Bioinformatic analyses reveal lysosomal-associated protein transmembrane 5 as a potential therapeutic target in lipotoxicity-induced injury in diabetic kidney disease.

Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.

Increased YKL-40 levels are linked with disease severity of initially diagnosed Graves' disease.

Background: YKL-40, which is also known as Chitiniase 3-like 1, has been found to be up-regulated in many autoimmune diseases including asthma, systemic sclerosis and systemic lupus, etc. However, the relationship between serum levels of YKL-40 and one another common autoinmmue thyroid disease - Graves' disease (GD) has not yet been investigated.Objective: The current study was performed to investigate the correlation of serum YKL-40 levels with disease severity of initially diagnosed GD.Methods: A total of 142 newly diagnosed active GD and 137 healthy individuals were enrolled in the study. Methimazole was given to 55 GD patients and then 2-month study of follow-up was performed. A commercial ELISA kit was applied for the detection of YKL-40 in serum. Degree of goiter was assessed according to Pérez's Grade. Receiver operating characteristic (ROC) curve analysis was carried out to detect the diagnostic value of serum YKL-40 with regard to goiter degree. The velocity of the peak systolic blood-flow and the thyroid tissue blood flow (TBF) were examined using Color Flow Doppler ultrasonography (CFDU).Results: The patients with GD exhibited dramatically higher YKL-40 in serum compared to those of healthy controls (606.1 ± 149.8 pg/mL vs. 397.4 ± 95.1 pg/mL, P < 0.001). Positive associations of YKL-40 with free T3 (FT3) and T4 (FT4), as well as the negative correlation of YKL-40 with TSH in serum, were observed. Additionally, the YKL-40 in serum was dramatically reduced after methimazole intervention, and the correlation of the decline with the reduced FT3 and FT4 was also found (all P < 0.001). Serum YKL-40 levels were positively correlated with goiter degree. ROC curve analysis demonstrated that serum YKL-40 concentration may act as a decent marker for goiter degree. The positive correlations of YKL-40 in serum with the average superior thyroid artery velocity (STV) and thyroid tissue blood flow (TBF) were also observed.Conclusion: Our findings implicated that YKL-40 may be closely connected to the pathogenesis of GD. Increased YKL-40 levels are linked with disease severity of initially diagnosed GD.

Plasma LncRNA MALAT1 Expressions Are Negatively Associated with Disease Severity of Postmenopausal Osteoporosis.

BACKGROUND: Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (LncRNA MALAT1) has been proven to promote osteogenesis in different health conditions. However, the role of plasma MALAT1 in postmenopausal osteoporosis (PMOP) has not been investigated. OBJECTIVE: To investigate whether plasma MALAT1 expressions are associated with severity of PMOP. METHODS: A total of 126 patients with PMOP and 126 healthy female control individuals were drafted into study participation. Plasma MALAT1 was detected using RT-PCR. Bone formation marker bone-specific alkaline phosphatase plasma concentration was determined using chemiluminescence immunoassay. Levels of bone absorption marker cross-linked N-telopeptidases of type I collagen were measured in duplicate using enzyme immunoassay. Bone mineral density (BMD) was examined in the total hips, femoral neck, and lumbar (L1-L4) spine using dual-energy x-ray absorptiometry. We used Genant semiquantitative (GSQ) criteria to assess the degree of vertebral deformity and fracture. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the potential diagnostic value of MALAT1 with regard to the GSQ grading. We used the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) to evaluate the symptomatic severity in and functional ability of the study participants. RESULTS: Plasma MALAT1 expressions were significantly lower in patients with PMOP, compared with healthy controls. Plasma MALAT1 expressions in patients with PMOP were positively associated with total hip, femoral neck, and lumbar (L1-L4) spine BMD. In total, 95 patients experienced vertebral deformity or fracture (VF), and 31 had no fractures. Plasma MALAT1 expressions were markedly decreased in patients with VF, compared with patients without fractures. Plasma MALAT1 expressions were negatively related to GSQ grading in patients with VF. ROC curve analysis demonstrated that decreased plasma MALAT1 expression exhibits decent diagnostic value with regard to GSQ grading. Finally, we discovered that plasma MALAT1 expression was also negatively associated with VAS and ODI. CONCLUSION: Plasma MALAT1 expressions are negatively associated with severity of PMOP.

