Role of connecting tubule glomerular feedback in obesity related renal damage.

Zucker obese rats (ZOR) have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by afferent (Af-Art) and efferent arteriole (Ef-Art) resistance. Af-Art resistance is regulated by factors that regulate other arterioles, such as myogenic response. In addition, it is also regulated by 2 intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation, which in turn increases PGC in ZOR. We performed a renal micropuncture experiment and measured stop-flow pressure (PSF), which is an indirect measurement of PGC in ZOR. Maximal TGF response at 40 nl/min was attenuated in ZOR (4.47 ± 0.60 mmHg) in comparison to the Zucker lean rats (ZLR; 8.54 ± 0.73 mmHg, P < 0.05), and CTGF was elevated in ZOR (5.34 ± 0.87 mmHg) compared with ZLR (1.12 ± 1.28 mmHg, P < 0.05). CTGF inhibition with epithelial sodium channel blocker normalized the maximum PSF change in ZOR indicating that CTGF plays a significant role in TGF attenuation (ZOR, 10.67 ± 1.07 mmHg vs. ZLR, 9.5 ± 1.53 mmHg). We conclude that enhanced CTGF contributes to TGF attenuation in ZOR and potentially contribute to progressive renal damage.

Therapeutic Potential of Cerium Oxide Nanoparticles for the Treatment of Peritonitis Induced by Polymicrobial Insult in Sprague-Dawley Rats.

OBJECTIVES: Peritonitis is a life-threatening disease that is associated with high mortality. The purpose of this study was to determine if cerium oxide nanoparticles can be used to diminish intra-abdominal infection-induced mortality and systemic inflammatory response syndrome in the laboratory rat. DESIGN: Randomized, controlled animal study and cell culture study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats aged 12 weeks, RAW 246.7 macrophage cell line. INTERVENTIONS: Intra-abdominal infection or peritonitis was induced by intraperitoneal injection of cecal material (600 mg/kg in 5% sterile dextrose water at a dosage of 5 mL/kg) obtained from healthy donors. Rats in control and peritonitis groups received 200 µL of sterile deionized water IV via the tail vein, whereas rats in cerium oxide-only group and peritonitis+cerium oxide group received cerium oxide nanoparticles (0.5 mg/kg) IV at the time of polymicrobial injection. Survival rate was monitored for 14 days, while in other experiments, animals were killed at 3 and 18 hours after induction of peritonitis for biochemical analysis. MEASUREMENTS AND MAIN RESULTS: Administration of a single dose (0.5 mg/kg) of cerium oxide nanoparticles IV to rats in the peritonitis group significantly improved survival rates and functioned to restore core body temperature toward baseline. Treatment-induced increases in animal survivability were associated with reduced systemic and hepatic oxidative stress, diminished serum cytokines, and chemokine levels. Changes in serum inflammatory markers with treatment were accompanied by decreased monocyte and lymphocyte extravasation into the peritoneal cavity along with decreased infiltration of macrophages into liver. In the heart, treatment diminished extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase-Stat-3 signaling and attenuated endothelial expression of P-selectin and vascular cell adhesion molecule-1. CONCLUSIONS: Cerium oxide nanoparticles attenuate the systemic inflammatory response associated with peritonitis, suggesting potential use as a novel therapeutic agent for the treatment of severe intra-abdominal infection.

Clinical Management of Mantle Cell Lymphoma With Concurrent Vascular Complications: A Case Report.

This is a case of a 70-year-old patient with no past medical history but a significant family history of cancer, who was admitted with acute pulmonary embolism and left lower extremity deep vein thrombosis concerning malignancy. Further investigations revealed mantle cell lymphoma. This case highlights the complex clinical management of patients presenting with concurrent hematological malignancy and vascular complications.

Bleeding Mystery Unveiled: A Case of Acquired Hemophilia A in the Shadow of Multiple Myeloma.

This case report is of a 50-year-old woman who had a working diagnosis of von Willebrand disease (vWD) due to a history of bleeding complications and continued to experience recurrent bleeding incidents and hematoma. A workup revealed multiple lytic lesions, and a bone marrow biopsy yielded the diagnosis of multiple myeloma. After stem cell transplantation, the patient's factor VIII levels normalized, supporting acquired factor VIII deficiency due to an autoimmune phenomenon. This case highlights the rare occurrence of acquired factor VIII deficiency secondary to multiple myeloma. It also emphasizes the importance of considering secondary causes in patients with a working diagnosis of vWD and recurrent bleeding incidents.

