The Interplay of the Unfolded Protein Response in Neurodegenerative Diseases: A Therapeutic Role of Curcumin.

Abnormal accumulation of misfolded proteins in the endoplasmic reticulum and their aggregation causes inflammation and endoplasmic reticulum stress. This promotes accumulation of toxic proteins in the body tissues especially brain leading to manifestation of neurodegenerative diseases. The studies suggest that deregulation of proteostasis, particularly aberrant unfolded protein response (UPR) signaling, may be a common morbific process in the development of neurodegeneration. Curcumin, the mixture of low molecular weight polyphenolic compounds from turmeric, Curcuma longa has shown promising response to prevents many diseases including current global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurodegenerative disorders. The UPR which correlates positively with neurodegenerative disorders were found affected by curcumin. In this review, we examine the evidence from many model systems illustrating how curcumin interacts with UPR and slows down the development of various neurodegenerative disorders (ND), e.g., Alzheimer's and Parkinson's diseases. The recent global increase in ND patients indicates that researchers and practitioners will need to develop a new pharmacological drug or treatment to manage and cure these neurodegenerative diseases.

Anemia and carnitine supplementation in hemodialyzed patients.

Carnitine supplementation in hemodialyzed patients was studied in a double-blinded, randomized, controlled trial in order to elucidate the effect of intravenous carnitine on renal anemia in patients treated with recombinant human erythropoietin (rHuEPO). Twenty stable hemodialysis (HD) patients received intravenous L-carnitine after each dialysis session in a dosage of 5 (N = 15) and 25 (N = 5) mg/kg, respectively, together with intravenous iron saccharate (20 mg/HD session) for four months and without iron for a further four months. Twenty patients received placebo instead of carnitine with an identical iron regimen. After a run-in phase of six months with a stable rHuEPO requirement, the rHuEPO dose was adjusted monthly when necessary to maintain target hemoglobin levels. At study entry (T0), plasma and red blood cell carnitine levels did not correlate significantly with the rHuEPO requirement. However, plasma free and total carnitine levels showed a significant negative correlation with erythrocyte survival time at T0. After four months of coadministration of intravenous iron and L-carnitine (T4), the rHuEPO requirement decreased in 8 of 19 evaluable HD patients. In these responders, the weekly rHuEPO dose was decreased significantly by 36.9+/-23.3% (183.7+/-131.7 at T0 vs. 126.6+/-127.9 U/kg/week at T4, P < 0.001). The rHuEPO requirement, however, was unchanged when all carnitine-treated patients were compared between T0 and T4 (T0: 172.0+/-118.0 vs. T4: 152.3+/-118.8 U/kg/week, P = 0.07, NS), but the erythropoietin resistance index decreased significantly in this group (T0: 16.0+/-11.0 vs. T4: 13.6+/-10.5 U/kg/week/g of hemoglobin, P < 0.02). The erythrocyte survival time was measured in five HD patients treated with iron and carnitine at T0 and T4. Two out of these patients were carnitine responders and showed an increase of erythrocyte survival time of 15 and 20%, respectively. After the withdrawal of iron supplementation, the rHuEPO requirement increased comparably in both L-carnitine- and placebo-treated patients during four more months. According to our data, L-carnitine, in addition to iron supplementation, may have an effect on erythropoietin resistance and erythrocyte survival time in HD patients. More than half of our patients, however, showed no benefit. Further studies to identify those HD patients who might have a benefit of carnitine supplementation, as well as studies concerning the optimal dosage, duration, and way of administration of carnitine supplementation and its mechanism of action, are required.

Methylene blue prevents pulmonary injury after intestinal ischemia-reperfusion.

OBJECTIVE: To investigate the effect of methylene blue, an inhibitor of oxygen radicals, on lung injury caused by reperfusion of ischemic tissue. METHODS: Intestinal ischemia-reperfusion injury was induced in rats by clamping the superior mesenteric artery for 1 hour. Thereafter, the experimental group was administered 1% methylene blue intraperitoneally and the control group received saline. After 4 hours, pulmonary histopathologic features were assessed, and lung wet-weight to dry-weight ratios and tissue xanthine oxidase were determined. RESULTS: The control group suffered from severe pulmonary parenchymal damage, compared with slight damage in the experimental group. The number of sequestered neutrophils was significantly higher in the control group (319 +/- 60 polymorphonuclear cells per 10 high-power fields) than in the methylene blue-treated group (91 +/- 8 polymorphonuclear cells per 10 high-power fields; p < 0.001). The wet-weight to dry-weight ratio was significantly increased in the saline-treated rats compared with the methylene blue-treated group (6.19 +/- 0.28 vs. 5.07 +/- 0.21; p < 0.001). Xanthine oxidase activity was similar in both groups. CONCLUSION: Methylene blue attenuated lung injury after intestinal ischemia-reperfusion. Inhibition of oxygen free radicals may be the protective mechanism.

