Biochemical Investigations Research Articles

Gaucher disease: A case presentation

Gaucher disease (GD) is an autosomal recessive genetic disorder. It is a rare disorder due to mutation in the acid-β-glucosidase (GBA1) gene. This mutation leads to deficiency of the enzyme glucocerebrosidase. The gene responsible for the disease is located on chromosome 1 band q21. The disorder is characterized by accumulation of gaucher cells in bone marrow, spleen and liver. Gaucher cells are macrophages with deposition of glucosylceramide. Gaucher disease is the most common lysosomal storage disorder. It affects all ethnicities. The clinical presentation of GD is highly variable which depends on geographic and ethnic origin. There are three clinical subtypes have been identified- Type 1 (Adult subtype- Non neuropathic), Type-2 (Infantile subtype-Acute neuropathic), Type -3 (Juvenile subtype- Chronic neuropathic) . Diagnosis is confirmed on the basis of identification of deficiency of glucocerebrosidase activity and also by Bone marrow biopsy examination which demonstrates Gaucher cells. The mainstay of treatment in gaucher disease is enzyme replacement therapy. In this study we reported a case of GD in a 39-year-old male with hepatosplenomegaly and pancytopenia. The diagnosis was challenging in this case since we needed to work out all the differential diagnosis of pancytopenia and hepatosplenomegaly. The patient was initially diagnosed as suffering from decompensated liver disease by radiological investigations and other biochemical investigations. Later on Bone marrow biopsy examination done which shows large number of gaucher cells. Special stain PAS and prussian blue were done on bone marrow biopsy and result came positive. Assesment of enzyme B-glucocerebrosidase level was done which was below the reference range so the diagnosis of GD confirmed.

Risk Factors Associated With Negative Appendicectomy Rates: A Retrospective Cohort Study.

Acute appendicitis (AA) is the most common emergency general surgical condition worldwide. Diagnosis is challenging and incorporates clinical, biochemical and radiological investigations. Our aim was to provide data from routine practice investigating widely utilised diagnostic methods from a single centre within the United Kingdom. We conducted a retrospective observational cohort study of patients who underwent a laparoscopic appendicectomy for AA between April 2022 and March 2023. AA was defined as the presence of transmural polymorphonuclear leukocytes in histology. Subgroup analysis was performed on paediatric patients.Factors associated with AA were investigated, and the diagnostic utility of biochemical and radiological investigations was examined. A total of 330 appendicectomies were analysed. We found an overall negative appendicectomy rate (NAR) of 38% and 48% in paediatric patients. Independent factors associated with AA on the multivariate analysis included elevated neutrophil counts (>7 × 109/L) (OR 4.04), elevated CRP (>5 mg/L) (OR 3.04) and a radiological diagnosis (OR 8.0). Computerised tomography (CT) and ultrasound had sensitivity/specificity of 98%/47% and 35%/86%, respectively. The positive-predictive values were 85% for CT and 50% for ultrasound, and the negative-predictive values were 86% for CT and 77% for ultrasound. Our study has highlighted the importance of utilising a combination of factors to improve the diagnostic certainty of AA. However, our routine practice data have shown different sensitivities and specificities of imaging in comparison to existing literature, resulting in a high NAR. Further real-world data are needed to understand whether these differences from the existing data are seen in other clinical settings.

Exploring the Longissimus Muscle: Unraveling its Correlation with Meat Quality in Bos indicus and Crossbred Bulls.

