Tailored synthesis of pH-responsive biodegradable microcapsules incorporating gelatin, alginate, and hyaluronic acid for effective-controlled release.

In response to escalating environmental concerns and the urgent need for sustainable drug delivery systems, this study introduces biodegradable pH-responsive microcapsules synthesized from a blend of gelatin, alginate, and hyaluronic acid. Employing the coacervation process, capsules were created with a spherical shape, multicore structure, and small sizes ranging from 10 to 20 µm, which exhibit outstanding vitamin E encapsulation efficiency. With substantial incorporation of hyaluronic acid, a pH-responsive component, the resulting microcapsules displayed noteworthy swelling behavior, facilitating proficient core ingredient release at pH 5.5 and 7.4. Notably, these capsules can effectively deliver active substances to the dermal layer under specific skin conditions, revealing promising applications in topical medications and cosmetics. Furthermore, the readily biodegradable nature of the designed capsules was demonstrated through Biochemical Oxygen Demand (BOD) testing, with over 80 % of microcapsules being degraded by microorganisms after one week of incubation. This research contributes to the development of responsive microcapsules and aligns with broader environmental initiatives, offering a promising pathway to mitigate the impact of microplastics while advancing various applications.

Anti-pollutant effect of oleic acid against urban particulate matter is mediated via regulation of AhR- and TRPV1-mediated signaling in vitro.

Urban Particulate Matter (UPM) induces skin aging and inflammatory responses by regulating skin cells through the transient receptor potential vanilloid 1 (TRPV1). Although oleic acid, an unsaturated free fatty acid (FFA), has some functional activities, its effect on UPM-induced skin damage has not been elucidated. Here, we investigated signaling pathways on how oleic acid is involved in attenuating UPM induced cell damage. UPM treatment increased XRE-promoter luciferase activity and increased translocation of AhR to the nucleus, resulting in the upregulation of CYP1A1 gene. However, oleic acid treatment attenuated the UPM effects on AhR signaling. Furthermore, while UPM induced activation of TRPV1 and MAPKs signaling which activated the downstream molecules NFκB and AP-1, these effects were reduced by cotreatment with oleic acid. UPM-dependent generation of reactive oxygen species (ROS) and reduction of cellular proliferation were also attenuated by the treatment of oleic acid. These data reveal that cell damage induced by UPM treatment occurs through AhR signaling and TRPV1 activation which in turn activates ERK and JNK, ultimately inducing NFκB and AP-1 activation. These effects were reduced by the cotreatment of oleic acid on HaCaT cells. These suggest that oleic acid reduces UPM-induced cell damage through inhibiting both the AhR signaling and activation of TRPV1 and its downstream molecules, leading to a reduction of pro-inflammatory cytokine and recovery of cell proliferation.

In vitro and in vivo neuroprotective effect of novel mPGES-1 inhibitor in animal model of Parkinson's disease.

mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE2 IC50 = 41.77 nM; mPGES-1 IC50 = 1.16 nM) exhibited a potent neuroprotection (ED50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC50 = >10 µM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients.

Antioxidant Activities and Mechanisms of Tomentosin in Human Keratinocytes.

Tomentosin, one of natural sesquiterpene lactones sourced from Inula viscosa L., exerts therapeutic effects in various cell types. Here, we investigated the antioxidant activities and the underlying action mechanisms of tomentosin in HaCaT cells (a human keratinocyte cell line). Specifically, we examined the involvement of tomentosin in aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Treatment with tomentosin for up to 60 min triggered the production of reactive oxygen species (ROS), whereas treatment for 4 h or longer decreased ROS production. Tomentosin treatment also induced the nuclear translocation of Nrf2 and upregulated the expression of Nrf2 and its target genes. These data indicate that tomentosin induces ROS production at an early stage which activates the Nrf2 pathway by disrupting the Nrf2-Keap1 complex. However, at a later stage, ROS levels were reduced by tomentosin-induced upregulation of antioxidant genes. In addition, tomentosin induced the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38 MAPK and c-Jun N-terminal kinase (JNK). SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inhibitor) attenuated the tomentosin-induced phosphorylation of Nrf2, suggesting that JNK and p38 MAPK signaling pathways can contribute to the tomentosin-induced Nrf2 activation through phosphorylation of Nrf2. Furthermore, N-acetyl-L-cysteine (NAC) treatment blocked both tomentosin-induced production of ROS and the nuclear translocation of Nrf2. These data suggest that tomentosin-induced Nrf2 signaling is mediated both by tomentosin-induced ROS production and the activation of p38 MAPK and JNK. Moreover, tomentosin inhibited the AhR signaling pathway, as evidenced by the suppression of xenobiotic-response element (XRE) reporter activity and the translocation of AhR into nucleus induced by urban pollutants, especially benzo[a]pyrene. These findings suggest that tomentosin can ameliorate skin damage induced by environmental pollutants.

Inducible Prostaglandin E Synthase as a Pharmacological Target for Ischemic Stroke.

