Protection of Proanthocyanidins Against HSP Serum-Induced Inflammation and Oxidative Stress on Human Umbilical Vein Endothelial Cells.

Background: Immune-mediated inflammation and oxidative stress play pivotal roles in Henoch-Schonlein purpura (HSP), primarily through the TLR4/MyD88/NF-κB pathway. Proanthocyanidins (PCs) exert anti-inflammatory and antioxidant effects by regulating some signals like TLR4/MyD88/NF-κB. Previous research uncovered that PCs could alleviate purpura-like lesions and pathological changes on rats likely through attenuating inflammation and OS damage. The mechanism of PCs on HSP deserves further investigation. Objective: To clarify the potential mechanism of PCs to HUVECs induced by the serum of HSP patients. Methods: HUVECs were randomly divided into blank, control, model, and low-, medium-, and high-concentration PCs group. Then, 25% HSP serum was assigned to the latter four groups, while 25% serum from healthy subjects to control group and serum-free culture medium to blank one. The last three groups separately received different concentrations of PCs. In addition, TAK-242, a TLR4 inhibitor, was applied to investigate the effect of TLR4-related signals in PCs against HSP serum-induced damage. Finally, inflammatory and OS-related parameters were detected by using cytological/molecular-biological techniques. Results: Treated with HSP serum later, the levels of immuno-inflammatory and oxidative indicators obviously went up (P < 0.05), and those of antioxidants remarkably went down (P < 0.05). PCs, however, reversed above phenomena (P < 0.05). Moreover, TLR4, MyD88 and NF-κB proteins/genes highly expressed in the model group; but significantly fell off in the presence of PCs (P < 0.05). Amazingly, all of above indicators showed no significant difference among the groups of different PCs concentrations (P > 0.05). These alterations likewise occurred after TAK-242 pretreatment with or without PCs, ie a notable drop of TLR4, MyD88 and NF-κB appeared in TAK-242 presence, few differences existing when compared to the PCs groups. Conclusion: PCs effectively protect HUVECs from inflammatory and OS damage provoked by HSP serum via blocking TLR4/MyD88/NF-κB signals.

Discovery of potent NAMPT-Targeting PROTACs using FK866 as the warhead.

Nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising target for cancer therapy due to its strong correlation with nicotinamide adenine dinucleotide (NAD+) metabolism and tumorigenesis. Proteolysis targeting chimeras (PROTACs) provided an attractive strategy for developing NAMPT-targeting NAD+-depleting cancer drugs. Herein, a series of von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs were designed using NAMPT inhibitor FK866 as the warhead. Among them, compound C5 degraded NAMPT (DC50 = 31.7 nM) in a VHL- and proteasome-dependent manner. Moreover, compound C5 effectively inhibited the proliferation of A2780 cells (IC50 = 30.6 nM) and significantly reduced the general cytotoxicity of FK866 to normal cells.

An Unusual Case of Cutaneous Pili Migrans in a 45-Day-Old Infant.

Cutaneous Pili Migrans (CPM), a rare skin condition, is composed of hair fragments embedded in the skin epidermis and dermis after skin trauma or for unknown reasons. To the best of our knowledge, there are few reports on cases of CPM in which hair is exposed outside of the skin. Herein, we report an unusual and rare case of 45 days old Chinese male infant with CPM.

Proanthocyanidins: A novel approach to Henoch­Schonlein purpura through balancing immunity and arresting oxidative stress via TLR4/MyD88/NF­κB signaling pathway (Review).