This study investigated muscle tissue in Bos indicus and crossbred bulls to explain differences in meat quality traits. Carcass traits, meat quality parameters, and biochemical and molecular investigations of myofibrillar proteins are described. Methods for evaluating pH, intramuscular fat (IMF), meat color (L*, a*, b*), water losses, tenderness, and molecular biology assays have been outlined. Specific procedures detailing calibration, sample preparation, and data analysis for each method are described. These include techniques such as infrared spectroscopy for IMF content, objective tenderness assessment, and electrophoretic separation of MyHC isoforms. Color parameters were highlighted as potential tools for predicting beef tenderness, a crucial quality trait influencing consumer decisions. The study employed the Warner-Bratzler shear force (WBSF) method, revealing values of 4.68 and 4.23 kg for Nellore and Angus-Nellore (P < 0.01), respectively. Total cooking losses and biochemical analyses, including myofibril fragmentation index (MFI), provided insights into tenderness variations. Muscle fiber types, particularly myosin heavy chain (MyHC) isoforms, were investigated, with a notable absence of MyHC-IIb isoform in the studied Zebu animals. The relationship between MyHC-I and meat tenderness revealed divergent findings in the literature, highlighting the complexity of this association. Overall, the study provides comprehensive insights into the factors influencing meat quality in Bos indicus and crossbred (Bos taurus × Bos indicus) bulls, offering valuable information for the beef industry.

To Evaluate Efficiency of Various Coronary Artery Disease Risk Scores With Traditional Risk Factors in Patients Undergoing Coronary Angiography.

To analyze and compare various cardiovascular disease risk scores in Western Indian patients undergoing Coronary angiogram (CAG). In this prospective cross-sectional study, 1213 patients who underwent conventional coronary angiography; clinical risk profile and biochemical investigations were evaluated prior to undergoing CAG. Apart from the demographic information, 10-year absolute risk of having a major cardiovascular event (cardiovascular death, myocardial infarction or stroke) was calculated for each patient using various available Traditional Risk Scores (TRS). The population was divided in low, intermediate and high-risk categories for each of these scores. Traditional cardiovascular risk factors like hypertension (41.8%) and diabetes mellitus-II (26.9%) were the two most prevalent risk factors in our study population. A higher risk value for all these TRS was more likely to be associated with obstructive coronary artery disease (OCAD) on CAG. Patients with high risk (≥20% for 10-year) QRESEARCH (QRISK3) score category had higher number of patients with obstructive CAD (49.6%) as compared to high risk category of risk score for those with high Global Registry of Acute Coronary Events (GRACE) score (46.6%) or risk Framingham (FRS CHD) score (29.2%) and risk atherosclerotic cardiovascular disease (ASCVD) score (30.1%) (P < 0.0001). A higher TRS was more likely to be associated with obstructive CAD, with the highest predictability being with QRISK3 (QRISK3 score 60.9%, GRACE score 54.9%, FRS-CHD score 34% and ASCVD score 42.1% respectively; P < 0.0001). A substantial study population (27.4%) cannot be identified using any of these TRS and hence a need of indigenous or modified risk scores is proposed. QRISK3 score was most efficacious for predicting obstructive CAD in our Indian study population on CAG. A higher risk score also correlated with the number of vessels involved on coronary angiogram. A substantial obstructive CAD patient could not be identified using traditional risk scores hence need for an indigenous or modified score.

Hepatoprotective Activity of Patra Swarasa of Guduchi (Tinospora Cordifolia) Against- Paracetamol Induced

Guduchi (Tinospora cordifolia (Willd.) Miers], Menispermaceae family, it is important medicinal plant is widely distributed through India. It is categorized as "Rasayana" and the whole plant is used medicinally. The aim of the present study is to evaluate the protective effect of Guduchi patra swaras against paracetamol induced liver damage in Wister albino rats. Material &amp; Methods: Wistar Albino rats (140-250g) will be divided into 6 group and each group 6 rats, into control group, paracetamol control, standard group, test group. The test drug Guduchi patra swarasa was administered orally for 10 consecutive days and two dose of the toxicant (paracetamol) were administered orally to each group, on two alternate days i.e., 7th and 9th day, 1hr after test drug administration. After 48 hours of toxicant paracetamol, and standard group. The blood was collected in EDTA tube and sent for biochemistry laboratory for biochemical investigations. Result: The analysis of serum biochemical parameters shows that administration of paracetamol leads to significant change in majority of the parameters. The overall activity profile indicated reversal of important parameters like SGOT, SGPT, total bilirubin, total protein, blood sugar level, serum globulin, serum albumin, serum total cholesterol and serum triglycerides. All three test groups of Guduchi patra Swarasa administered are found to be effective heapto-protective especially based on histo-pathological study. Among the three groups, the double dose group and therapeutic group has shown good results in comparison with the other two groups. Conclusion: In the present study, the overall activity profile of Guduchi patra Swarasa administered are found to be effective hepatoprotective among the three groups therapeutic double dose shows good results in comparison with the other group.