Serum C-C Motif Ligand 11/eotaxin-1 May Serve as a Candidate Biomarker for Postmenopausal Osteoporosis.

BACKGROUND: The chemokine C-C motif ligand 11, also known as eotaxin-1, has been identified as a novel mediator of inflammatory bone resorption. However, little is known regarding a potential role for CCL11/Eotaxin-1 in postmenopausal osteoporosis. OBJECTIVE: The scope of this study was to explore the relationship between serum CCL11/Eotaxin-1 concentrations and disease progression of postmenopausal females with osteoporosis. METHODS: A total of 83 postmenopausal women diagnosed with osteoporosis were enrolled. Meanwhile, 82 postmenopausal women with normal bone mineral density (BMD) and 85 healthy controls inner child-bearing age were enrolled as control. The Dual-energy X-ray absorptiometry was used to examine the BMDs at the femoral neck, lumbar spine 1-4 and total hip of all participants. Serum CCL11/Eotaxin-1 levels were examined by enzyme-linked immunosorbent assay. We also included inflammation marker interleukin-6 (IL-6) as well as a serum marker of bone resorption C-telopeptide cross-linked collagen type 1 (CTX-1). The Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) were recorded to evaluate the clinical severity in POMP females. RESULTS: Serum CCL11/Eotaxin-1 levels were significantly elevated in postmenopausal osteoporotic patients PMOP patients compared with PMNOP and healthy controls. We observed a significant negative correlation of serum CCL11/Eotaxin-1 levels with lumbar spine, femoral neck and total hip BMD. Furthermore, serum CCL11/ Eotaxin-1 concentrations were also positively related to the VAS and ODI scores. Last, serum CCL11/ Eotaxin-1 concentrations were positively associated with IL-6 and CTX-1 levels. These correlations remain significant after adjusting for age and BMI. Multivariate linear regression analysis demonstrated that CCL11/Eotaxin-1 could serve as an independent marker. CONCLUSIONS: Serum CCL 11/Eotaxin-1 may serve as a candidate biomarker for postmenopausal osteoporosis. Therapeutics targeting CCL11/Eotaxin-1 and its related signalling way to prevent and slow progression of PMOP deserve further study.

The Neuropeptide Vasoactive Intestinal Peptide Levels in Serum are Inversely Related to Disease Severity of Postmenopausal Osteoporosis: A Cross-Sectional Study.

Background: The neuropeptide vasoactive intestinal peptide (VIP) has been identified as inhibiting osteoclastogenesis and suppressing inflammation. Objective: This study was conducted to examine serum VIP levels in postmenopausal osteoporosis (PMOP) patients and explore the correlation of serum VIP levels with disease severity of PMOP. Methods: A total of 106 postmenopausal women diagnosed as osteoporotic were enrolled in the study and 102 postmenopausal women with normal bone mineral density (BMD) were enrolled as controls. BMD at the femoral neck (FN), lumbar spine 1-4, and total hip were examined using dual-energy X-ray absorptiometry. Genant semiquantitative grading was used for vertebral morphometry and fracture. Serum VIP levels were tested using enzyme-linked immunosorbent assay. Serum inflammatory factor interleukin-1ß (IL-1ß), osteoclastic activity marker tartrate-resistant acid phosphatase 5b (TRACP-5b), and estrogen-2 (E2) were also examined. Receiver operating characteristic (ROC) analyses was performed to determine the diagnostic values of serum VIP, IL-1ß, TRCAP-5, and E2 with regard to Genant grade. Results: Our findings demonstrated a reduction in the serum level of VIP expressed in PMOP patients compared with controls. In the PMOP group, patients with lumbar fracture had significantly lower serum VIP concentrations in comparison with healthy controls. Serum VIP concentrations were positively associated with BMD at the FN, lumbar spine 1-4, and total hip. We also observed that serum VIP levels were positively correlated with E2 levels but negatively correlated with IL-1ß and TRCAP-5 levels. In addition, ROC analysis found that reduction of serum VIP in combination with elevation of TRACP-5b may serve as an indicator of a severe Genant grade. Conclusions: Attenuated serum VIP levels were linked to disease severity of PMOP and may act as a protective marker for PMOP.