Novel Small Molecule, UTS-1401, as a Radioprotector for Total-Body Irradiation.

We report on a new radioprotector, UTS-1401, a small molecule that was synthesized (by one of us, JS) and evaluated here for its radioprotective effect against total-body irradiation (TBI). Female and male NIH Swiss mice were subjected to TBI at doses of 6.5, 7.5 and 8.5 Gy either with or without a 24 h pretreatment of UTS-1401 given ip and observed for 30 days. Survival rates were significantly increased when mice were treated with UTS-1401 compared to those not treated. The radioprotective effect of UTS-1401 was drug-dose dependent for male mice exposed to 8.5 Gy TBI with 150 mg/kg of UTS-1401 as the optimal dose. The radioprotective effect of UTS-1401 on female mice exposed to 8.5 Gy TBI was observed at 50, 100, and 150 mg/kg, with no dose response relationship noted. Female mice were more radioresistant than male mice with LD50/30 values of 7.8 Gy vs. 6.8 Gy, respectively. Weight changes after UTS-1401 alone showed a significant body weight increase at 150 mg/kg. Both the ip and iv route for UTS-1401 were similarly effective for male mice exposed to 8 Gy TBI. Further analysis using an endogenous spleen colony assay demonstrated that pretreatment of UTS-1401 for up to 72h prior to TBI protected both spleen weight and hematopoietic stem cells with a treated/untreated ratio between 2.0 and 3.2 for the latter for times between 0.5 h and 72 h. A separate in vivo study showed that pretreatment of UTS-1401 protected bone marrow CFU-GM for mice exposed to TBI. In summary, UTS-1401 is a promising small-molecule radioprotective agent as demonstrated by whole animal, hematopoietic stem cell and bone marrow myeloid progenitor cell survival.

Eyes on the Line: A Case of Ocular Granulomatosis With Polyangiitis.

Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a small vessel vasculitis with a positive ANCA in the serum. One of three diseases that fall under this category is granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis. This case report presents a patient with an ocular manifestation of GPA, rendering a difficult diagnosis and multi-specialty approach to managing the disease.

A Rare Rheumatologic Case of Catastrophic Antiphospholipid Syndrome.

A very rare and severe disease catastrophic antiphospholipid syndrome is defined by small vessel occlusions resulting in multi-organ involvement in the presence of antiphospholipid antibodies. This case report presents a case of catastrophic antiphospholipid syndrome in a young female without past medical history.

Whippets Causing Vitamin B12 Deficiency.

On the rise due to its effects of euphoria, recreational use of nitrous oxide can cause severe neurologic symptoms caused by marked and rapid onset of vitamin B12 deficiency. This is a case of a young 34-year-old male who presented with an inability to walk and confusion caused by vitamin B12 deficiency in the setting of recreational nitrous oxide use.

Coccidioidomycosis Causing Hydrocephalus.

Coccidoidomycosis is caused by Coccidoides imitis and C. posadasii infection. Coccidioidomycosis is also known as San Joaquin Valley fever or desert rheumatism. It is only seen in the Southwest United States (Arizona, New Mexico, California, Texas, Nevada, and Utah), and Central and South America. This infection is acquired by the inhalation of fungal spores in the air. The most severe extrapulmonary coccidioidomycosis is coccidioidomycosis meningitis, in which patients present with headaches, photophobia, altered mental status, and hearing difficulties. This is a case report of a person with disseminated coccidioidomycosis meningitis complicated by hydrocephalus, presenting as a headache.

"Speedballing" to Severe Rhabdomyolysis and Hemodialysis in a 27-Year-Old Male.

With the popularity of smartphones, many drug users buy counterfeit pills online that can lead to serious adverse effects and be detrimental to their health. This case report showcases a young 27-year-old male who smoked and snorted four blue pills called "M30," which were bought online, resulting in severe rhabdomyolysis and fulminant kidney failure requiring regular hemodialysis.

