Inhibition of Melanoma Cell Growth by Salvianolic Acid A through CHK2-CDC25A Pathway Modulation.

BACKGROUND: This study investigated the impact of salvianolic acids, derived from Danshen, on melanoma cell growth. Specifically, we assessed the ability of salvianolic acid A (Sal A) to modulate melanoma cell proliferation. METHODS: We used human melanoma A2058 and A375 cell lines to investigate the effects of Sal A on cell proliferation and death by measuring bromodeoxyuridine incorporation and lactate dehydrogenase release. We assessed cell viability and cycle progression using water soluble tetrazolium salt-1 (WST-1) mitochondrial staining and propidium iodide. Additionally, we used a phospho-kinase array to investigate intracellular kinase phosphorylation, specifically measuring the influence of Sal A on checkpoint kinase-2 (Chk-2) via western blot analysis. RESULTS: Sal A inhibited the growth of A2058 and A375 cells dose-responsively and induced cell cycle arrest at the G2/M phase. Notably, Sal A selectively induces Chk-2 phosphorylation without affecting Chk-1, thereby degrading Chk-2-regulated genes Cdc25A and Cdc2. However, Sal A does not affect the Chk1-Cdc25C pathway. CONCLUSIONS: Salvianolic acids, especially Sal A, effectively hinder melanoma cell growth by inducing Chk-2 phosphorylation and disrupting G2/M checkpoint regulation.

NGF facilitates ICAM-1-dependent monocyte adhesion and M1 macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder in which monocytes adhering to synovial tissue differentiate into the pro-inflammatory M1 macrophage phenotype. Nerve growth factors (NGF) referred to as neurotrophins have been associated with inflammatory events; however, researchers have yet to elucidate the role of NGF in RA. Our examination of clinical tissue samples and analysis of data sourced from the Gene Expression Omnibus dataset unveiled elevated expression levels of M1 macrophage markers in human RA synovial tissue samples compared to normal tissue, with no such distinction observed for M2 markers. Furthermore, immunofluorescence data depicted increased expression levels of NGF and M1 macrophages in RA mice in contrast to normal mice. It appears that NGF stimulation facilitates macrophage polarization from the M0 to the M1 phenotype. It also appears that NGF promotes ICAM-1 production in human RA synovial fibroblasts, which enhances monocyte adhesion through the TrkA, MEK/ERK, and AP-1 signaling cascades. Our findings indicate NGF/TrkA axis as a novel target for the treatment of RA.

CXCL13 promotes TNF-α synthesis in rheumatoid arthritis through activating ERK/p38 pathway and inhibiting miR-330-3p generation.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder associated with joint pain, joint swelling, cartilage and bone degradation as well as deformity. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a crucial role in multiple cellular pathogenesis processes, including RA. TNF-α is a vital proinflammatory factor in the progression of RA. However, the role of CXCL13 in TNF-α production in RA has not been fully explored. Our analysis of both database and clinical samples revealed higher levels of CXCL13 and TNF-α in RA samples compared to healthy controls. CXCL13 concentration-dependently induces TNF-α synthesis in RA synovial fibroblasts. CXCL13 enhances TNF-α expression by interacting with the CXCR5 receptor, activating the ERK/p38 pathways, and inhibiting miR-330-3p generation. Importantly, treatment with CXCL13 shRNA counteracted the upregulation of TNF-α production induced by collagen-induced arthritis. Our findings support the notion that CXCL13 is a promising target in the treatment of RA.

Omentin-1 ameliorates the progress of osteoarthritis by promoting IL-4-dependent anti-inflammatory responses and M2 macrophage polarization.

