Renal histology of Fanconi syndrome associated with adefovir dipivoxil: A case report.

A sporadic occurrence of Fanconi syndrome associated with adefovir dipivoxil (ADV) has been reported, particularly when confirmed by renal biopsy. This study presents the case of a 53-year-old man who had been taking ADV 10 mg daily for 10 years to treat chronic hepatitis B (CHB) and subsequently developed Fanconi syndrome. The clinical manifestations included hypophosphatemic osteomalacia, glucosuria, renal tubular acidosis, low-molecular-weight proteinuria, and renal insufficiency. Renal biopsy revealed significant injury to proximal tubular epithelial cells, including vacuolar degeneration and regeneration of tubular epithelial cells. The ultrastructural pathology indicated severe morphological abnormalities of mitochondria, such as densely packed and enlarged mitochondria, with loss, blunting, and disordered arrangement of cristae. Following discontinuation of ADV and supplementation with oral phosphate, hypophosphatemia, glucosuria, and proteinuria were resolved. These findings support the previous hypothesis that ADV-induced nephrotoxicity may involve mitochondrial injury.

Subcutaneous Rapid Dissolution Microneedle Patch Integrated with CuO2 and Disulfiram for Augmented Antimelanoma Efficacy through Multimodal Synergy of Photothermal Therapy, Chemodynamic Therapy, and Chemotherapy.

Melanoma is a malignancy of the skin that is resistant to conventional treatment, necessitating the development of effective and safe new therapies. The percutaneous microneedle (MN) system has garnered increasing interest as a viable treatment option due to its high efficacy, minimal invasiveness, painlessness, and secure benefits. In this investigation, a sensitive MN system with multiple functions was created to combat melanoma effectively. This MN system utilized polyvinylpyrrolidone (PVP) as microneedle substrates and biocompatibility panax notoginseng polysaccharide (PNPS) as microneedle tips, which encapsulated PVP-stabilized CuO2 nanoparticles as a therapeutic agent and disulfiram-containing F127 micelles to enhance the tumor treatment effect. The MN system had sufficient mechanical properties to pierce the skin, and the excellent water solubility of PNPS brought high-speed dissolution properties under the bio conditions, allowing the MNs to effectively penetrate the skin and deliver the CuO2 nanoparticles as well as the drug-loaded micelles to the melanoma site. CuO2 nanoparticles released by the MN system generated Cu2+ and H2O2 in the tumor acidic environment to achieve self-supply of hydrogen peroxide to chemodynamic therapy (CDT). In addition, Cu2+ was chelated with disulfiram to produce CuET, which killed tumor cells. And the MN system had excellent near-infrared (NIR) photothermal properties due to the loading of CuO2 nanoparticles and induced localized thermotherapy in the melanoma region to further inhibit tumor growth. Thus, the designed MN system accomplished effective tumor suppression and minimal side effects in vivo via combined therapy, offering patients a safe and effective option for melanoma treatment.

1α,25-Dihydroxyvitamin D3 Supplementation during Pregnancy Is Associated with Allergic Rhinitis in the Offspring by Modulating Immunity.

BACKGROUND: Maternal supplementation with 1α,25-dihydroxyvitamin D3 (VD3) has immunologic effects on the developing fetus through multiple pathways. This study was aimed at investigating the effects of VD3 supplementation on immune dysregulation in the offspring during allergic rhinitis. METHODS: Different doses of VD3 as well as control were given to pregnant female mice. Ovalbumin (OVA) challenge and aluminum hydroxide gel in sterile saline were used to induce allergic rhinitis in offspring mice. Nasal lavage fluids (NLF) were collected, and eosinophils were counted in NLF 24 hours after the OVA challenge. Th1, Th2, Th17, and Treg subtype-relevant cytokines, including IFN-γ, IL-4, IL-10, IL-17, TGF-ß, and OVA-IgE levels from the blood and NLF of offspring mice, were detected by the enzyme-linked immunosorbent assay (ELISA) method. The Treg subtype was analyzed by flow cytometry. Treg cells were purified from offspring and were adoptively transferred to OVA-sensitized allogenic offspring mice. The outcomes were assessed in allogenic offspring. RESULTS: Our data showed that VD3 supplementation significantly decreased the number of eosinophils, basophils, and lymphocytes in the peripheral blood and NLF. The proportion of CD4+CD25+FoxP3+Tregs had a positive correlation with VD3 in a dose-dependent manner. The levels of serum IgE, IL-4, and IL-17 were decreased while the expressions of IFN-γ, IL-10, and TGF-ß were significantly enhanced in VD3 supplementation groups. Adoptive transfer CD4+CD25+FoxP3+Tregs of VD3 supplementation groups promoted Th1 and suppressed Th2 responses in the offspring during allergic rhinitis. CONCLUSION: Our findings indicated that low dose VD3 supply in pregnant mice's diet suppressed Th2 and Th17 responses in allergic rhinitis by elevating the Th1 subtype and the proportion of CD4+CD25+FoxP3+Tregs in offspring. It suggested that low dose VD3 supply may have the potential to act as a new therapeutic strategy for allergic rhinitis.