Bradycardia Related to Remdesivir During COVID-19: Persistent or Permanent?

Remdesivir is an antiviral that inhibits RNA-dependent RNA polymerases of coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a cornerstone of therapy for hospitalized patients with coronavirus disease 2019 (COVID-19), especially those worsening from a respiratory standpoint despite being started on antibiotics, dexamethasone, zinc, and vitamin C. This is a case report describing two COVID-19-positive patients with bradycardia after starting remdesivir. Once remdesivir was discontinued, one patient corrected to normal sinus rhythm, and the other continued with persistent bradycardia.

COVID Booster Shots: The Need of the Hour.

Breakthrough cases of COVID-19 infections in fully vaccinated patients are rising. The number of patients requiring supplemental oxygen and airway management, along with multiple therapies, including remdesivir, baricitinib, steroids, and antibiotics, is more than ever among the vaccinated group. Despite being fully vaccinated for SARS-CoV-2 earlier this year, some are getting hospitalized for COVID-19 possibly due to waning immunity. Few such patients decline for the worse requiring intubation as they have not received the SARS-CoV-2 booster dose yet. This case report showcases four fully vaccinated patients who get hospitalized for COVID-19.

Reinvestigation of Mycothiazole Reveals the Penta-2,4-dien-1-ol Residue Imparts Picomolar Potency and 8S Configuration.

Reinvestigation of mycothiazole (1) revealed picomolar potency (IC50 = 0.00016, 0.00027, 0.00035 µM) against pancreatic, (PANC-1), liver (HepG2), and colon (HCT-116) tumor cell lines. Reevaluation of 1 provided [α]D data indicating Vanuatu specimens of C. mycofijiensis contain the 8S enantiomer of 1 and not the 8R configuration previously reported. Semisynthesis provided 8-O-acetylmycothiazole (2), 8-oxomycothiazole (8), mycothiazole nitrosobenzene derivatives (MND1, MND2: 9a, 9b), and MND3 (10) with IC50 = 0.00129, >1.0, >1.0, >1.0, >1.0 µM, respectively, against PANC-1 cell lines. These results highlight the significance of the penta-2,4-dien-1-ol residue as a key structural feature of 1 required for its cytotoxicty against tumor cell lines.

Thymosin ß4 Deficiency Exacerbates Renal and Cardiac Injury in Angiotensin-II-Induced Hypertension.

Thymosin ß4 (Tß4), a ubiquitous peptide, regulates several cellular processes that include cell morphology, wound healing, and inflammatory response. Administration of exogenous Tß4 is protective in diabetic nephropathy and in a unilateral ureteral obstruction model. However, the role of endogenous Tß4 in health and disease conditions remains unclear. To elucidate the pathophysiological role of endogenous Tß4 in hypertension, we examined angiotensin-II (Ang-II)-induced renal and cardiac damage in Tß4 knockout (Tß4 KO) mice. Tß4 KO and wild-type C57BL/6 mice were infused continuously for 6 weeks with either vehicle or Ang-II (980 ng/kg per minute). At baseline, Tß4 deficiency did not affect renal and cardiac function. Systolic blood pressure in the Ang-II group was similar in wild-type and Tß4 KO mice (wild-type Ang-II, 179.25±10.11 mm Hg; Tß4 KO Ang-II, 169.81±6.54 mm Hg). Despite the similar systolic blood pressure after Ang-II infusion, Tß4-deficient mice had dramatically increased albuminuria and decreased nephrin expression in the kidney (P<0.005). In the heart of Tß4 KO mice, Ang-II reduced ejection fraction and shortening fraction (ejection fraction: wild-type Ang-II 77.95%±1.03%; Tß4 KO Ang-II 62.58%±3.25%; P<0.005), which was accompanied by cardiac hypertrophy and left ventricular dilatation. In addition, renal and cardiac infiltration of CD68 macrophages, intercellular adhesion molecule-1, and total collagen content were increased after Ang-II infusion in Tß4 KO mice (P<0.005). Overall, our data indicate that endogenous Tß4 is crucial in preventing tissue injury from Ang-II-induced hypertension. This study gives new insights into the protective role of endogenous Tß4 in hypertensive end-organ damage.

