UNASSIGNED: Partial necrosis of skin flaps is still a substantial problem in plastic and reconstructive surgery. In this study, the role of miR-590-3p in adipose-derived stem cells (ADSCs) transplantation in improving the survival of skin flap in a mouse model was delved into.
UNASSIGNED: An abdominal perforator flap model was established in mice. The histopathological examination of mice skin tissues after ADSCs transplantation was implemented using Hematoxylin & eosin (H&E) staining. Immunohistochemistry (IHC) or immunofluorescence (IF) staining was utilized to assess the PCNA or CD31 levels. The concentrations of VEGFA in the culture medium were quantified using a VEGFA ELISA kit.
UNASSIGNED: The damage of tissue in the skin flap was dramatically relieved by ADSCs transplantation. MiR-590-3p overexpression notably suppressed, while miR-590-3p knockdown facilitated skin flap survival by regulating PCNA, VCAM-1, and VEGFA levels. MiR-590-3p targeted VEGFA to regulate its expression. The knockdown of VEGFA significantly inhibited, while overexpression of VEGFA notably promoted the survival of skin flap.
UNASSIGNED: ADSCs transplantation promotes skin flap survival by boosting angiogenesis. The miR-590-3p/VEGFA axis modulates skin flap angiogenesis and survival in ADSCs. These results reveal that interfering with miR-590-3p in ADSCs could potentially be a novel therapeutic target for the improvement of skin flap survival.

Molecular targeted therapy has become an emerging promising strategy in cancer treatment, and screening the agents targeting at cancer cell specific targets is very desirable for cancer treatment. Our previous study firstly found that a secretory peroxidase of class III derived from foxtail millet bran (FMBP) exhibited excellent targeting anti-colorectal cancer (CRC) activity in vivo and in vitro, whereas its underlying target remains unclear. The highlight of present study focuses on the finding that cell surface glucose-regulated protein 78 (csGRP78) abnormally located on CRC is positively correlated with the anti-CRC effects of FMBP, indicating it serves as a potential target of FMBP against CRC. Further, we demonstrated that the combination of FMBP with the nucleotide binding domain (NBD) of csGRP78 interfered with the downstream activation of signal transducer and activator of transcription 3 (STAT3) in CRC cells, thus promoting the intracellular accumulation of reactive oxygen species (ROS) and cell grown inhibition. These phenomena were further confirmed in nude mice tumor model. Collectively, our study highlights csGRP78 acts as an underlying target of FMBP against CRC, uncovering the clinical potential of FMBP as a targeted agent for CRC in the future.

UNASSIGNED: Hepatocellular carcinoma (HCC) is rising steadily in incidence, and more effective methods are needed for early cancer detection and image-guided surgery.
UNASSIGNED: We used a structural model to optimize the peptide sequence. Specific binding was validated in vitro with knockdown, competition, and co-localization assays. Multi-modal imaging was performed to validate specific binding in vivo in orthotopically-implanted human xenograft tumors.
UNASSIGNED: Binding properties of WKGWSYLWTQQA were characterized by an apparent dissociation constant of kd = 43 nM, and an apparent association time constant of k = 0.26 min-1. The target-to-background ratio was significantly higher for the target versus control for both modalities. Ex-vivo evaluation using human HCC specimens supported the ability of the peptide to distinguish HCC from other liver pathologies.
UNASSIGNED: We have identified a peptide specific for CD44 with properties that are promising for clinical translation to image HCC in vivo.

Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer, their inefficient therapeutic outcomes, serious adverse effects, and high cost of mass production remain crucial challenges. Herein, we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers (TFENs). These nanovehicles had desirable particle sizes (131 nm), exosome-like morphology, and negative zeta potentials. Furthermore, TFENs were found to contain large amounts of polyphenols, flavonoids, functional proteins, and lipids. Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species (ROS) amplification. The increased intracellular ROS amounts could not only trigger mitochondrial damage, but also arrest cell cycle, resulting in the in vitro anti-proliferation, anti-migration, and anti-invasion activities against breast cancer cells. Further mice investigations demonstrated that TFENs after intravenous (i.v.) injection or oral administration could accumulate in breast tumors and lung metastatic sites, inhibit the growth and metastasis of breast cancer, and modulate gut microbiota. This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v. and oral routes.

