Search Results (97)

Skin health is significantly impacted by factors such as melanin production, UV-induced photodamage, and wound healing. Excessive melanin leads to hyperpigmentation, while UVA radiation accelerates skin aging and oxidative stress. This study investigated the multi-functional dermatological potential of S strain LS-derived cell-free supernatant (CFS-LS) to address these concerns. Our findings demonstrate that CFS-LS effectively inhibits melanogenesis in B16F10 cells. It significantly reduced α-MSH-induced melanin synthesis, comparable to arbutin, by downregulating key melanogenic enzymes (tyrosinase, TRP-1, and TRP-2) and regulatory proteins (p-CREB, MITF, SOX9, and SOX10). Mechanistically, CFS-LS suppressed the phosphorylation of MEK, ERK, p38, and JNK, indicating a dual inhibitory effect on both PKA/CREB and MAPK pathways. Furthermore, CFS-LS mitigated UVA-induced photodamage in HaCaT cells by significantly reducing intracellular reactive oxygen species and suppressing the downstream phosphorylation of p53 and α-MSH levels. It also restored UVA-suppressed Nrf-2 and HO-1 expression, enhancing cellular antioxidant defenses. Lastly, CFS-LS promoted skin wound healing by significantly enhancing HaCaT cell migration in a scratch assay, associated with increased p-MEK1/2 and p-ERK1/2 levels, and notably elevated collagen type I synthesis. Collectively, these results highlight CFS-LS as a potent multi-functional agent for skin protection and repair, with significant potential for cosmetic and therapeutic applications. The active components of CFS-LS warrant further investigation. Full article

Polynucleotide (PN), a high-molecular-weight DNA fragment derived from salmon and other fish sources, shows promising anti-aging and regenerative effects on the skin. This study investigated how PN enhances collagen synthesis, focusing on its effect on phosphoenolpyruvate carboxykinase 1 (PCK1) in senescent macrophages and its downstream effects on fibroblasts. Using in vitro senescent cell models and in vivo aged animal models, PN significantly upregulated the adenosine 2A receptor (A2AR), adenylate cyclase (AC), cyclic AMP (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) in senescent macrophages. This led to increased PCK1 expression, which reduced oxidative stress and promoted M2 macrophage polarization, associated with elevated levels of interleukin-10 and tumor growth factor-β. Conditioned media from PN-treated macrophages enhanced SMAD family member 2 and signal transducer and activator of transcription 3 phosphorylation in senescent fibroblasts, increasing collagen I and III synthesis and reducing nuclear factor-κB activity. In vivo, PN administration elevated expression of the A2AR/AC/PKA/CREB/PCK1 pathway, reduced oxidative stress, increased M2 macrophage markers, and significantly improved collagen density and skin elasticity over time. Use of a PCK1 inhibitor attenuated these effects, highlighting the pivotal role of PCK1. Overall, PN modulates macrophage-fibroblast interactions via the CREB/PCK1 axis, enhancing collagen synthesis and counteracting age-related skin changes. PN has emerged as a promising therapeutic agent for skin rejuvenation by targeting cellular senescence and promoting extracellular matrix restoration. Full article

Allicin (ALC), a naturally occurring organosulfur compound derived from garlic (Allium sativum), exhibits potential neuroprotective properties. Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by degeneration of dopaminergic neurons and motor dysfunction. This study utilized bioinformatics and network pharmacology methods to predict the anti-PD mechanism of ALC and established in vivo and in vitro PD models using 6-hydroxydopamine (6-OHDA) for experimental verification. Network pharmacological analysis indicates that apoptosis regulation and the PKA/p-CREB/BDNF signaling pathway are closely related to the anti-PD effect of ALC, and protein kinase A (PKA) and dopamine transporter (DAT) are key molecular targets. The experimental results show that ALC administration can alleviate the cytotoxicity of SH-SY5Y induced by 6-OHDA and simultaneously improve the motor dysfunction and dopaminergic neuron loss in PD mice. In addition, ALC can also activate the PKA/p-CREB/BDNF signaling pathway and increase the DAT level in brain tissue, regulate the expression of BAX and Bcl-2, and reduce neuronal apoptosis. These results indicate that ALC can exert anti-PD effects by up-regulating the PKA/p-CREB/BDNF/DAT signaling pathway and inhibiting neuronal apoptosis, providing theoretical support for the application of ALC in PD. Full article

Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article

Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article

Depression is the most disabling neuropsychiatric disorder, but its exact mechanisms remain unclear. Mitochondrial energy metabolism may play a key role in the onset and development of depression. Cytokines such as PGC-1α, NLRP3, and BDNF can influence mitochondrial energy metabolism by regulating mitochondrial biogenesis, immune inflammation, and neuroplasticity, thereby mediating the occurrence and progression of depression. Exercise can improve depression by regulating mitochondrial energy metabolism. The molecular mechanisms are closely related to the upregulation of exercise-induced PGC-1α, AMPK, SIRT1, and BDNF expression, as well as the downregulation of NLRP3 expression. These factors can activate key factors or pathways such as Nrf2, AMPK, and PKA/CREB, while inhibiting the excessive activation of NF-κB. Through these mechanisms, they regulate the expression of downstream target genes (such as TFAM, NRF1, CREB, and Bcl-2), thereby enhancing mitochondrial biogenesis and improving the quantity and quality of mitochondria. Additionally, they can act to inhibit the release of inflammatory factors to improve immune inflammation, enhance neuroplasticity, promote neuronal growth, and facilitate synapse formation and remodeling, thereby enhancing mitochondrial energy metabolism and improving its dysfunction, which in turn alleviates depression. Currently, there is a lack of systematic and comprehensive research on the mechanisms by which exercise improves depression through mitochondrial energy metabolism. Therefore, this article aims to review and analyze the role of mitochondrial energy metabolism in the improvement of depression through exercise, in order to provide a new theoretical basis and research ideas for the prevention and treatment of depression. Full article

Pentagalloylglucose (PGG) is a powerful antioxidant and a naturally derived polyphenolic compound present in tannins. In this study, we investigated the ability of PGG to selectively inhibit hyperpigmentation through the regulation of melanogenesis in melanocytes. PGG inhibited melanin production in α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. Furthermore, PGG suppressed the expression of melanin synthesis enzymes, such as tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. The mRNA and protein expression of the microphthalmia-associated transcription factor, which is involved in the mechanism of melanogenesis, was also reduced by PGG, and this effect was induced via PKA/CREB and MAPK phosphorylation. These results suggest that PGG inhibits α-MSH-induced melanin production by regulating the PKA/CREB/MAPK signaling pathway, indicating that natural compounds can serve as inhibitors of melanogenesis. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine (SCOP)-induced cognitive impairment in mice. Forty male albino mice were divided into five groups: normal control, SCOP control, CGA + SCOP, CILO + SCOP and CILO + CGA + SCOP. Behavioral assessments, including the Y-maze and pole climbing tests, demonstrated that SCOP significantly impaired cognition, while treatment with CILO and CGA reversed these deficits, with the combination group showing the greatest improvement. Histopathological analyses revealed that CILO and CGA reduced neuronal damage and amyloid beta (Aβ) accumulation. Immunohistochemical and biochemical assessments confirmed a decrease in neuroinflammatory markers, including tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). Molecular analyses showed that CILO restored cyclic adenosine monophosphate (cAMP) levels, leading to activation of protein kinase A (PKA), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), key regulators of neuronal plasticity and survival. CGA enhanced these effects by further inhibiting PDE4, amplifying the neuroprotective response. These findings suggest that PDE4 inhibitors, particularly in combination with CGA, may represent promising therapeutic strategies for AD-related cognitive impairment. Full article