Correlation of Serum CCL3/MIP-1α Levels with Disease Severity in Postmenopausal Osteoporotic Females

BACKGROUND: The pro-inflammatory protein chemokine cytokine ligand 3 is well established as a vital regulator of bone resorption and osteoclast stimulation. AIMS: To investigate if serum cytokine ligand 3 levels correlated with disease severity in postmenopausal osteoporotic women. STUDY DESIGN: Cross-sectional study. METHODS: Eighty-two postmenopausal osteoporotic women, 76 postmenopausal non-osteoporotic women, and 80 healthy women of childbearing age were recruited. The total hip, femoral neck, and L1-L4 spine bone mineral density were assessed by dual-energy X-ray absorptiometry. Serum cytokine ligand 3 concentrations were examined using a commercial enzyme-linked immunosorbent assay kit. Serum inflammatory cytokine interleukin-6, tumor necrosis factor-alpha, and the bone metabolic markers, carboxy-terminal crosslinked and tartrate-resistant acid phosphatase 5b were also examined. Scores on both the visual analogue scale and the Oswestry Disability Index were utilized to assess clinical severity. RESULTS: Patients in the postmenopausal osteoporotic group had significantly increased serum cytokine ligand 3 levels compared with those in both the postmenopausal non-osteoporotic group (40.9±15.1 pg/mL vs 24.2±8.7 pg/mL, p<0.001) and control group (40.9±15.1 pg/mL vs 23.9±9.1 pg/mL, p<0.001). Serum cytokine ligand 3 levels negatively correlated with bone mineral density at the total hip (r=-0.345, p=0.002), femoral neck (r=-0.329, p=0.003), and L1-L4 lumbar spine (r=-0.354, p=0.001) and positively correlated with visual analogue scale scores (r=0.413, p<0.001) and the Oswestry Disability Index (r=0.360, p<0.001). Moreover, serum cytokine ligand 3 levels were correlated with increased tumor necrosis factor-alpha (r=0.305, p=0.005), interleukin-6 (r=0.288, p=0.008), terminal crosslinked and tartrate-resistant acid phosphatase 5b (r=0.371, p<0.001), and carboxy-terminal crosslinked (r=0.317, p=0.004) levels. All correlations were still significant after adjusting for both body mass index and age. CONCLUSION: Chemokine cytokine ligand 3 may be a useful biomarker that can be used to predict disease severity of postmenopausal osteoporosis. Therapies targeting cytokine ligand 3 and its related signaling pathways to inhibit and delay the osteoclastogenesis process deserve further investigation.

Lymphangiogenesis and colorectal cancer.

Lymphatic metastasis is an important event in the progress of metastasis in colorectal cancer (CRC). The purpose of this article is to assess the role of lymphangiogenesis on CRC. In peritumoral areas of CRC, the lymphatic microvessel density (LMVD) is higher than those in normal colorectal tissues. Morever, the high LMVD is correlated with DFS and local recurrence in CRC. The VEGF-C/VEGF-D/VEGFR-3 pathway, sonic hedgehog (Shh) signaling pathway and extracellular matrix (ECM) are involved in the regulation of lymphangiogenesis in CRC. Inhibition of the VEGF-C/VEGF-D/VEGFR-3 pathway by specific antibodies has been reported to efficiently inhibit experimental tumor lymphangiogenesis and metastasis in animal experiments. Although lymphangiogenesis has been reported to play an important role in the occurrence of colon cancer and to be associated with prognosis, it remains unclear whether it is a valid therapeutic target molecule. Further study of the potential of targeting this process for anti-lymphatic therapies is worthwhile.