Haematological Profile in Patients With Acute Falciparum Malaria: A Hospital-Based Study.

Introduction Malaria is the most common parasitic disease affecting humans. Haematological alterations in malaria are expected, and these changes play a significant role in fatal complications. The present study aims to assess the clinical and haematological profile in patients with acute falciparum malaria and the significance of various haematological and coagulation alterations with the clinical severity of malaria. Methods The prospective cross-sectional study included 68 acute falciparum malaria cases. Thick and thin blood film microscopy and a rapid diagnostic kit were used to diagnose malaria. The cases were subjected to various haematological and biochemical investigations. Bone marrow aspiration samples were also collected. Using appropriate statistical methods, the findings were compared between severe and uncomplicated malaria cases. A p-value below 0.05 was considered significant. Results The participants' ages ranged from 14 to 78. Most participants (n = 51, 75%) were male and belonged to the lower income group (33, 48.5%). Significant variations in mean parasite count between severe and uncomplicated malaria cases (p-value < 0.01) were observed. The severe and uncomplicated groups showed significant differences in haemoglobin (gm/dL), haematocrit, red blood cell count, reticulocyte, serum iron, and ESR levels (p-value < 0.05). The severe malaria group had considerably reduced mean platelet counts (p-value < 0.01). Only five instances (7.3%) had an appropriate erythropoietic response after day 28. Erythroid hyperplasia with dyserythropoietic alterations was most common in patients with severe anaemia and low-grade parasitaemia. Conclusion Acute falciparum malaria is often associated with haematological alterations. Anaemia and thrombocytopenia were the most expected alterations associated with disease prognosis and mortality.

Differential physical interactions of wild-type and S59L mutant CHCHD10 with mitochondrial proteases

Background CHCHD10 is a small mitochondrial protein with a C-terminal coiled-coil-helix–coiled-coil-helix domain. The N-terminal region of CHCHD10 is mostly intrinsically disordered. Therefore, CHCHD10 has no catalytic activity other than protein-protein interactions through the CHCH domain or intrinsically disordered region. The S59L mutation in CHCHD10 has been identified as a genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. However, the disease-causing mechanisms of CHCHD10S59L are not yet fully understood. Our previous study showed that CHCHD10S59L induces PINK1 and Parkin accumulation. PINK1 stabilization in the mitochondria is dependent on proteolytic processing by mitochondrial proteases. It has also been reported that mutant CHCHD10 disrupts protein homeostasis within mitochondria. Therefore, we hypothesized that CHCHD10S59L physically interacts with mitochondrial proteases during the disease pathogenesis. Methods To test this hypothesis, we performed co-immunoprecipitation using transiently transfected wild-type and mutant S59L CHCHD10 in HeLa cells. We employed a dithiobis (succinimidyl propionate) cross-linker to detect transient physical interactions. Results We expected that CHCHD10S59L may activate mitochondrial protease processing or expression and that it interacts with more diverse mitochondrial proteases than the wild type. In general, however, there was no difference in the expression and processing levels of mitochondrial proteases and the proteases that interact with wild-type and CHCHD10S59L. LonP1 degrading unfolded proteins in the mitochondrial matrix was the major proteases that can bind to wild-type CHCHD10 and CHCHD10S59L. LonP1 and HtrA2 were significantly less strongly bound to CHCHD10S59L. Conclusions This result can be interpreted in many different ways, including the regulatory role of CHCHD10 in mitochondrial proteases. However, more precise biochemical and cell biological investigations are required to determine the role of CHCHD10 in the activity of mitochondrial proteases, mechanism of PINK1 stabilization, and disruption of mitochondrial proteostasis.