Henoch-Schonlein purpura (HSP), a recurrent and immunoglobulin (Ig)A-mediated vasculitis, presents not only as skin lesions but also as systemic involvement that can be life-threatening. Although the etiology of HSP remains unknown, immune imbalance and oxidative stress (OS) are primary contributors to its pathogenesis, alongside the abnormal activation of Toll-like receptor (TLR)/myeloid differentiation primary response gene 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. TLRs, especially TLR4, stimulate downstream signaling molecules such as NF-κB and proinflammatory cytokines, which are released when TLRs combine with the key adapter molecule MyD88. This leads to the activation of T helper (Th) cell 2/Th17 and overproduction of reactive oxygen species (ROS). The function of regulatory T (Treg) cells is suppressed in the process. Th17/Treg imbalance then produces various inflammatory cytokines to promote proliferation and differentiation of B cells and the secretion of antibodies. IgA is secreted, and it binds to vascular endothelial surface receptors where the complex induces injury of the vascular endothelial cells. Additionally, excessive ROS creates OS that leads to an inflammatory response and vascular cell apoptosis or necrosis, thereby contributing to vascular endothelial damage and HSP occurrence. Proanthocyanidins are active compounds naturally enriched in fruits, vegetables and plants. Proanthocyanidins have diverse properties, including anti-inflammatory, antioxidant, antibacterial, immunoregulatory, anticarcinogenic and vascular protective effects. Proanthocyanidins are used in the management of various diseases. Proanthocyanidins regulate T cells, equilibrate immunity and arrest OS by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Considering the pathogenesis of HSP and the properties of proanthocyanidins, the present study hypothesized that these compounds may potentially lead to HSP recovery through modulating the immune equilibrium and preventing OS by inhibiting the TLR4/MyD88/NF-κB pathway. To the best of our knowledge, however, little is known about the positive effects of proanthocyanidins against HSP. The present review summarizes the potential of proanthocyanidins to treat HSP.

Associations between exposure to a mixture of perfluoroalkyl and polyfluoroalkyl substances and age at menarche in adolescent girls utilizing three statistical models.

Exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) is suggested to interfere with endocrine function and may affect female pubertal development. However, the epidemiological evidence on age at menarche associated with PFAS exposure is still inconsistent. Our objective was to investigate association of serum PFAS concentrations with age at menarche among 12-19 years old girls. We used data on 432 girls from National Health and Nutrition Examination Survey (NHANES) 2007-2012 cycles. NHANES reported serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) as quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Age at menarche was self-reported by girls or their guardians. Multivariable linear regression models were applied to estimate the association of individual PFAS exposure with age at menarche. The combined effects of PFAS mixture exposures on age at menarche were assessed using three statistical methods, including Bayesian kernel machine regression (BKMR), weighted quantile sum regression (WQS), and elastic net regression (ENR). In the single-chemical model, girls in the middle tertile of serum PFOA concentration had a lower age at menarche [regression coefficient (ß) = -0.73 years, 95% confidence interval (CI): -1.44, -0.01; P = 0.047], compared with those in the lower tertile. Girls in the higher tertile of PFNA exposure were associated with older age at menarche (ß = 0.36 years, 95% CI: 0.03, 0.80; P = 0.027), compared with those in the lower tertile. In the multiple-chemical models using BKMR and ENR approaches, higher PFNA exposure was significantly associated with older age at menarche among girls, after adjusting for other PFAS. We found suggestive evidence that higher PFAS mixture exposures may be related to an increase in age at menarche using the BKMR model. In conclusion, exposure to PFNA was associated with the later timing of menarche among girls.

Associations between exposure to a mixture of phenols and sex steroid hormones among pre- and postmenopausal women: evidence from NHANES 2015-2016.