Background: The early nutritional metabolism of piglets is intimately associated with the regulation of immune function, and amino acids play a crucial role in modulating the fate and function of porcine immune cells, especially macrophages. However, the metabolic changes upon macrophage activation remain elusive. Methods: We established an in vitro activation model of porcine macrophages and investigated alterations in metabolites involved in polyamine and tryptophan metabolism upon activation by various toll-like receptor (TLR) activators. Results: TLR activation inhibits the production of spermine and alters the kynurenine pathway of the tryptophan metabolism toward the kynurenic acid biosynthesis. Specifically, TLR9 activation redirects the metabolic pathway of tryptophan toward kynurenic acid synthesis, which subsequently inhibits melatonin production via the protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)/cAMP-responsive element-binding protein (CREB) signaling pathways. Conclusions: TLR activation reprograms the polyamine and tryptophan metabolism in porcine macrophages. Knowledge of the metabolic alterations in polyamine and tryptophan upon TLR activation in macrophages offers valuable insights and potential strategies for nutritional intervention to enhance piglet immunity. Full article

L-Theanine, a natural amino acid found in green tea (Camellia sinensis) leaves, is known for its diverse psychotropic effects. This study aimed to evaluate the inhibitory effect of L-theanine on melanin production and uncover its regulatory mechanism. We evaluated the anti-melanogenic activities of L-theanine in vitro and in vivo. In B16F10 murine melanoma cells induced by α-melanocyte-stimulating hormone, melanin content and intracellular tyrosinase activity were determined, and melanogenesis-related protein expression and signaling pathways were analyzed by Western blotting. Melanin reduction was further assessed using the zebrafish (Danio rerio) test. L-Theanine reduced the intracellular tyrosinase activity and melanin content of B16F10 cells. It also attenuated the expression of melanogenesis-related proteins, such as microphthalmia- associated transcription factor, tyrosinase (TYR), TYR-related protein-1, and dopachrome tautomerase. L-Theanine modulated the protein kinase A (PKA), cAMP responder element binding protein (CREB), phosphorylation of/protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), and β-catenin. The antimelanogenic activity of L-theanine (<2 mg/mL) was further confirmed using zebrafish larvae. L-Theanine inhibited melanogenesis by downregulating the PKA/CREB and Akt/GSK-3β/β-catenin signaling pathways. In summary, L-theanine shows potential as a skin-whitening compound, warranting further investigation for its possible applications in cosmetic and pharmaceutical products. Full article

Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications in treating hyperpigmentation disorders. Methods: The anti-melanogenic effects of voglibose were investigated using B16F10 melanoma cells. Cell viability, melanin content, and tyrosinase activity were assessed following voglibose treatment. Western blot analysis was performed to examine changes in melanogenic proteins and transcription factors. The role of signaling pathways, including PKA/CREB, MAPK, PI3K/AKT, and GSK3β/β-Catenin, was analyzed. Primary human skin irritation tests were conducted to evaluate the topical safety of voglibose. Results: Voglibose significantly reduced melanin synthesis and tyrosinase activity in B16F10 cells in a dose-dependent manner. Western blot analysis revealed decreased expression of MITF, TRP-1, and TRP-2, indicating the inhibition of melanogenesis. Voglibose modulated key signaling pathways, including the suppression of PKA/CREB, MAPK, and AKT activation, while restoring GSK3β activity to inhibit β-catenin stabilization. Human skin irritation tests confirmed voglibose’s safety for topical application, showing no adverse reactions at 50 and 100 μM concentrations. Conclusions: Voglibose demonstrates anti-melanogenic properties through the modulation of multiple signaling pathways and the inhibition of melanin biosynthesis. Its safety profile and efficacy suggest its potential as a repurposed drug for managing hyperpigmentation and advancing cosmeceutical applications. Full article