A rat model of SHPT with bone abnormalities in CKD induced by adenine and a high phosphorus diet.

The study of parathyroid hyperplasia with bone disease as a critical manifestation of chronic kidney disease-mineral and bone disorders (CKD-MBDs) is challenging due to the lack of a suitable research model. Here, we established a rat model with secondary hyperparathyroidism (SHPT) and bone disease induced by adenine and a high phosphorous diet and analyzed the skeletal characteristics. We performed blood analysis, emission computed tomography (ECT), dual energy X-ray absorptiometry (DEXA), micro-computed tomography (micro-CT), bone histomorphometry, and bone mechanical tests. The CKD rats with SHPT induced by adenine and a high phosphorus diet showed severe abnormalities in calcium and phosphorus metabolism and exhibited parathyroid hyperplasia. The bone mineral density (BMD) of femurs and lumbar vertebrae was significantly lower in the CKD rats than in the control (CTL) rats. The cortical and trabecular bone parameters of femurs showed significant bone loss. In addition, we found decreases in ultimate force, work to failure, stiffness, and elastic modulus in the CKD rats. In conclusion, our findings demonstrated that the CKD rats with SHPT induced by adenine and a high phosphorus diet may serve as a useful model for skeletal analysis in CKD with SHPT.

Chemosensitizing Effect of Astragalus Polysaccharides on Nasopharyngeal Carcinoma Cells by Inducing Apoptosis and Modulating Expression of Bax/Bcl-2 Ratio and Caspases.

BACKGROUND Platinum-based chemotherapy is the most effective regimen for nasopharyngeal carcinoma, which presents highly invasive and metastatic activity. However, the dose-related toxicity of chemotherapy agents limits the dose administration. Astragalus polysaccharide (APS) is the major active ingredient extracted from Chinese herb Radix Astragali and is proven to be active against carcinomas. We aimed to assess the chemosensitizing effects of Astragalus polysaccharides on nasopharyngeal carcinoma in vitro and in vivo and to explore the underlying mechanism. MATERIAL AND METHODS We used BALB/c nu/nu mice and human nasopharyngeal carcinoma cell lines CNE-1, CNE-2, and SUNE-1. MTT, Annexin V/PI, Western blot analysis, and TUNEL assay were carried out. RESULTS APS significantly promoted anti-proliferative and apoptotic effects of cisplatin on nasopharyngeal carcinoma cells. APS also enhanced the anti-tumor effects and cisplatin-induced apoptosis in the xenograft model. The level of Bcl-2 decreased, while the levels of Bax, caspase-3, and caspase-9 increased in cisplatin combined with APS treatment compared to cisplatin only treatment. The ratio of Bax to Bcl-2 was significantly enhanced by the APS to cisplatin. CONCLUSIONS APS enhanced the anti-proliferative and apoptotic effect of cisplatin by modulating expression of Bax/Bcl-2 ratio and caspases on nasopharyngeal carcinoma cells and in the xenograft model.

[Effect of Cordyceps sinensis powder on renal oxidative stress and mitochondria functions in 5/6 nephrectomized rats].