Internal Hernia Post-Single Anastomosis Gastric Bypass: Case Series with Review of Literature.

Obesity is an emerging worldwide health care issue. It has a direct and indirect bearing on health-related outcomes. Rates of overweight and obesity have grown manifold in the past few decades globally. Once considered a problem of the affluent societies only, obesity is now dramatically on the rise in low- and middle-income countries also. Single anastomosis gastric bypass (SAGB) is one of the combined bariatric procedures adopted for weight loss in patients failing maximal medical therapy. Internal hernia (IH) after SAGB is a less recognized clinical entity. We hereby report our experience with four such cases under light of current available literature. Bariatric procedures are associated with some short- and long-term limitations. IHs are among one of the dreaded complications associated with some bariatric procedures with rates reaching up to 16% after classic Roux-en-Y gastric bypass. The incidence of IH post-SAGB is comparatively rare and is very less frequently reported. Symptoms of IH post-SAGB are quite nonspecific and depend on the time and extent of herniation. The symptoms can vary from benign intermittent colicky pain to severe intra-abdominal pain presenting as a surgical emergency. Routine physical examination and biochemical investigations are nonspecific and unreliable in evaluating those patients. Computed tomography (CT) with intravenous and oral contrast is the most common imaging modality used for preoperative evaluation of those symptoms. The CT findings can be unremarkable in patients having intermittent symptoms/herniation. Diagnostic laparoscopy is the cornerstone for diagnosis and management of patients having high suspicion of IH.

Reno-protective effect of Roflumilast against kidney injury induced by ischemia/reperfusion in rats: Evidence from biochemical and histological investigations

Oxidative stress, inflammation, and apoptosis are major contributors to renal ischemia/reperfusion (I/R) injury. This study aimed to investigate the effects of pretreatment with the PDE4 inhibitor roflumilast (Rof) on renal I/R and its underlying mechanisms. Sprague-Dawley rats were subjected to 30 minutes of unilateral renal ischemia followed by 45 minutes of reperfusion. Rof (1.5 and 3 mg/kg) was administered for seven days prior to I/R induction. The findings showed that Rof significantly and dose-dependently attenuated kidney damage by reducing blood urea nitrogen and creatinine levels. Rof also exhibited antioxidant and anti-inflammatory effects, as evidenced by improved glutathione and malondialdehyde levels and decreased proinflammatory cytokines (IL-6 and TNF-α). Furthermore, Rof prevented the downregulation of HO-1 and Nrf2 expression. These results suggest that Rof therapy could protect the kidneys from I/R-induced injury through its antioxidant and anti-inflammatory properties, providing a potential therapeutic approach for the management of renal I/R damage.

STAMBP is Required for Long-Term Maintenance of Neural Progenitor Cells Derived from hESCs.

Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro.

Should Empiric Anti-Fungals Be Administered Routinely for All Patients with Perforated Peptic Ulcers? A Critical Review of the Existing Literature.

A perforated peptic ulcer (PPU) is a surgical emergency with a high mortality rate. PPUs cause secondary peritonitis due to bacterial and fungal peritoneal contamination. Surgery is the main treatment modality and patient's comorbidites impacts perioperative morbidity and surgical outcomes. Even after surgery, resuscitation efforts should continue. While empiric antibiotics are recommended, the role of empiric anti-fungal treatment is unclear due to a lack of scientific evidence. This literature review demonstrated a paucity of studies evaluating the role of empiric anti-fungals in PPUs, and with conflicting results. Studies were heterogeneous in terms of patient demographics and underlying surgical pathology (PPUs vs. any gastrointestinal perforation), type of anti-fungal agent, timing of administration and duration of use. Other considerations include the need to differentiate between fungal colonization vs. invasive fungal infection. Despite positive fungal isolates from fluid culture, it is important for clinical judgement to identify the right group of patients for anti-fungal administration. Biochemistry investigations including new fungal biomarkers may help to guide management. Multidisciplinary discussions may help in decision making for this conundrum. Moving forward, further research may be conducted to select the right group of patients who may benefit from empiric anti-fungal use.