Environmental phenols are well known as emerging endocrine-disrupting chemicals; however, their impacts on sex hormone homeostasis among pre- and postmenopausal women remain unknown. Our objective was to evaluate independent and combined relationships between phenol levels in urine and sex steroid hormones among 323 premenopausal women and 263 postmenopausal women from National Health and Nutrition Examination Survey (NHANES) 2015-2016. A total of 10 phenol concentrations in urine were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum concentrations of estradiol and total testosterone were measured by LC-MS/MS and serum sex hormone-binding globulin (SHBG) concentrations were measured using an immunofluorometric assay. Multivariable linear regression models were conducted to explore associations of individual phenol concentration in urine with natural logarithm-transformed serum hormone levels. Bayesian kernel machine regression (BKMR) model was conducted to evaluate phenol mixtures exposure in association with sex hormones among pre- and postmenopausal women, respectively. Considering both single-chemical models and multiple-chemical models, each doubling of urinary BPS concentration was significantly inversely related to serum SHBG concentration in premenopausal women (percent change: -6.70%, 95% confidence interval, CI: -11.12%, -2.73%; P = 0.002). Moreover, every doubling of urinary BP-3 concentration was significantly positively associated with SHBG level in serum (percent change: 3.53%, 95%CI: 0.70%, 5.70%; P = 0.008). Regarding postmenopausal women, inverse associations between urinary BPS levels and serum estradiol concentrations were observed (percent change: -8.62%, 95% CI: -15.33%, -2.06%; P = 0.012). The results revealed that BPS and BP-3 exposure may adversely disrupt sex hormone homeostasis at the current exposure levels among women in the USA. The findings and their underlying mechanisms are warranted to be confirmed and comprehensively interpreted in further epidemiological and experimental studies.

The protective effect of proanthocyanidins on the psoriasis-like cell models via PI3K/AKT and HO-1.

BACKGROUND: Inflammation and oxidative stress (OS) are important contributors to psoriasis pathogenesis. Proanthocyanidins (PCs) have anti-inflammatory and anti-oxidative activities. Previously, we discovered that PCs alleviated psoriasis-like mice symptoms, likely via mitigating inflammation and OS damage. OBJECTIVE: To elucidate the protective mechanism underlying PCs against the damage of TNF-ɑ-induced psoriasis-like cell models. METHODS: Psoriasis-like cell models were established with 7.5 ng/mL TNF-ɑ and then subjected to different-concentrations PCs treatment. Finally, inflammatory and oxidative parameters were determined. Besides, LY294002 (PI3K inhibitor) and ZnPP (HO-1 inhibitor) were employed to investigate the roles of PI3K/AKT and HO-1 in PCs against psoriasis-like cell models. RESULTS: After TNF-α treatment, cells organized tightly and proliferated greatly (P<0.01); HO-1 expression dropped obviously, along with the increased OS/inflammatory indicators and the decreased antioxidants (P<0.05); consequently, psoriasis-like cell models were well established. In the presence of PCs, nevertheless, the proliferation rate and number of psoriasis-like cells evidently decreased (P<0.01), accompanied with enhanced HO-1 and antioxidants, and lowered OS/inflammatory indicators as well as phosphorylated JAK2/STAT3/PI3/AKT (P<0.01). Similar changes appeared after LY294002 pretreatment, regardless of PCs or not. But after ZnPP pretreatment with or without PCs, the opposite occurred. CONCLUSION: The study reveals that PCs can suppress psoriasis-like cell proliferation and reduce inflammatory/OS damage through PI3K/AKT inhibition and HO-1 activation, thus promising a candidate for PCs in treating psoriasis.

An Emerging Role of Proanthocyanidins on Psoriasis: Evidence from a Psoriasis-Like Mouse Model.