Low nitric oxide production in patients with chronic renal failure.

BACKGROUND: Rats with chronic renal failure have a low nitric oxide (NO) production and a diminished NO excretion. The supplementation of L-arginine has an inhibitory effect on the progression of renal insufficiency. METHODS: The present study was designed to determine whether chronic renal failure patients have a low NO production. Plasma and urine nitrate (NO3) and nitrite (NO2), stable metabolites of NO, were measured in 83 consecutive patients with chronic renal failure. The 83 chronic renal failure patients were divided into three groups: group 1, mild renal failure (creatinine clearance >60 ml/min/1.73 m2); group 2, moderate renal failure (creatinine clearance >30 <60 ml/min/1.73 m2), and group 3, severe renal failure (creatinine clearance <30 ml/min/1.73 m2). Thirty-three healthy volunteers served as controls. RESULTS: The daily urinary NO excretion was significantly lower in patients with moderate and severe renal failure as compared with those with mild renal failure and normal controls. The lowest values were found in the severe renal failure group. When the 24-hour urinary NO excretion or NO per milligram creatinine and the NO clearance were correlated with the renal function in all patients as a group, these parameters were directly correlated with the creatinine clearance and inversely correlated with the serum creatinine level. The plasma NO concentration was not different between the three chronic renal failure groups, but higher than in the controls. Plasma NO in renal failure patients was not correlated with the creatinine clearance or serum creatinine levels. CONCLUSIONS: Chronic renal failure is a state of NO deficiency. Treatment strategies to increase NO production (L-arginine supplementation or other NO compounds) may prove to be useful in maintaining the renal function and slow the progression of renal disease.

[Diagnosis in chronic inflammatory bowel diseases--report of the Austrian Chronic Inflammatory Bowel Disease Study Group]. / Diagnostik bei chronisch entzündlichen Darmerkrankungen--Bericht der Osterreichischen Arbeitsgruppe für chronisch entzündliche Darmerkrankungen.

Diagnostic procedures in inflammatory bowel diseases (IBD) serve to secure the diagnosis and to optimize treatment. Upon initial diagnosis endoscopy up to the terminal ileum is mandatory including multiple step biopsies. When diagnostic guidelines are followed and adequate clinical information is available, IBD will be correctly classified in about 80 to 90% of cases upon first examination. In contrast endoscopic studies are only of limited value in monitoring treatment. The decision if and when to perform endoscopy during exacerbation of disease must be an individual one. When disease activity is evaluated, a distinction must be made between degree of activity as reflected by laboratory parameters and severity of illness as reflected by the clinical presentation with abdominal complaints, fistulas, abscesses, etc. Distinct activity indices are useful in clinical studies to obtain an objective evaluation of activity and severity of disease. At clinical routine visits questions should not only concern the basic illness but also ask for quality of life and psychosocial status. Only a small number of laboratory tests are needed for basic diagnosis and follow-up. A small bowel enteroclysis should always be performed upon primary diagnosis of Crohn's disease and during the course of disease when there is suspicion of small-bowel involvement. Double contrast barium enema should be limited to special indications as incomplete colonoscopy e.g. due to stenosis or suspected fistula. Sonography is the primary investigation when complications are suspected. CT is useful as an adjunct or when the afore mentioned methods do not show clear findings. NMR is the procedure of choice for detection of pararectal fistulas and abscesses. Transrectal endosonography is comparably good but limited to the experience of the investigators and by patient's tolerability.

Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats.

Changes in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO2) + nitrate (NO3) levels were measured in plasma and urine. The effects of chronic oral supplementation with L-arginine and an NO synthase inhibitor (N-omega-nitro-L-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90 +/- 22 microliters.min-1. 100g body weight-1, p < 0.005), and higher fractional excretion of sodium (FENa)% (10.90 +/- 4.2, p < 0.001) and protein excretion (2078 +/- 69 micrograms/ml creatinine clearance, p < 0.001) compared with the respective values in the non-diabetic groups (163 +/- 30; 1.46 +/- 86; 453.3 +/- 31). The plasma and urine NO2 + NO3 levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p < 0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO2 + NO3 excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The L-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.