OBJECTIVE: To observe the effect of Cordyceps sinensis (CS) powder on renal oxidative stress and mitochondria functions in 5/6 nephrectomized rats, and to primarily explore its possible mechanisms. METHODS: Totally 30 male Sprague-Dawley rats were divided into the sham-operation group, the model group, and the treatment group by random digit table, 10 in each group. A chronic kidney disease (CKD) rat model was prepared by one step 5/6 nephrectomy. Rats in the treatment group were intragastrically administered with CS powder solution at the daily dose of 2 g/kg, once per day. Equal volume of double distilled water was intragastrically administered to rats in the sham-operation group and the model group. All medication lasted for 12 weeks. The general condition of rats, their body weight, blood pressure, 24 h proteinuria, urinary N-acetyl-ß-D-glucosaminidase (NAG), serum creatinine (SCr) , and blood urea nitrogen (BUN) were assessed before surgery, at week 2, 4, 6, 8, 10, and 10 after surgery. Pathological changes of renal tissues were observed under light microscope. Morphological changes of mitochondria in renal tubular epithelial cells were observed under transmission electron microscope. Activities of antioxidant enzymes including reduced glutathione (GSH), manganese superoxide dismutase (MnSOD), and malondialdehyde (MDA) in fresh renal tissue homogenate were detected. Mitochondria of renal tissues were extracted to detect levels of mitochondrial membrane potential and changes of reactive oxygen species (ROS). And expressions of cytochrome-C (Cyto-C) and prohibitin in both mitochondria and cytoplasm of the renal cortex were also measured by Western blot. RESULTS: (1) Compared with the sham-operation group, body weight was significantly decreased at week 2 (P <0. 01), but blood pressure increased at week 4 (P <0. 05) in the model group. Compared with the model group, body weight was significantly increased at week 12 (P <0. 01), but blood pressure decreased at week 8 (P < 0. 01) in the treatment group. (2) Compared with the sham-operation group, 24 h proteinuria, urinary NAG, blood SCr and BUN significantly increased in the model group (all P <0. 01). Compared with the model group, blood and urinary biochemical indices all significantly decreased in the treatment group (all P <0. 01). (3) Results of pathological renal scoring: Glomerular sclerosis index, scoring for tubulointerstitial fibrosis, degree of tubulointerstitial inflammatory infiltration were all obviously higher in the model group than in the sham-operation group (all P <0. 01). All the aforesaid indices were more obviously improved in the treatment group than in the model group (all P <0. 01). (4) Compared with the sham-operation group, activities of MnSOD and GSH-Px were significantly reduced, but MDA contents obviously increased in the renal cortex of the model group (all P <0. 01). Compared with the model group, activities of MnSOD and GSH-Px obviously increased (P <0. 05, P <0. 01), but MDA contents obviously decreased in the renal cortex of the treatment group (P <0. 01). (5) Compared with the sham-operation group, the mitochondrial membrane potential significantly decreased, but ROS levels significantly increased in the model group (all P <0.01). Compared with the model group, mitochondrial transmembrane potential increased in the treatment group, thereby inhibiting the tendency of increased production of ROS (both P < 0. 01). (6) Results of Western blot showed that, compared with the sham-operation group, expression levels of mitochondrial Cyto-C and Prohibitin were significantly reduced in the renal cortex (P <0. 01), but significantly elevated in the cytoplasm of the model group (P <0. 01). Compared with the model group, each index was obviously improved in the treatment group with statistical difference (P <0. 05, P <0. 01). CONCLUSION: CS powder had renal protection, and its mechanism might partially depend on in- hibition of oxidative stress and protection for mitochondria.

Sphingosine-1-phosphate receptor agonist, FTY720, restores coronary flow reserve in diabetic rats.

BACKGROUND: Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05). CONCLUSIONS: In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.

Inhibition of TGF-ß1/Smad signal pathway is involved in the effect of Cordyceps sinensis against renal fibrosis in 5/6 nephrectomy rats.

UNLABELLED: The present study aimed to investigate the effects of Cordyceps sinensis on renal fibrosis and its possible mechanisms. Sprague-Dawley rats were randomly divided into three groups: sham operation (SHAM) group, 5/6 subtotal nephrectomy (SNx) untreated group, and 5/6 subtotal nephrectomy treated with C. sinensis (2.0 g/kg d) (CS) group. Rats were studied 12 weeks after the surgery, and the CS group presented with significantly lower proteinuria, and better renal function compared with the SNx group (p<0.05). Pathological study showed that the glomerulosclerosis tubulointerstitial injury score was significantly reduced in the CS group compared with the SNx group. Furthermore, the mRNA expression of TGF-ß1, Smad2 and Smad3 and the protein expression of TGF-ß1, TßRI, TßRII and p-Smad2/3 were attenuated by the C. sinensis treatment. In constrast, the mRNA and protein expression of Smad7 was upregulated. Furthermore, the expression of α-SMA and FSP1 was also significantly attenuated, accompanied by the increasing expression of E-cadherin, suggesting the inhibition of the epithelial-mesenchymal transition (EMT). IN CONCLUSION: C. sinensis exerted its antifibrotic effect on the SNx rats through the inhibition of the TGF-ß1/Smad pathway.

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats.

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-ß-D-glycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-ß(1), connective tissue growth factor, α-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.