Osteoarthritis (OA) is a prevalent joint disease commonly associated with aging and obesity, which can lead to pain, stiffness, joint dysfunction, and disability. Omentin-1 (also called intelectin-1) is a newly discovered adipokine, which plays a protective role in suppressing the secretion of pro-inflammatory cytokines. Based on data from the Gene Expression Omnibus (GEO) dataset and clinical samples obtained at our institution revealed, determined that omentin-1 and IL-4 (an anti-inflammatory cytokine) levels were significantly lower in OA patients than in normal controls. Omentin-1 was shown to induce IL-4-depedent anti-inflammatory responses and M2 macrophage polarization in OA synovial fibroblasts via the PI3K, ERK, and AMPK pathways. Administering omentin-1 was shown to block cartilage degradation and bone erosion resulting from anterior cruciate ligament transection by inhibiting the production of pro-inflammatory cytokines and promoting M2 macrophage polarization in vivo. Our findings indicate omentin-1 as a promising therapeutic avenue for the treatment for OA.

Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma.

Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.

Alleviative Effect of Ficus formosana Extract on Peripheral Neuropathy in Ovariectomized Diabetic Mice.

In diabetes mellitus, Ficus formosana has been reported to ameliorate blood sugar levels and inhibit inflammation through its polyphenol and flavonoid contents. However, its effect on diabetic peripheral neuropathy (DPN) remains unknown. This study aimed to investigate the effect of Ficus formosana extract (FFE) on DPN in ovariectomized diabetic mice. Ovariectomized female C57BL/6J mice fed a high-fat diet plus streptozotocin injections to induce type 2 diabetes were orally administered FEE at 20 or 200 mg/kg BW daily, for 6 weeks. To evaluate the pain responses in the paws of the mice, a von Frey filament test and a thermal hyperalgesia test were performed. Additionally, the intraepidermal and sciatic nerve sections were examined, along with an assessment of inflammation- and pain response-related mRNA expression in the paws of the mice. The results showed that the oral administration of both 20 and 200 mg/kg BW FEE significantly alleviated the hypersensitivity of the paw and the abnormal proliferation and rupture of the C fiber, and reduced the mRNA expression of interleukin-1ß, interleukin-6, interferon-γ, cyclooxygenase-2, and voltage-gated sodium channel 1.8 in the sciatic nerve of ovariectomized diabetic mice. We propose that FFE ameliorates peripheral neuropathy by suppressing oxidative damage in ovariectomized diabetic mice.

Chemokine Ligand 2 Promotes Migration in Osteosarcoma by Regulating the miR-3659/MMP-3 Axis.

Osteosarcoma is a common malignant tumor in children and adolescents, known for its aggressive invasion and distant metastasis, leading to a poor prognosis. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basement membranes through their proteolytic activity, thereby promoting osteosarcoma metastasis. Chemokine ligand 2 (CCL2) is a well-studied chemokine that plays a significant role in the cell motility of many cancers. However, its specific involvement in osteosarcoma metastasis is not fully understood. The aim of this study is to examine the role of miRNAs in CCL2-mediated MMP expression and cell motility in human osteosarcoma. The analysis of immunohistochemistry data and databases associated a positive correlation between CCL2 or MMP-3 levels with the metastasis of osteosarcoma patients. The in vivo lung metastatic osteosarcoma model also demonstrated similar effects, showing higher levels of CCL2 and MMP-3 in lung metastatic osteosarcoma tissues. The stimulation of osteosarcoma cells with CCL2 enhanced migration and invasion abilities through the upregulation of MMP-3 synthesis. Our results also indicate that CCL2 enhances MMP-3-dependent cell motility by inhibiting miR-3659 synthesis. Therefore, CCL2 represents a promising therapeutic target for treating metastasis in osteosarcoma.

Alleviative effects of α-lipoic acid on muscle atrophy via the modulation of TNF-α/JNK and PI3K/AKT pathways in high-fat diet and streptozotocin-induced type 2 diabetic rats.