Nitric oxide in streptozotocin-induced diabetes mellitus in rats.

1. The present study was performed to determine the relationship between diabetic glomerular hyperfiltration and nitric oxide as modulated by the chronic administration of L-arginine and/or N-omega-nitro-L-arginine, a known nitric oxide synthase inhibitor in streptozotocin-induced diabetic rats. 2. Normal rats and rats drinking hypertonic glucose (10%) were used as time-controlled groups. Six weeks after administration of streptozotocin the diabetic rats had significantly higher creatinine clearance (667 +/- 53 microliters min-1 100 g-1 body weight) than before and streptozotocin (456 +/- 38 microliters min-1 100 g-1 body weight, P < 0.005) and very high plasma (37.8 +/- 10.9 mumol/l) and urinary (3.492 +/- 0.179 nmol min-1 100 g-1 body weight) nitrite+nitrate (stable metabolites of nitric oxide) values compared with before streptozotocin administration [19.3 +/- 2.8 mumol/l (P < 0.001) and 0.420 +/- 0.051 nmol min-1 100 g-1 body weight (P < 0.001) respectively]. The 6-week diabetic rats had higher systolic blood pressure (124.2 +/- 2.9 mmHg, P < 0.05) than before streptozotocin (108 +/- 8 mmHg), but had a value similar to that of the hypertonic-glucose-drinking rats. 3. The diabetic rats supplemented with L-arginine did not show an increase in creatinine clearance and had a lower urinary excretion of nitrite+nitrate (0.999 +/- 0.27 nmol min-1 100 g-1 body weight, P < 0.005) than the respective untreated streptozotocin-induced diabetic rats. Creatinine clearance increased in the normal and glucose-drinking rats that received L-arginine. The administration of L-arginine resulted in significant reduction in blood pressure in all groups studied. The chronic nitric oxide synthase inhibitor resulted in high blood pressure, and in a significant decrease in creatinine clearance and urinary nitrite+nitrate excretion in all groups studied. In both diabetic and glucose-drinking rats, the L-arginine therapy resulted in significantly lower plasma and urinary glucose levels than in their respective untreated control groups. 4. The nitric oxide synthase inhibitor increased the plasma and urinary glucose concentration in both diabetic and glucose-drinking rats. 5. Our results indicate that diabetic rats are characterized by high plasma concentrations and elevated urinary excretion of nitrite+nitrate, suggesting a state of high nitric oxide production. The vascular response to nitric oxide in diabetic rats may be different at the glomerular and peripheral vascular bed.

Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis.

Iron deficiency may develop in hemodialysis patients, especially when erythropoietin is given. The role of iron deficiency in the anemia of predialysis chronic renal failure (CRF), however, is much less clear. We have intravenously (IV) administered iron as ferric saccharate in a total dose of 200 mg elemental iron monthly for 5 months to 33 CRF patients who remained anemic despite oral iron supplementation and who had no laboratory signs of iron overload. None was receiving erythropoietin therapy. In 22 of the patients there was an increase in the hematocrit values by the end of the study. These patients were considered responders to intravenous iron (IV Fe) therapy. In 11 patients the iron administration was not associated with improvement of the anemia (nonresponders). Before onset of the IV Fe therapy there were no differences between the responders and nonresponders with regard to degree of anemia, serum ferritin, iron saturation, renal function, or blood pressure. One additional patient was excluded from the study because of a mild reaction during an IV test dose before the study. No worsening of kidney function and no other side effects were noted. In four patients (three responders and one nonresponder) the control of blood pressure necessitated antihypertensive drug therapy adjustment. In conclusion, IV Fe supplementation in two thirds of anemic CRF patients not receiving dialysis resulted in a significant improvement of the anemia, thus avoiding the necessity of erythropoietin or blood administration. This could be achieved by increasing the plasma ferritin levels to 200 to 400 microns/L and/or increasing the iron saturation to 25% to 35%. Intravenous ferric saccharate appears to be a safe and effective method of administering iron for the correction of anemia in CRF patients not receiving dialysis.

Intravenous ferric saccharate as an iron supplement in dialysis patients.