Preliminary results of clinical, biochemical, and radiological investigation into the oxidative status in patients with rotator cuff tendinopathy.

We investigated oxidative status in patients with rotator cuff tendinopathy (RCT) and evaluated their relationship with radiological and clinical parameters. In this cross-section study, 88 patients with RCT (59 males and 29 females) and 86 healthy controls (66 males, 20 females) were enrolled. The sample consisted of nontraumatic patients who are suffering from shoulder pain because of rotator cuff disease, which was established by clinical tests and MRI scanning. Oxidative stress in patients with RCT was analyzed via the dynamic thiol/disulfide homeostasis (TDH). Thiol/disulfide homeostasis was measured by a new colorimetric method. Furthermore, oxidative stress was indirectly measured by serum total oxidant status (TOS), oxidative stress index (OSI), and total antioxidant capacity (TAC). Serum disulfide levels and the other oxidative stress parameters of the RCT group were significantly greater than those of the control group (P < .001 for all), whereas the anti-oxidative stress parameters remained unchanged (P > .05 for all). The lowest and highest serum disulfide levels were detected in patients with grades 1 and 3, respectively (P < .001). Furthermore, in a multiple regression analysis, the disulfide/natural thiol ratio (β=-4.886, P = .004) and the MRI grading (β=0.314, P=.001) were independently associated with the Western Ontario Rotator Cuff Index WORC score. We found an association between the levels of various serum markers of oxidative injury, especially serum disulfide levels, and the increasing severity of RCT. Thiol/disulfide homeostasis seems to play a critical role in RCT, both in the beginning and during the progression of disease.

Native mass spectrometry of membrane protein-lipid interactions in different detergent environments.

Native mass spectrometry (MS) is revealing the role of specific lipids in modulating membrane protein structure and function. Membrane proteins solubilized in detergents are often introduced into the mass spectrometer; however, commonly used detergents for structural studies, such as dodecylmaltoside, tend to generate highly charged ions, leading to protein unfolding, thereby diminishing their utility for characterizing protein-lipid interactions. Thus, there is a critical need to develop approaches to investigate protein-lipid interactions in different detergents. Here, we demonstrate how charge-reducing molecules, such as spermine and trimethylamine-N-oxide, enable characterization of lipid binding to the bacterial water channel (AqpZ) and ammonia channel (AmtB) in complex with regulatory protein GlnK in different detergent environments. We find protein-lipid interactions are not only protein-dependent but can also be influenced by the detergent and type of charge-reducing molecule. AqpZ-lipid interactions are enhanced in LDAO (n-dodecyl-N,N-dimethylamine-N-oxide), whereas the interaction of AmtB-GlnK with lipids is comparable among different detergents. A fluorescent lipid binding assay also shows detergent dependence for AqpZ-lipid interactions, consistent with results from native MS. Taken together, native MS will play a pivotal role in establishing optimal experimental parameters that will be invaluable for various applications, such as drug discovery, as well as biochemical and structural investigations.

Thermo-Optoplasmonic Single-Molecule Sensing on Optical Microcavities.

Whispering-gallery-mode (WGM) resonators are powerful instruments for single-molecule sensing in biological and biochemical investigations. WGM sensors leveraged by plasmonic nanostructures, known as optoplasmonic sensors, provide sensitivity down to single atomic ions. In this article, we describe that the response of optoplasmonic sensors upon the attachment of single protein molecules strongly depends on the intensity of WGM. At low intensity, protein binding causes red shifts of WGM resonance wavelengths, known as the reactive sensing mechanism. By contrast, blue shifts are obtained at high intensities, which we explain as thermo-optoplasmonic (TOP) sensing, where molecules transform absorbed WGM radiation into heat. To support our conclusions, we experimentally investigated seven molecules and complexes; we observed blue shifts for dye molecules, amino acids, and anomalous absorption of enzymes in the near-infrared spectral region. As an example of an application, we propose a physical model of TOP sensing that can be used for the development of single-molecule absorption spectrometers.