Chalcones are recognized for their diverse pharmacological properties, including anti-inflammatory and anti-melanogenic effects. However, studies on 2′-hydroxy-2-methoxychalcone derivatives remain limited. This study investigated the anti-inflammatory and melanin synthesis-inhibitory effects of three derivatives: 2′-hydroxy-2,4-dimethoxychalcone (2,4-DMC), 2′-hydroxy-2,5′-dimethoxychalcone (2,5′-DMC), and 2′-hydroxy-2,6′-dimethoxychalcone (2,6′-DMC). In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, 2,6′-DMC demonstrated a superior inhibition of nitric oxide (NO) production, pro-inflammatory cytokines, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) compared to the other derivatives. A mechanistic analysis revealed that 2,6′-DMC modulates the NF-κB and MAPK signaling pathways to attenuate inflammation. Additionally, 2,6′-DMC exhibited a significant inhibition of α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16F10 melanoma cells by downregulating tyrosinase, TRP-1, TRP-2, and MITF expression. This regulation was achieved through the suppression of the Wnt/β-catenin, PI3K/AKT, MAPK, and PKA/CREB pathways. Compared to 2,4-DMC and 2,5′-DMC, 2,6′-DMC’s structural configuration, characterized by methoxy groups at the 2- and 6′-positions, contributed to its enhanced molecular stability and binding affinity, amplifying its inhibitory effects. A primary skin irritation test confirmed that 2,6′-DMC exhibited minimal irritation, demonstrating its safety for dermal applications. These findings suggest that 2,6′-DMC holds promise as a dual-function agent for managing inflammatory conditions and hyperpigmentation-related disorders. Full article

Prolactinomas are commonly treated with dopamine receptor agonists (DAs), such as bromocriptine (BRC) and cabergoline (CAB). However, 10–30% of patients exhibit resistance to DA therapies. DA resistance is largely associated with reduced dopamine D2 receptor (DRD2) expression, potentially regulated by epigenetic modifications, though the underlying mechanisms are still unclear. Clinical samples were assessed for p300 expression. MMQ and AtT-20 cells were engineered to overexpress either wild-type p300 or a histone acetyltransferase (HAT) domain-mutant form of p300. Mechanistic studies included cell proliferation assays, flow cytometry, immunohistochemistry, immunofluorescence, co-immunoprecipitation, chromatin immunoprecipitation followed by quantitative PCR, reverse transcription quantitative PCR, and Western blotting. Additionally, an in vivo nude mouse xenograft model was used to confirm the in vitro findings. DAs downregulated p300 through the cAMP-PKA-CREB pathway. Activation of the HAT domain of p300 increased H3K18/27 acetylation, promoted DRD2 transcription, and worked synergistically with DA to exert anti-tumor effects both in vitro and in vivo. Tanshinone IIA (Tan IIA) upregulated p300 and DRD2, enhancing the therapeutic efficacy of BRC. These findings highlight the role of p300 in regulating DRD2 transcription in DA-resistant prolactinomas. Combining Tan IIA with BRC may offer a promising strategy to overcome DA resistance. Full article

Asthma is a chronic airway inflammation that is considered a serious public health concern worldwide. Nobiletin (5,6,7,8,3′,4′-hexamethyl flavonoid), an important compound isolated from several traditional Chinese medicines, especially Citri Reticulatae Pericarpium, is widely used for a number of indications, including cancer, allergic diseases, and chronic inflammation. However, the mechanism by which nobiletin exerts its anti-asthmatic effect remains unclear. In this research, we comprehensively demonstrated the anti-asthmatic effects of nobiletin in an animal model of asthma. It was found that nobiletin significantly reduced the levels of inflammatory cells and cytokines in mice and alleviated airway hyperresponsiveness. To explore the target of nobiletin, we identified PDE4B as the target of nobiletin through pharmacophore modeling, molecular docking, molecular dynamics simulation, SPR, and enzyme activity assays. Subsequently, it was found that nobiletin could activate the cAMP-PKA-CREB signaling pathway downstream of PDE4B in mouse lung tissues. Additionally, we studied the anti-inflammatory and anti-airway remodeling effects of nobiletin in LPS-induced RAW264.7 cells and TGF-β1-induced ASM cells, confirming the activation of the cAMP-PKA-CREB signaling pathway by nobiletin. Further validation in PDE4B-deficient RAW264.7 cells confirmed that the increase in cAMP levels induced by nobiletin depended on the inhibition of PDE4B. In conclusion, nobiletin exerts anti-asthmatic activity by targeting PDE4B and activating the cAMP-PKA-CREB signaling pathway. Full article

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), K_ATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists. Full article