Background: Psoriasis is an immune-mediated, chronic inflammatory disease, and genetic, immune, oxidative stress (OS), and environmental factors are all thought to contribute to its occurrence. Proanthocyanidins (PCs) are natural flavonoids consisting of catechins and epicatechins which have anti-inflammatory and anti-OS activities. PCs have been widely used to treat various diseases, but reports regarding psoriasis are rare. Objective: To investigate the therapeutic effect and potential mechanisms of action of PCs in a psoriasis-like mouse model. Methods: Thirty male BALB/c hairless mice were assigned to six groups (n = 5): normal, model, low-dose PCs, medium-dose PCs, high-dose PCs, and control groups. The final five groups were dorsally exposed to 5% imiquimod (IMQ) cream once a day for 6 consecutive days, while the normal group received no intervention. Following the first day of IMQ application, mice in the PC-treated group were dosed with different amounts of PCs daily by oral gavage for six days, whereas mice in the control group received normal saline in the same way. One week later, skin lesions were evaluated by the severity of scoring system based on psoriasis area and severity index (PASI), and pathological alterations were assessed by hematoxylin-eosin (HE) staining. Indicators of inflammation or OS, such as interleukin- (IL-) 17, IL-23, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), catalase (CAT), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and heme oxygenase-1 (HO-1), were determined by ELISA, RT-PCR, western blot, and immunohistochemistry (IHC) analysis. Results: IMQ administration induced the formation of large dark red plaques with thickly layered scales on the dorsal skin of mice; nevertheless, the lesions were substantially alleviated by PC administration. Histopathological alterations were observed in both model and control groups with epidermal hyperkeratosis, granulosa layer thinning, acanthosis, downward extension of rete ridges, dermal papillae expansion, capillary hyperplasia, and infiltration by inflammatory cells around blood vessels. These pathological changes, however, were restored by a range of doses of PCs, high-dose PCs in particular. Different doses of PCs significantly lowered the spleen index, levels of inflammatory or oxidative proteins (IL-17, IL-23, MDA, ROS, p-PI3K, and p-STAT3), and the mRNA expression of Il-17, Il-23, Vegf, and iNos. Protein and mRNA levels of anti-OS and anti-inflammatory biomarkers, including SOD, CAT, GSH, and HO-1, greatly increased after PC treatment, especially at the highest dose. Conclusions: Our findings reveal that PCs ameliorate psoriasis-like symptoms, suppressing the inflammatory response and mitigating OS damage in an IMQ-induced psoriasis-like mouse model. These effects are probably related to the inactivation of STAT3 and PI3K and activation of HO-1 signaling.

Hydrophobic Tagging-Induced Degradation of PDEδ in Colon Cancer Cells.

The development of KRAS-PDEδ protein-protein interaction (PPI) inhibitors is generally hampered by limited antitumor activity. Herein, the first hydrophobic tagging (HyT)-based PDEδ degraders were designed. Compound 17c efficiently bound to PDEδ and induced degradation of PDEδ in SW480 colon cancer cells. As compared with PDEδ inhibitor deltazinone, HyT-based degrader 17c exhibited improved antitumor activity toward KRAS mutant cancer cells. This study highlighted the potential of HyT as a valuable chemical tool for tumorigenic PDEδ knockdown, which could be developed into a promising strategy for antitumor drug discovery.

Current evidence to support the therapeutic potential of flavonoids in oxidative stress-related dermatoses.

BACKGROUND: Skin, as a crucial external defense organ, is more vulnerable to oxidative stress (OS) insult, reactive oxygen species (ROS)-mediated OS in particular. OS results from a redox imbalance caused by various extrinsic stimuli and occurs once the oxidants production overwhelming the antioxidants capacity, through mediating in DNA damage, lipid peroxidation (LPO), protein oxidation and a serial of signaling pathways activation/inactivation, thereby offering favorable conditions for the occurrence and development of numerous diseases especially some dermatoses, e.g. psoriasis, vitiligo, skin photodamage, skin cancer, systemic sclerosis (SSc), chloasma, atopic dermatitis (AD), pemphigus, etc. Targeting OS molecular mechanism, a variety of anti-OS agents emerge, in which flavonoids, natural plant extracts, stand out. OBJECTIVES: To discuss the possible mechanisms of OS mediating in dermatoses and summarize the properties of flavonoids as well as their applications in OS-related skin disorders. METHODS: Published papers on flavonoids and OS-related skin diseases were collected and reviewed via database searching on PubMed, MEDLINE and Embase, etc. RESULTS: It has been confirmed that flavonoids, belonging to polyphenols, are a class of plant secondary metabolites widely distributed in various plants and possess diverse bioactivities especially their potent antioxidant capacity. Moreover, flavonoids benefit to suppress OS via eliminating free radicals and mediating the corresponding signals, further excellently working in the prevention and management of OS-related skin diseases. CONCLUSION: Flavonoids have the potential therapeutic effects on oxidative stress-related dermatoses. However, more studies on specific mechanism as well as the dosage of flavonoids are needed in future.