Serum CX3CL1/fractalkine concentrations are positively associated with disease severity in postmenopausal osteoporotic patients.

BACKGROUND: The chemokine (C-X3-C motif) ligand 1 (CX3CL1), also called fractalkine (FKN), has recently been reported to be involved in osteoclastogenic process and pathological bone destruction. OBJECTIVE: This study aimed to investigate the link between serum CX3CL1/FKN levels with disease progression of postmenopausal osteoporotic patients. METHODS: A total of 53 women with postmenopausal osteoporosis (PMOP group), 51 postmenopausal non-osteoporotic female patients (PMNOP group) and 50 premenopausal non-osteoporotic healthy women of childbearing age (control group) were enrolled in the study. The bone mineral density (BMD) for all subjects was determined via dual-energy X-ray absorptiometry of the lumbar spine, femoral neck, internal trochanter, total hip, greater trochanter and Ward's triangle. The levels of FKN in the serum were examined using the enzyme-linked immunosorbent assay method. The serum bone resorption markers TRACP-5b, NTX levels, inflammation markers IL-1ß and IL-6 as well as oestrogen-2(E2) were also detected in all participants. The visual analogue scores (VAS) and Oswestry Disability Index (ODI) for low back pain were recorded in PMOP females for evaluation of osteoporotic pain and function. RESULTS: FKN levels were significantly higher in postmenopausal osteoporotic patients compared with postmenopausal non-osteoporotic females (139.8 ± 44.3 pg/mL VS 116.5 ± 23.1 pg/mL, p < 0.05) and healthy controls (139.8 ± 44.3 pg/mL VS 109.7 ± 19.4 pg/mL, p < 0.05). Serum FKN concentrations were negatively associated with BMD at femoral neck (r = -0.394, p = 0.004), total hip(r = -0.374, p = 0.006), internal trochanter(r = -0.340, p = 0.013), greater trochanter(r = -0.376, p = 0.006), Ward's triangle(r = -0.343, p = 0.012), L1-L4 lumbar spine(r = -0.339, p = 0.013) and positively associated with VAS (r = 0.321, p = 0.019) and ODI (r = 0.377, p = 0.005) scores, bone turnover makers (TRACP-5b:r = 0.341, p = 0.012; NTX:r = 0.364, p = 0.007)as well as inflammation markers (IL-1ß: r = 0.396, p = 0.003; IL-6:r = 0.355, p = 0.009) in postmenopausal osteoporotic patients. CONCLUSIONS: Serum FKN may serve as a novel biomarker for assessing disease progression and a new potential therapeutic target for anti-resorptive treatment in osteoporosis patients.

Endogenous CSE/H2 S system mediates TNF-α-induced insulin resistance in 3T3-L1 adipocytes.

Tumour necrosis factor-α (TNF- α)is a major contributor to the pathogenesis of insulin resistance associated with obesity and type 2 diabetes. It has been found that endogenous hydrogen sulfide (H2 S) contributes to the pathogenesis of diabetes. We have hypothesized that TNF-α-induced insulin resistance is involved in endogenous H2 S generation. The aim of the present study is to investigate the role of endogenous H2 S in TNF-α-induced insulin resistance by studying 3T3-L1 adipocytes. We found that treatment of 3T3-L1 adipocytes with TNF-α leads to deficiency in insulin-stimulated glucose consumption and uptake and increase in endogenous H2 S generation. We show that cystathionine γ-lyase (CSE) is catalysed in 3T3-L1 adipocytes to generate H2 S and that CSE expression and activity are upregulated by TNF-α treatment. Inhibited CSE by its potent inhibitors significantly attenuates TNF-α-induced insulin resistance in 3T3-L1 adipocytes, whereas H2 S treatment of 3T3-L1 adipocytes impairs insulin-stimulated glucose consumption and uptake. These data indicate that endogenous CSE/H2 S system contributes to TNF-α-caused insulin resistance in 3T3-L1 adipocytes. Our findings suggest that modulation of CSE/H2 S system is a potential therapeutic avenue for insulin resistance.