then, ALP and alizarin red staining (ARS) were used to detect osteoblast activities and mineral deposition. Western blotting was conducted to confirm the protein levels. The regulatory relationship among miR-204-5p, FOXC1 and GDF7 was verified by dual-luciferase activity and chromatin immunoprecipitation (ChIP) assays. RESULTS: miR-204-5p expression was downregulated in hADSC osteogenesis, and overexpression of miR-204-5p suppressed osteogenic differentiation. Furthermore, the levels of FOXC1 and GDF7 were decreased in the miR-204-5p mimics group, which indicates that miR-204-5p overexpression suppresses the expression of FOXC1 and GDF7 by binding to their 3'-untranslated regions (UTRs). Overexpression of FOXC1 or GDF7 improved the inhibition of osteogenic differentiation of hADSCs induced by the miR-204-5p mimics. Moreover, FOXC1 was found to bind to the promoter of miR-204-5p and GDF7, promote the deacetylation of miR-204-5p and reduce the expression of miR-204-5p, thus promoting the expression of GDF7 during osteogenic differentiation. GDF7 induced hADSC osteogenesis differentiation by activating the AKT and P38 signalling pathways. CONCLUSIONS: Our results demonstrated that the miR-204-5p/FOXC1/GDF7 axis regulates the osteogenic differentiation of hADSCs via the AKT and p38 signalling pathways. This study further revealed the regulatory mechanism of hADSC differentiation from the perspective of miRNA regulation.