Diabetes mellitus (DM) is often accompanied by clinical complications such as sarcopenia. Previous studies have indicated that oxidative stress and insulin resistance (IR) are highly associated with the pathogenesis of diabetic myopathy. α-lipoic acid (ALA), a potent biological antioxidant, exists abundantly in a variety of plants and vegetables. This study aimed to investigate the ameliorative effect of ALA on muscle atrophy in type 2 diabetic rats induced by high-fat diet feeding (HFD) plus streptozotocin (STZ) injection. The HFD/STZ-induced diabetic rats were orally administered 50, 100, or 200 mg/kg body weight ALA once a day for 13 weeks. The results showed that ALA at the tested concentrations significantly increased the soleus muscle mass and muscle fibers in diabetic rats. Proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, were found to decrease in both the serum and muscle of ALA-treated diabetic rats. ALA significantly reduced the protein-expression levels of phosphorylated c-Jun N-terminal kinase (pJNK)/JNK, forkhead box O3 (FOXO3), and muscle ring-finger protein-1 (Murf1); whereas, it enhanced the protein-expression levels of phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (pAKT)/AKT, myogenin determination gene D (MyoD), the mechanistic target of rapamycin (mTOR), and myosin heavy chain (MyHC) in the soleus muscle of diabetic rats. The results from this study suggested that ALA treatment may preserve soleus muscle mass, alleviate muscle atrophy by suppressing the TNF-α/JNK pathway, and ameliorate the PI3K/AKT pathway in HFD/STZ-induced type 2 diabetic rats.

Melatonin inhibits chondrosarcoma cell proliferation and metastasis by enhancing miR-520f-3p production and suppressing MMP7 expression.

Chondrosarcoma has a high propensity to metastasize and responds poorly to chemotherapy and radiation treatment. The enzymatic activity of matrix metalloproteinases (MMPs) is very important in chondrosarcoma metastasis. Melatonin exhibits anticarcinogenic activity in many types of cancers by suppressing the expression of certain MMP family members, but this has not yet been clearly determined in chondrosarcoma. Our study demonstrates that MMP7 plays an essential role in chondrosarcoma cell proliferation, migration, and anoikis resistance. We also found that MMP7 is highly expressed in chondrosarcomas. Our in vitro and in vivo investigations show that melatonin strongly inhibits chondrosarcoma cell proliferation, migration, and anoikis resistance by directly suppressing MMP7 expression. Melatonin reduced MMP7 synthesis by promoting levels of miR-520f-3p expression, which were downregulated in human chondrosarcoma tissue samples. Pharmacological inhibition of miR-520f-3p markedly reversed the effects of melatonin upon chondrosarcoma proliferation and metastasis. Thus, our study suggests that melatonin has therapeutic potential for reducing the tumorigenesis and metastatic potential of chondrosarcoma via the miR-520f-3p/MMP7 axis.

IOX-1 suppresses metastasis of osteosarcoma by upregulating histone H3 lysine trimethylation.

New therapeutic approaches are needed for metastatic osteosarcoma (OS), as survival rates remain low despite surgery and chemotherapy. Epigenetic changes, such as histone H3 methylation, play key roles in many cancers including OS, although the underlying mechanisms are not clear. In this study, human OS tissue and OS cell lines displayed lower levels of histone H3 lysine trimethylation compared with normal bone tissue and osteoblast cells. Treating OS cells with the histone lysine demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX-1) dose-dependently increased histone H3 methylation and inhibited cellular migratory and invasive capabilities, suppressed matrix metalloproteinase expression, reversed epithelial-to-mesenchymal transition by increasing levels of epithelial markers E-cadherin and ZO-1 and decreasing the expression of mesenchymal markers N-cadherin, vimentin, and TWIST, and also reduced stemness properties. An analysis of cultivated MG63 cisplatin-resistant (MG63-CR) cells revealed lower histone H3 lysine trimethylation levels compared with levels in MG63 cells. Exposing MG63-CR cells to IOX-1 increased histone H3 trimethylation and ATP-binding cassette transporter expression, potentially sensitizing MG63-CR cells to cisplatin. In conclusion, our study suggests that histone H3 lysine trimethylation is associated with metastatic OS and that IOX-1 or other epigenetic modulators present promising strategies to inhibit metastatic OS progression.