In the present prospective study we examined the long-term effect of intravenous supplementation with ferric saccharate (IV Fe) in the treatment of the anemia of chronic dialysis patients. All patients, 64 on chronic hemodialysis (HD) and 9 on chronic ambulatory peritoneal dialysis (CAPD), were treated intravenously with this preparation in a dose of 100 mg elemental iron twice monthly. There were five groups. Group 1: 41 HD patients who were receiving erythropoietin (EPO) for at least 6 months prior to the addition of IV Fe. In this group, when IV Fe was given over 6 months, the hematocrit (Hct) increased from a mean of 28.7 to 33.7%. Over the next 6 months, the EPO dose was gradually reduced by a mean of 61.1%, but the mean Hct remained unchanged. Group 2: 11 HD patients who started IV EPO simultaneously with the IV Fe. In this group, over 6 months, the mean Hct increased from 28.1 to 34.1. Over the next 6 months, the EPO dose was gradually reduced by 75.7%, but the mean Hct remained unchanged. Group 3: 12 HD patients who received IV Fe alone for 12 months. The mean Hct increased from 30.5 to 37.9%. Group 4: 4 CAPD patients who had been receiving subcutaneous EPO for at least 6 months prior to IV Fe therapy. Over the subsequent 6 months of IV Fe, the mean Hct increased from 28.4 to 33.3%. Group 5: 5 CAPD patients not on EPO who received IV Fe for 6 months. The mean Hct increased from 27.7 to 35.6%. No adverse effects were seen in any patients throughout the study. In conclusion, adequate Fe supplementation may allow the target Hct of about 33% to be reached without, or with only very low doses of EPO. IV Fe as ferric saccharate is a new and safe form of parenteral iron therapy of the anemia of chronic dialysis patients.

Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production.

The effect of oral supplementation of L-arginine, the substrate of nitric oxide, (1.25 g/liter water) and captopril (15 mg/liter water) was studied in 5/6 nephrectomized rats for a period of three months. N-omega-nitro L-arginine, a nitric oxide synthase inhibitor, was given orally (70 mg/liter water) with or without L-arginine or captopril. The urinary excretion of nitrite (NO2) + nitrate (NO3), the known metabolites of nitric oxide, was taken as an index of nitric oxide production. Chronic renal failure rats were characterized by a low creatinine clearance, high FENa%, proteinuria, hypertension and a low urinary excretion of NO2 + NO3; 0.152 +/- 0.06 (P < 0.001) nmol/micrograms creatinine compared with 0.481 +/- 0.004 (P < 0.001) in normal rats and 0.479 +/- 0.11 (P < 0.001) in untreated sham-operated rats. Both L-arginine and captopril were effective in the normalization of all these parameters. The combination of L-arginine and captopril had no additive effects. The nitric oxide synthase inhibitor significantly diminished the captopril beneficial effect. It is concluded that chronic renal failure in rats is a low nitric oxide production state. The supplementation of L-arginine is shown to overcome this condition. It is suggested that the beneficial effect of captopril on chronic renal failure is through a specific L-arginine--nitric oxide synthase--nitric oxide pathway.

Role of nitric oxide in glycerol-induced acute renal failure in rats.

EDRF results from the metabolism of L-arginine. N-omega-nitro-L-arginine is a nitric oxide synthase inhibitor (L-arginine competitive inhibitor). Acute renal failure was induced by i.m glycerol (50%) 5 ml/kg bw. L-arginine: 3 mg/kg bw/min for 60 min before and 60 min after glycerol administration. L-arginine inhibitor (150 micrograms/kg bw/min for 120 min). Cin, Cpah and FENa% were measured immediately or 24 h after glycerol (mean of three periods of 20 min). A second series of similar experiments was done in dehydrated (16 h) rats with a high dose of glycerol (50% solution, 10 ml/kg bw). L-arginine ameliorates the severity of ARF immediately after glycerol administration and enhances the recovery of glycerol-induced ARF. The L-arginine inhibitor resulted in a more severe ARF. Urinary cGMP decreased significantly after glycerol administration. It is concluded that nitric oxide has an important pathogenetic role in the glycerol induced ARF.

Respiratory depression following retrobulbar bupivacaine: three case reports and literature review.

Retrobulbar bupivacaine (0.75%) administration has been implicated as a causative factor in respiratory distress, cardiovascular dysfunction, and various central nervous system disturbances. The three cases here demonstrate two separate occurrences of respiratory and central nervous system (CNS) complications following retrobulbar bupivacaine (Marcaine) injection. It is thought that the immediate and delayed occurrences result from inadvertent injection at either of two sites: intravascularly or directly into the membranous sheath surrounding the optic nerve.