The protective role of two oxindole derivatives is mediated by modulating NLRP3/caspase-1 and PI3K/AKT pathways in a preclinical animal model of hepatic ischemia reperfusion injury

AimHepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats. Main methodsHIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed. Key findingsHIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1β, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway. SignificanceCoxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways.

Investigating Antiprotozoal Chemotherapies with Novel Proteomic Tools-Chances and Limitations: A Critical Review.

Identification of drug targets and biochemical investigations on mechanisms of action are major issues in modern drug development. The present article is a critical review of the classical "one drug"-"one target" paradigm. In fact, novel methods for target deconvolution and for investigation of resistant strains based on protein mass spectrometry have shown that multiple gene products and adaptation mechanisms are involved in the responses of pathogens to xenobiotics rather than one single gene or gene product. Resistance to drugs may be linked to differential expression of other proteins than those interacting with the drug in protein binding studies and result in complex cell physiological adaptation. Consequently, the unraveling of mechanisms of action needs approaches beyond proteomics. This review is focused on protozoan pathogens. The conclusions can, however, be extended to chemotherapies against other pathogens or cancer.

Frequency of Delayed Puberty in Boys with Contemporary Management of Duchenne Muscular Dystrophy

Delayed puberty is thought to be common in boys with Duchenne muscular dystrophy (DMD) treated with long term oral glucocorticoid. The aim of this study was to report the frequency of delayed puberty in DMD from examination by a paediatric endocrinologist alongside detailed endocrine investigations. All boys with DMD aged at least 14 years in January 2022 known to the paediatric neuromuscular service (2016-2022) were included. Delayed puberty was defined based on testicular volume and genital staging in comparison to a published puberty nomogram. Twenty-four out of 37 boys (65%) had evidence of delayed puberty and 23/24 (96%) were on glucocorticoid therapy, all of whom were on daily glucocorticoid. However, 7/13 (54%) with normal timing of puberty were on glucocorticoid; 2/7 (29%) were on the intermittent regimen. Of those who were on daily glucocorticoid therapy at the time of assessment of puberty, 23/28 (82%) had evidence of delayed puberty. In boys with delayed puberty, endocrine investigations showed low luteinizing hormone with undetectable testosterone levels, a pre-pubertal response with lutenizing hormone releasing hormone test and sub-optimal testosterone levels with prolonged human chorionic gonadotropin stimulation. The frequency of delayed puberty in boys with DMD was 65%. Eighty-two percent of adolescent boys with DMD on daily glucocorticoid had evidence of delayed puberty. Biochemical investigations point to functional central hypogonadism in these adolescents. Our data supports the routine monitoring of puberty in boys with DMD.

Piracetam mitigates nephrotoxicity induced by cisplatin via the AMPK-mediated PI3K/Akt and MAPK/JNK/ERK signaling pathways