Melatonin Inhibits VEGF-Induced Endothelial Progenitor Cell Angiogenesis in Neovascular Age-Related Macular Degeneration.

Neovascular age-related macular degeneration (AMD) is described as abnormal angiogenesis in the retina and the leaking of fluid and blood that generates a huge, dark, blind spot in the center of the visual field, causing severe vision loss in over 90% of patients. Bone marrow-derived endothelial progenitor cells (EPCs) contribute to pathologic angiogenesis. Gene expression profiles downloaded from the eyeIntegration v1.0 database for healthy retinas and retinas from patients with neovascular AMD identified significantly higher levels of EPC-specific markers (CD34, CD133) and blood vessel markers (CD31, VEGF) in the neovascular AMD retinas compared with healthy retinas. Melatonin is a hormone that is mainly secreted by the pineal gland, and is also produced in the retina. Whether melatonin affects vascular endothelial growth factor (VEGF)-induced EPC angiogenesis in neovascular AMD is unknown. Our study revealed that melatonin inhibits VEGF-induced stimulation of EPC migration and tube formation. By directly binding with the VEGFR2 extracellular domain, melatonin significantly and dose-dependently inhibited VEGF-induced PDGF-BB expression and angiogenesis in EPCs via c-Src and FAK, NF-κB and AP-1 signaling. The corneal alkali burn model demonstrated that melatonin markedly inhibited EPC angiogenesis and neovascular AMD. Melatonin appears promising for reducing EPC angiogenesis in neovascular AMD.

Oral Administration of Clostridium butyricum GKB7 Ameliorates Signs of Osteoarthritis in Rats.

Osteoarthritis (OA) is a degenerative and painful inflammatory joint disease affecting the cartilage, bone, and synovial membranes, without any effective treatment that targets the underlying mechanisms of OA. Our study evaluated the therapeutic effects of a live probiotic strain, Clostridium butyricum GKB7, administered for 6 weeks to rats with knee OA (KOA) induced by anterior cruciate ligament transection (ACLT) of the right knee. All rats underwent weekly weight-bearing behavioral testing and body weight measurements. At 6 weeks, all rats were sacrificed, and the right hind knees were collected for micro-computed tomography imaging and histopathological and immunohistochemical analyses. Compared with rats in the ACLT-only group, ACLT rats administered the probiotic exhibited dramatic improvements in pain-related behavior from postoperative week 2, had significantly less osseous and cartilaginous damage at week 6, and significantly lower levels of the inflammatory markers interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in cartilage and synovium sections. C. butyricum GKB7 appeared to slow or even reverse OA progression and is worth investigating as a novel therapeutic for OA.

Nerve growth factor promotes lysyl oxidase-dependent chondrosarcoma cell metastasis by suppressing miR-149-5p synthesis.

Chondrosarcoma is a malignancy of soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is critical for neuronal cell growth, apoptosis, and differentiation, and also appears to promote the progression and metastasis of several different types of tumors, although the effects of NGF upon chondrosarcoma mechanisms are not very clear. We report that NGF facilitates lysyl oxidase (LOX)-dependent cellular migration and invasion in human chondrosarcoma cells, and that NGF overexpression enhances lung metastasis in a mouse model of chondrosarcoma. NGF-induced stimulation of LOX production and cell motility occurs through the inhibition of miR-149-5p expression, which was reversed by PI3K, Akt, and mTOR inhibitors and their respective short interfering RNAs. Notably, levels of NGF and LOX expression correlated with tumor stage in human chondrosarcoma samples. Thus, NGF appears to be a worthwhile therapeutic target for metastatic chondrosarcoma.

The mir-423-5p/MMP-2 Axis Regulates the Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis.