As the inducible terminal enzyme for prostaglandin E2 (PGE2) synthesis, microsomal PGE synthase-1 (mPGES-1) contributes to neuroinflammation and secondary brain injury after cerebral ischemia via producing excessive PGE2. However, a proof of concept that mPGES-1 is a therapeutic target for ischemic stroke has not been established by a pharmacological strategy mainly due to the lack of drug-like mPGES-1 inhibitors that can be used in relevant rodent models. To this end, we recently developed a series of novel small-molecule compounds that can inhibit both human and rodent mPGES-1. In this study, blockade of mPGES-1 by our several novel compounds abolished the lipopolysaccharide (LPS)-induced PGE2 and pro-inflammatory cytokines interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α) in mouse primary brain microglia. Inhibition of mPGES-1 also decreased PGE2 produced by neuronal cells under oxygen-glucose deprivation (OGD) stress. Among the five enzymes for PGE2 biosynthesis, mPGES-1 was the most induced one in cerebral ischemic lesions. Systemic treatment with our lead compound MPO-0063 (5 or 10 mg/kg, i.p.) in mice after transient middle cerebral artery occlusion (MCAO) improved post-stroke well-being, decreased infarction and edema, suppressed induction of brain cytokines (IL-1ß, IL-6, and TNF-α), alleviated locomotor dysfunction and anxiety-like behavior, and reduced the long-term cognitive impairments. The therapeutic effects of MPO-0063 in this proof-of-concept study provide the first pharmacological evidence that mPGES-1 represents a feasible target for delayed, adjunct treatment - along with reperfusion therapies - for acute brain ischemia.

Olfactory Receptor OR7A17 Expression Correlates with All-Trans Retinoic Acid (ATRA)-Induced Suppression of Proliferation in Human Keratinocyte Cells.

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.

Protective Effects of Maclurin against Benzo[a]pyrene via Aryl Hydrocarbon Receptor and Nuclear Factor Erythroid 2-Related Factor 2 Targeting.

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon formed during the incomplete combustion of organic matter, has harmful effects. Therefore, much research is ongoing to develop agents that can mitigate the effects of B[a]P. The aim of this study was to examine the effect of maclurin, one component of the branches of Morus alba L., on the B[a]P-induced effects in HaCaT cells, a human keratinocyte cell line. Maclurin treatment inhibited aryl hydrocarbon receptor (AHR) signaling as evidenced by reduced xenobiotic response element (XRE) reporter activity, decreased expression of cytochrome P450 1A1 (CYP1A1), and reduced nuclear translocation of AHR. The B[a]P-induced dissociation of AHR from AHR-interacting protein (AIP) was suppressed by maclurin. Maclurin also inhibited the production of intracellular reactive oxygen species (ROS) induced by B[a]P. In addition, the antioxidant property of maclurin itself was demonstrated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Furthermore, maclurin activated antioxidant response element (ARE) signaling through enhancement of ARE luciferase reporter activity and the expression of ARE-dependent genes including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). Nrf2 activation and its nuclear translocation were promoted by maclurin through p38 MAPK activation. These data indicate that maclurin had antagonistic activity against B[a]P effects through activation of Nrf2-mediated signaling and inhibition of AHR signaling and, suggesting its potential in protecting from harmful B[a]P-containing pollutants.

Mechanisms of Resorcinol Antagonism of Benzo[a]pyrene-Induced Damage to Human Keratinocytes.

Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon and ubiquitous environmental toxin with known harmful effects to human health. Abnormal phenotypes of keratinocytes are closely associated with their exposure to B[a]P. Resorcinol is a component of argan oil with reported anticancer activities, but its mechanism of action and potential effect on B[a]P damage to the skin is unknown. In this study, we investigated the effects of resorcinol on B[a]P-induced abnormal keratinocyte biology and its mechanisms of action in human epidermal keratinocyte cell line HaCaT. Resorcinol suppressed aryl hydrocarbon receptor (AhR) activity as evidenced by the inhibition of B[a]P-induced xenobiotic response element (XRE)-reporter activation and cytochrome P450 1A1 (CYP1A1) expression. In addition, resorcinol attenuated B[a]P-induced nuclear translocation of AhR, and production of ROS and pro-inflammatory cytokines. We also found that resorcinol increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activity. Antioxidant response element (ARE)-reporter activity and expression of ARE-dependent genes NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase-1 (HO-1) were increased by resorcinol. Consistently, resorcinol treatment induced nuclear localization of Nrf2 as seen by Western analysis. Knockdown of Nrf2 attenuated the resorcinol effects on ARE signaling, but knockdown of AhR did not affect resorcinol activation of Nrf2. This suggests that activation of antioxidant activity by resorcinol is not mediated by AhR. These results indicate that resorcinol is protective against effects of B[a]P exposure. The mechanism of action of resorcinol is inhibition of AhR and activation of Nrf2-mediated antioxidant signaling. Our findings suggest that resorcinol may have potential as a protective agent against B[a]P-containing pollutants.

Blue Light Irradiation Induces Human Keratinocyte Cell Damage via Transient Receptor Potential Vanilloid 1 (TRPV1) Regulation.

Although blue light has been reported to affect skin cells negatively, little is known about its action mechanisms in skin cells. Therefore, we investigated the role of the transient receptor potential vanilloid 1 (TRPV1) in blue light-induced effects on human keratinocytes and its underlying mechanisms. Blue light decreased cell proliferation and upregulated TRPV1 expression. Blue light also suppressed the epidermal growth factor receptor- (EGFR-) mediated signaling pathway by reducing the protein levels of EGFR and suppressing the EGFR/PI3K/AKT/GSK3ß/FoxO3a pathway. The blue light-induced effect in cell proliferation was reversed by TRPV1 siRNA, but not capsazepine, a TRPV1-specific antagonist. In addition, blue light irradiation increased the production of reactive oxygen species (ROS) and tumor necrosis factor-α (TNF-α). Blue light irradiation also increased both phosphorylation levels of TRPV1 and calcium influx. The blue light-induced increase in production of ROS and TNF-α was reversed by capsazepine. Furthermore, the blue light-induced increase in production of TNF-α was attenuated by SP600125 or PDTC. These findings show that blue light regulates cell survival and production of ROS and TNF-α; its effects are mediated via TRPV1. Specifically, the effects of blue light on cell proliferation are mediated by upregulating TRPV1, a negative regulator of EGFR-FoxO3a signaling. Blue light-induced production of ROS and TNF-α is also mediated through increased calcium influx via TRPV1 activation.