Renal Protective Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) in Obese Rats on a High-Salt Diet.

BACKGROUND: Obesity is a public health problem, associated with salt sensitive hypertension, kidney inflammation, and fibrosis. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a tetra peptide with anti-inflammatory and anti-fibrotic properties. However, its effect on preventing kidney damage in obesity is unknown. We hypothesized that Zucker obese (ZO) rats on a high-salt (HS) diet develop renal damage, inflammation, fibrosis, and this is prevented with Ac-SDKP treatment. METHODS: Zucker lean (ZL) and ZO rats (8 weeks old) were treated with Ac-SDKP (1.6 mg/kg/day) while maintained on either a normal-salt (NS; 0.4%) or HS (4%) diet for 8 weeks. Systolic blood pressure (SBP), albuminuria, renal inflammation, and fibrosis were evaluated. RESULTS: HS diet increased macrophage infiltration in the kidneys of both ZL and ZO rats but was significantly higher in ZO rats receiving the HS diet (ZL + NS, 13.9 ± 1.3 vs. ZL + HS, 19.14 ± 1.5 and ZO + NS, 25.5 ± 1.4 vs. ZO + HS, 87.8 ± 10.8 cells/mm2; P < 0.05). Ac-SDKP prevented macrophage infiltration in ZO rats (ZO + HS + Ac-SDKP, 32.18 ± 2.4 cells/mm2; P < 0.05). Similarly, glomerulosclerosis, cortical, and medullary interstitial fibrosis were increased in ZO rats fed the HS diet, and Ac-SDKP attenuated these alterations (P < 0.05). SBP was increased in ZO rats fed the HS diet (ZO + NS, 121.3 ± 8.9 vs. ZO + HS, 164 ± 6.9 mm Hg; P < 0.05), and it was significantly decreased with Ac-SDKP treatment (ZO + HS + Ac-SDKP, 144.05 ± 14.1 mm Hg; P = 0.004). Albuminuria was higher in ZO rats than in ZL rats; however, neither HS nor Ac-SDKP treatment affected it. CONCLUSIONS: Ac-SDKP treatment in ZO rats fed a HS diet prevented renal damage by reducing inflammation, fibrosis, and SBP.

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction.

The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO2) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile (P(o)) function (sham: 25.6±1.6 N/cm(2) vs CeO2: 23.4±0.8 N/cm(2) vs Sep: 15.9±1.0 N/cm(2) vs Sep+CeO2: 20.0±1.0 N/cm(2), P<0.05). These improvements in diaphragm contractile function were accompanied by a normalization of protein translation signaling (Akt, FOXO-1, and 4EBP1), diminished proteolysis (caspase 8 and ubiquitin levels), and decreased inflammatory signaling (Stat3 and iNOS). Histological analysis suggested that nanoparticle treatment was associated with diminished sarcolemma damage and diminished inflammatory cell infiltration. These data indicate CeO2 nanoparticles may improve diaphragmatic function in the septic laboratory rat.

Inhibition of MAP kinase/NF-kB mediated signaling and attenuation of lipopolysaccharide induced severe sepsis by cerium oxide nanoparticles.

Sepsis is a life threatening disease that is associated with high mortality. Existing treatments have failed to improve survivability in septic patients. The purpose of this present study is to evaluate whether cerium oxide nanoparticles (CeO2NPs) can prevent lipopolysaccharide (LPS) induced severe sepsis mortality by preventing hepatic dysfunction in male Sprague Dawley rats. Administration of a single dose (0.5 mg/kg) of CeO2NPs intravenously to septic rats significantly improved survival rates and functioned to restore body temperature, respiratory rate and blood pressure towards baseline. Treatment-induced increases in animal survivability were associated with decreased hepatic damage along with reductions in serum cytokines/chemokines, and diminished inflammatory related signaling. Kupffer cells and macrophage cells exposed to CeO2NPs exhibited decreases in LPS-induced cytokine release (TNF-α, IL-1ß, IL-6, HMGB1) which were associated with diminished cellular ROS, reduced levels of nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and decreased nuclear factor-kappa light chain enhancer of activated B cells (NF-kB) transcriptional activity. The findings of this study indicate that CeO2NPs may be useful as a therapeutic agent for sepsis.