A chondrosarcoma is a common tumor of the soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is capable of promoting the progression and metastasis of several different types of tumors although the effects of NGF in a chondrosarcoma are not confirmed. Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with the tumor stage in patients with a chondrosarcoma. NGF facilitated the MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells while the overexpression of NGF enhanced the lung metastasis in a mouse model of a chondrosarcoma. NGF promoted the MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of a metastatic chondrosarcoma.

Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

miR-144-3p ameliorates the progression of osteoarthritis by targeting IL-1ß: Potential therapeutic implications.

The pro-inflammatory cytokine interleukin 1 beta (IL-1ß) plays a critical role in osteoarthritis (OA) disease pathogenesis. MicroRNA (miRNA) activity is related to inflammation in OA and some miRNAs specifically regulate IL-mediated degradation of cartilage type II collagen. Previous studies have indicated that miR-144-3p is a useful target in the regulation of pro-inflammatory cytokines in different diseases. However, the role of miR-144-3p in OA is unclear. In this study, we observed a negative correlation between miR-144-3p and IL-1ß expression in OA. miR-144-3p mimic transfection of OA synovial fibroblasts downregulated levels of IL-1ß expression, while blocking the MAPK, PI3K/Akt, and NF-κB signaling pathways relating to IL-1ß production, and effectively increased miR-144-3p expression in OASFs. Findings from an anterior cruciate ligament transection rat model revealed that administration of miR-144-3p mimic effectively ameliorated OA progression and reduced the numbers of IL-1ß-positive cells in synovial tissue. This study suggests that miR-144-3p is a useful therapeutic target in OA disease.

Antcin K Inhibits TNF-α, IL-1ß and IL-8 Expression in Synovial Fibroblasts and Ameliorates Cartilage Degradation: Implications for the Treatment of Rheumatoid Arthritis.

Extracts from Taiwan's traditional medicinal mushroom, Antrodia cinnamomea, exhibit anti-inflammatory activities in cellular and preclinical studies. However, this paper is the first to report that Antcin K, a triterpenoid isolated from A. cinnamomea, inhibits proinflammatory cytokine production in human rheumatoid synovial fibroblasts (RASFs), which are major players in rheumatoid arthritis (RA) disease. In our analysis of the mechanism of action, Antcin K inhibited the expression of three cytokines (tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1ß] and IL-8) in human RASFs; cytokines that are crucial to RA synovial inflammation. Notably, incubation of RASFs with Antcin K reduced the phosphorylation of the focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-κB (NF-κB) signaling cascades, all of which promote cytokine production in RA. Intraperitoneal injections of Antcin K (10 mg/kg or 30 mg/kg) attenuated paw swelling, cartilage degradation and bone erosion, and decreased serum levels of TNF-α, IL-1ß, IL-8 in collagen-induced arthritis (CIA) mice; in further experiments, IL-6 levels were similarly reduced. The inhibitory effects of Antcin K upon TNF-α, IL-1ß and IL-8 expression in human RASFs was achieved through the downregulation of the FAK, PI3K, AKT and NF-κB signaling cascades. Our data support clinical investigations using Antcin K in RA disease.

A combination of bimalleolar fracture and fracture on talar body and neck: A rare case report.