AimsCisplatin (CDDP) is commonly employed as an antineoplastic agent, but its use is significantly limited by the occurrence of dose-dependent nephrotoxicity, the detailed mechanisms of which remain unclear. This research is aimed to explore the molecular mechanisms of Piracetam (PIR)’s protective effects on nephrotoxicity resulting from CDDP exposure and to elucidate the mechanisms responsible for these effects. Main methodsPIR was given in dosages of 100 and 300 mg/kg body weight for a duration of 15 days; concurrently, on the last day, a single 10 mg/kg dose of CDDP was delivered via intraperitoneal injection. Forty-eight hours post-CDDP injection, the animals were sacrificed to assess nephrotoxicity. Blood samples and renal tissues were taken for biochemical and histopathological investigations. Serum creatinine and blood urea nitrogen (BUN) were measured. AMP-activated protein kinase (AMPK), caspase-9 and nuclear factor kappa b p65 (NF-κB p65) were assessed by immunohistochemistry method. Enzyme-linked immunosorbent assay (ELISA) analysis was employed to determine cytochrome c (Cyt. c), Bcl-2-associated X-protein (BAX), caspase-3, nuclear factor erythroid 2–related factor 2 (Nrf2), Heme oxygenase-1 (HO-1), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), myeloperoxidase (MPO), and interleukin-1β (IL-1β) levels in renal tissue homogenates. The mRNA levels of tumor protein P53 (TP53), phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinases (JNK) were tested by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, histopathological evaluations of the renal tissues and the binding affinity of PIR to AMPK by molecular docking were also performed. Key findingsPre-treatment with PIR enhanced renal function markers such as urea and creatinine, mitigated histological damage, and diminished inflammatory cell presence in renal tubules. PIR demonstrated antioxidant effects by reestablishing the equilibrium between pro-oxidants and antioxidants such as MPO, HO-1, Nrf2, as well as SOD. Furthermore, PIR inhibited the inflammatory pathways through the MAPK/NF-κB pathway. Additionally, PIR counteracted the CDDP-induced decline in PI3K/Akt activity and hindered caspase-dependent apoptotic processes. SignificanceIn summary, PIR appears to be an effective therapeutic strategy for reducing CDDP-induced nephrotoxicity, attributed to its antioxidant, anti-inflammatory, and antiapoptotic mechanisms. Consequently, PIR may serve as a complementary treatment alongside CDDP to alleviate nephrotoxicity associated with CDDP.

Comprehensive Evaluation of Sporadic Late-Onset Cerebellar Ataxias: Clinical Presentation, Diagnostic Challenges, and Treatment Outcomes.

Sporadic late-onset cerebellar ataxias (SLOCA) present a diagnostic challenge due to their heterogeneous etiologies and complex clinical manifestations. This retrospective study aimed to conduct a comprehensive evaluation of six male patients diagnosed with SLOCA, with a mean age of 55 years and an average symptom onset at 47 years. All patients presented with gait and balance disturbances, with additional sensory abnormalities observed in two cases. Neurological examinations revealed varied cerebellar syndromes, including static and static-kinetic presentations, accompanied by peripheral neurogenic syndromes in some instances. Brain MRI findings showed cerebellar atrophy, predominantly involving the vermis, in a subset of patients. Biochemical and serological investigations yielded mostly unremarkable results, although two patients exhibited significant vitamin E deficiency and anti-Hu antibodies (anti-neuronal nuclear antibody type 1). Electromyography confirmed sensory axonal neuropathy in those with peripheral neurogenic syndromes. Treatment with TOCO 500 mg (Vitamin E) was administered to four patients, with follow-up indicating stable disease progression in two cases. This study underscores the complexity of SLOCA and the need for a multidisciplinary approach to diagnosis and management. Further research is warranted to elucidate the underlying mechanisms and improve clinical outcomes for affected individuals.

Yak meat content in feed and its impact on the growth of rats.

To evaluate the effects of varying proportions of yak meat in feed on the growth of rats and provide a theoretical basis for selecting the optimal feed proportion suitable for rats. This study was designed as a one-variable experiment. Fifty male rats were divided into five groups. The ratios of yak meat to basal feed of rats in four dietary treatment groups were 2:8, 4:6, 6:4, and 8:2, respectively, while those in the control group were only provided a basal diet. In the feeding experiment, the body weights of the rats were recorded on Day 0 and subsequently in the first, second, third, and fourth weeks, along with quantities of feed intake. The body and tail lengths, as well as the waist circumference of the rats, were measured, and blood samples were collected in the fourth week for routine blood and biochemistry investigations. The rats in the 4:6 feed group had the best body condition. They had normal body and tail lengths, smaller waist circumferences, good posture, and were in better overall health than rats in the other groups. The results indicate that the 4:6 diet was optimal for enhancing rats' growth performance compared to the other diets.