Excessive interleukin (IL)-6 production is a driver for malignancy and drug resistance in colorectal cancer (CRC). Our study investigated a seven-week post-treatment with the anti-inflammatory drug, Diacerein (Diac), alone or in combination with 5-fluorouracil (5-FU), using a 1,2-dimethylhydrazine (DMH) rat model of CRC. Diac alone and 5-FU+Diac reduced serum levels of carcino-embryonic antigen (CEA), while all regimens decreased serum levels of colon cancer-specific antigen (CCSA), a more specific CRC biomarker. Additionally, Diac, 5-FU and their combination suppressed colonic content/gene expression of IL-6, its downstream oncogene, Kirsten rat sarcoma viral oncogene homolog (K-Ras), and consequently Notch intracellular domain and nuclear factor-kappa B (NF-κB) p65. In turn, NF-κB downstream factors, viz., matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), c-Myc, and B-cell lymphoma-2 (Bcl-2) were also downregulated, while E-cadherin was elevated. Additionally, the drugs reduced the immunoreactivity of CD31 to prove their anti-angiogenic effect, while the TUNEL assay confirmed the apoptotic effect. The apoptotic effect was confirmed by transferase dUTP nick-end labeling assay. Moreover, these drugs inhibited colon content of p-Akt, β-catenin, and cyclin D1 immunoreactivity. The drugs also activated the tumor suppressor glycogen synthase kinase 3- β (GSK3-β) and upregulated the expression of the Nur77 gene, which represents the second arm of IL-6 signaling. However, only 5-FU upregulated miR-200a, another K-Ras downstream factor. The in-vitro cytotoxic and migration/invasion assays verified the molecular trajectories. Accordingly, we evaluated the antineoplastic effect of Diac alone and its possible chemosensitization effect when added to 5-FU. This combination may target critical oncogenic pathways, including the IL-6/K-Ras/Notch/NF-κB p65 axis, p-Akt/GSK3-β/β-catenin/cyclin D-1 hub, and Nur77.

Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN.

The objective was to investigate the effect of kinsenoside (Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis (OA) progression. RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium (CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection (ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB (NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases (MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages, promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.

UNASSIGNED: Non-alcoholic fatty liver disease (NAFLD) is emerging as an important cause of liver disease in India. NAFLD is characterized by hepatic steatosis in absence of a significant alcohol use or other known liver disease. Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD which deserves particular attention because it is more prone for development of fibrosis. Liver biopsy is the gold standard for diagnosis of NASH by evaluating necroinflammatory activity and stages of fibrosis. The aim of the study was to analyze liver biopsy specimens and identify risk factors associated with fibrosis in patients of NAFLD in eastern coastal India.
UNASSIGNED: A total of 216 subjects with fatty liver in ultrasonography (USG) were selected for needle biopsy. Those NAFLD cases showing fibrosis in biopsy were analyzed for risk factors association.
UNASSIGNED: Definite NASH was diagnosed in 50 (23.14%), borderline NASH in 66 (30.55%) and not NASH in 100 (46.39%) of cases. Those patients with fibrosis (22%) were taken as cases and those without fibrosis (78%) were taken as controls for risk factor analysis. Age > 40 [odds ratio (OR) 2.01 (1.09-4.04)], female gender [OR 2.74 (1.24-6.05)], body mass index (BMI) > 23 [OR 15.36 (4.59-51.37)] and moderate fatty change in USG [OR 1.89 (1.01-3.62)] were observed as risk factors for progression to fibrosis in NAFLD cases.
UNASSIGNED: Older age, females, obesity and moderate fatty liver on USG are risk factors for development of fibrosis in patients with NAFLD. Patients with these risk factors should be selected for liver biopsy and to be kept for close follow-up.

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.

A 26-year-old woman with gross hematuria was seen in a previous hospital. Magnetic resonance imaging (MRI) showed a tumor at the dome of the urinary bladder with invasion outside of the bladder wall. The patient underwent transurethral resection of the bladder tumor (TUR-BT). From the result of the pathological examination, the tumor was suggested to be carcinosarcoma of the bladder. The patient was then referred to our hospital for treatment. We performed radical cystectomy and ileal conduit diversion. Pathological examination of the excised specimen revealed an inflammatory myofibroblastic tumor as the basis for immunostaining of anaplastic lymphoma kinase (ALK).