RATIONALE: Talar fracture accompanied with malleolar fracture is rare, and its management is complex. Ankle soft tissue is much thinner than other parts of the human body, and the shape of the ankle makes wounds difficult to close immediately after surgery, which may result in poor skin condition if the wound tension is too high. However, joint congruity and osteonecrosis are the main concerns of talar fracture. PATIENT CONCERNS: A 57-year-old man presented at the emergency department following a motorcycle accident. DIAGNOSES: Physical examination revealed swelling and tenderness of the left ankle and midfoot. The patient had comminuted talar fracture and was indicated for dual-screw fixation or even plate with screw fixation. INTERVENTIONS: We performed single screw fixation after assessing the soft tissue condition and employed a technique of using continuous longitudinal force to bring together fracture fragments (ankle ligamentotaxis) during surgery. Open reduction with a mini-hook plate and tension band wire was used for bimalleolar fracture repair using the combined anteromedial and anterolateral approach with extension of the incision. Kirschner wire for temporary fixation was performed using ligamentotaxis, and a 2.4 headless screw was inserted from the posteromedial to the anterolateral direction. OUTCOMES: The patient was discharged with a standard short leg splint and was instructed not to bear weight on the affected ankle for 2 months. The patient walked well without discomfort, and the Hawkins sign was clearly visible. Single screw fixation preserves the integrity of the talus bone as minimal space is used for this operative technique. Single screw fixation preserves more bony stock when most of the internal fixator is located within the bone. Additionally, surgery time is shorter than multiple implantations even when performing the same procedure; as a result, there was less ankle soft tissue swelling. LESSONS: This case provides evidence of using the single screw fixation technique for addressing both malleolar and talar fractures, and that talar fracture management can be less aggressive with limited weight bearing and initial limited range of motion given the presence of malleolar fracture. The alignment and stability of bony fragments also benefit from ankle ligamentotaxis.

Effect of Ruellia tuberosa L. on aorta endothelial damage-associated factors in high-fat diet and streptozotocin-induced type 2 diabetic rats.

Hyperglycemia plays crucial roles in vascular disease development, including macrovascular and microvascular diseases from diabetes mellitus (DM). Our previous study demonstrated that Ruellia tuberosa L. (RTL) aqueous and ethanol extracts alleviate hyperglycemia and inhibit insulin resistance in diabetic rats. This study investigated the protective effect of RTL ethanol extract against aorta dysfunction in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 DM (T2DM) rats. Results showed that RTL ethanol extract (100 and 400 mg/kg BW/day) ameliorated serum lipid profiles, including triglyceride, free fatty acid, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. It also significantly reduced the level of serum cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 in T2DM rats. Additionally, RTL extract decreased endothelin-1 and endothelial nitric oxide contents, reduced the level of cell adhesion factors, including monocyte chemoattractant protein-1 and cell adhesion factor vascular cell adhesion molecule-1, while decreasing content of damage factors, namely tissue factor and von Willebrand factor in aortic tissues of diabetic rats. Equally noteworthy is that RTL extract enhanced the activity of aorta antioxidative enzymes, including superoxidase dismutase and catalase in diabetic rats, suggesting that RTL ethanol extract may ameliorate aorta dysfunction via enhancing aortic antioxidative enzyme activity, which subsequently suppresses aorta endothelial damage-associated factors in HFD with STZ-induced T2DM rats.

Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities.

Gut microbiota alterations manifest as intermittent hypoxia and fragmented sleep, thereby mimicking obstructive sleep apnea-hypopnea syndrome (OSAHS). Here, we sought to perform the first direct survey of gut microbial dysbiosis over a range of apnea-hypopnea indices (AHI) among patients with OSAHS. We obtained fecal samples from 93 patients with OSAHS [5 < AHI ≤ 15 (n=40), 15 < AHI ≤ 30 (n=23), and AHI ≥ 30 (n=30)] and 20 controls (AHI ≤ 5) and determined the microbiome composition via 16S rRNA pyrosequencing and bioinformatics analysis of variable regions 3-4. We measured fasting levels of homocysteine (HCY), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Results revealed gut microbial dysbiosis in several patients with varying severities of OSAHS, reliably separating them from controls with a receiver operating characteristic-area under the curve (ROC-AUC) of 0.789. Functional analysis in the microbiomes of patients revealed alterations; additionally, decreased in short-chain fatty acid (SCFA)-producing bacteria and increased pathogens, accompanied by elevated levels of IL-6. Lactobacillus levels correlated with HCY levels. Stratification analysis revealed that the Ruminococcus enterotype posed the highest risk for patients with OSAHS. Our results show that the presence of an altered microbiome is associated with HCY among OSAHS patients. These changes in the levels of SCFA affect the levels of pathogens that play a pathophysiological role in OSAHS and related metabolic comorbidities.