Lipopolysaccharide induced MAP kinase activation in RAW 264.7 cells attenuated by cerium oxide nanoparticles.

High mortality rates are associated with the life threatening disease of sepsis. Improvements in septic patient survivability have failed to materialize with currently available treatments. This article represents data regarding a study published in biomaterials (Vellaisamy et al., Biomaterials, 2015, in press). with the purpose of evaluating whether severe sepsis mortality and associated hepatic dysfunction induced by lipopolysaccharide (LPS) can be prevented by cerium oxide nanoparticles (CeO2NPs) treatment in male Sprague Dawley rats. Here we provide the information about the method and processing of raw data related to our study publish in Biomaterials and Data in Brief (Vellaisamy et al., Biomaterials, 2015, in press; Vellaisamy et al., Data in Brief, 2015, in press.). The data contained in this article evaluates the contribution of MAPK signaling in LPS induced sepsis. Macrophage cells (RAW 264.7) were treated with a range of cerium oxide nanoparticle concentration in the presence and absence of LPS. Immunoblotting was performed on the cell lysates to evaluate the effect of cerium oxide nanoparticle treatment on LPS induced changes in Mitogen Activated Protein Kinases (MAPK) p-38, ERK 1/2, and SAPK/JNK phosphorylation.

Cerium oxide nanoparticles inhibit lipopolysaccharide induced MAP kinase/NF-kB mediated severe sepsis.

The life threatening disease of sepsis is associated with high mortality. Septic patient survivability with currently available treatments has failed to improve. The purpose of this study was to evaluate whether lipopolysaccharide (LPS) induced sepsis mortality and associated hepatic dysfunction can be prevented by cerium oxide nanoparticles (CeO2NPs) treatment in male Sprague Dawley rats. Here we provide the information about the methods processing of raw data related to our study published in Biomaterials (Selvaraj et al., Biomaterials, 2015, In press) and Data in Brief (Selvaraj et al., Data in Brief, 2015, In Press). The data present here provides confirmation of cerium oxide nanoparticle treatments ability to prevent the LPS induced sepsis associated changes in physiological, blood cell count, inflammatory protein and growth factors in vivo. In vitro assays investigation the treated of macrophages cells with different concentrations of cerium oxide nanoparticle demonstrate that concentration of cerium oxide nanoparticles below 1 µg/ml did not significantly influence cell survival as determined by the MTT assay.

Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade.

INTRODUCTION: Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes. METHODS: To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining. RESULTS: During adipogenesis in vitro, differentiating pre-adipocytes display transient increases in the expression of genes involved in canonical Wnt signaling cascade. Increased levels of HO-1 expression and HO activity resulted in elevated levels of ß-catenin, pGSK3ß, Wnt10b, Pref-1, and shh along with increased levels of adiponectin (P < 0.05). In addition, induction of HO-1 resulted in a reduction in C/EBPα, PPARγ, Peg-1/Mest, aP2, CD36 expression and lipid accumulation (P < 0.05). Suppression of HO-1 gene by siRNA decreased Wnt10b, pGSK3ß and ß-catenin expression, and increased lipid accumulation. The canonical Wnt responsive genes, IL-8 and SFRP1, were upregulated by CoPP and their expression was decreased by the concurrent administration of tin mesoporphyrin (SnMP), an inhibitor of HO activity. Furthermore, knockdown of Wnt10b gene expression by using siRNA showed increased lipid accumulation, and this effect was not decreased by concurrent treatment with CoPP. Also our results show that blocking the Wnt 10b antagonist, Dickkopf 1 (Dkk-1), by siRNA decreased lipid accumulation and this effect was further enhanced by concurrent administration of CoPP. CONCLUSIONS: This is the first study to demonstrate that HO-1 acts upstream of canonical Wnt signaling cascade and decreases lipogenesis and adipocyte differentiation suggesting that the HO-1 mediated increase in Wnt10b can modulate the adipocyte phenotype by regulating the transcriptional factors that play a role in adipogenesis. This is evidenced by a decrease in lipid accumulation and inflammatory cytokine levels, increased adiponectin levels and elevation of the expression of genes of the canonical Wnt signaling cascade.