Vital Organs Research Articles

Development and therapeutic evaluation of 5D3(CC-MLN8237)3.2 antibody-theranostic conjugates for PSMA-positive prostate cancer therapy

Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with in vitro or in vivo imaging agents, ADCs can be used as antibody-theranostic conjugates (ATCs) for diagnostic and image-guided drug delivery. In this study, we have developed a novel ATC for PSMA (+) PC therapy utilizing (a) anti-PSMA 5D3 mAb, (b) Aurora A kinase inhibitor, MLN8237, and (c) for the first time using tetrazine (Tz) and trans-cyclooctene (TCO) click chemistry-based conjugation linker (CC linker) in ADC development. The resulting 5D3(CC-MLN8237)3.2 was labeled with suitable fluorophores for in vitro and in vivo imaging. The products were characterized by SDS-PAGE, MALDI-TOF, and DLS and evaluated in vitro by optical imaging, flow cytometry, and WST-8 assay for cytotoxicity in PSMA (+/−) cells. Therapeutic efficacy was determined in human PC xenograft mouse models following a designed treatment schedule. After the treatment study animals were euthanized, and toxicological studies, complete blood count (CBC), blood clinical chemistry analysis, and H&E staining of vital organs were conducted to determine side effects and systemic toxicities. The IC50 values of 5D3(CC-MLN8237)3.2-AF488 in PSMA (+) PC3-PIP and PMSA (−) PC3-Flu cells are 8.17 nM and 161.9 nM, respectively. Pure MLN8237 shows 736.9 nM and 873.4 nM IC50 values for PC3-PIP and PC3-Flu cells, respectively. In vivo study in human xenograft mouse models confirmed high therapeutic efficacy of 5D3(CC-MLN8237)3.2-CF750 with significant control of PSMA (+) tumor growth with minimal systemic toxicity in the treated group compared to PSMA (−) treated and untreated groups. Approximately 70% of PSMA (+) PC3-PIP tumors did not exceed the threshold of the tumor size in the surrogate Kaplan-Meyer analysis. The novel ATC successfully controlled the growth of PSMA (+) tumors in preclinical settings with minimal systemic toxicities. The therapeutic efficacy and favorable safety profile of novel 5D3(CC-MLN8237)3.2 ATC demonstrates their potential use as a theranostic against aggressive PC.

Tumor Targeting with Apatinib-loaded Nanoparticles and Sonodynamic Combined Therapy.

This study implies the enhancement of apatinib killing effect in 4T1 tumor cells through constructing drug-loaded nanoparticles apatinib/Ce6@ZIF- 8@Membranes (aCZM) to enhance tumor therapeutic targeting and reduce toxic side following sonodynamic therapy (SDT). apatinib/Ce6@ZIF-8 (aCZ) were synthesized by in situ encapsulation, and aCZM were constructed by encapsulating the nanoparticles with extracted breast cancer 4T1 cell membranes. aCZM were characterized and tested for the stability by electron microscopy, and the membrane proteins on the nanoparticles' surface were assessed using SDS-PAGE gel electrophoresis. The cell viability of 4T1 cells following treatment with aCZM was tested using cell counting kit-8 (CCK-8). The uptake of nanoparticles was detected by laser confocal microscopy and flow cytometry, and the SDT-mediated production of reactive oxygen species (ROS) was verified by singlet oxygen sensor green (SOSG), electron spin resonance (ESR), and DCFH-DA fluorescent probes. The CCK-8 assay and flow cytometry using Calcein/PI were used to assess the antitumoral effect of aCZM nanoparticles under SDT. The biosafety of aCZM was further verified in vitro and in vivo using the hemolysis assay, routine blood test and H&E staining of vital organs in Balb/c mice. aCZM with an average particle size of about 210.26 nm were successfully synthesized. The results of the SDS-PAGE gel electrophoresis experiment showed that aCZM have a band similar to that of pure cell membrane proteins. The CCK-8 assay demonstrated the absence of effects on cell viability at a low concentration range, and the relative cell survival rate reached more than 95%. Laser confocal microscopy and flow cytometry analysis showed that aCZM treated group has the strongest fluorescence and the highest cellular uptake of nanoparticles. SOSG, ESR, and DCFH-DA fluorescent probes all indicated that the aCZM + SDT treated group has the highest ROS production. The CCK-8 assay also showed that when the ultrasound intensity was fixed at 0.5 W/cm2, the relative cell survival rates in the medium concentration group (10 μg/ml) (5.54 ± 1.26%) and the high concentration group (20 μg/ml) (2.14 ± 1.63%) were significantly lower than those in the low concentration group (5 μg/ml) (53.40 ± 4.25%). Moreover, there was a concentration and intensity dependence associated with the cellkilling effect. The mortality rate of the aCZM in the ultrasound group (44.95 ± 3.03%) was significantly higher than that of the non-ultrasound (17.00 ± 2.26%) group and aCZ + SDT group (24.85 ± 3.08%) (P<0.0001). The live and dead cells' staining (Calcein/PI) also supported this result. Finally, in vitro hemolysis test at 4 and 24 hours showed that the hemolysis rate of the highest concentration group was less than 1%. The blood routine, biochemistry, and H&E staining results of major organs in Balb/c mice undergoing nano-treatments showed no obvious functional abnormalities and tissue damage in 30 days. In this study, a multifunctional bionic drug delivery nanoparticles (aCZM) system with good biosafety and compatibility in response to acoustic dynamics was successfully constructed and characterized. This system enhanced apatinib killing effect on tumor cells and reduced toxic side effects under SDT.

Comparative Toxicology of Algal Cell Extracts and Pure Cyanotoxins: Insights into Toxic Effects and Mechanisms of Harmful Cyanobacteria Raphidiopsis raciborskii

Ongoing research on cyanotoxins, driven by the socioeconomic impact of harmful algal blooms, emphasizes the critical necessity of elucidating the toxicological profiles of algal cell extracts and pure toxins. This study comprehensively compares Raphidiopsis raciborskii dissolved extract (RDE) and cylindrospermopsin (CYN) based on Daphnia magna assays. Both RDE and CYN target vital organs and disrupt reproduction, development, and digestion, thereby causing acute and chronic toxicity. Disturbances in locomotion, reduced behavioral activity, and weakened swimming capability in D. magna have also been reported for both RDE and CYN, indicating the insufficiency of conventional toxicity evaluation parameters for distinguishing between the toxic effects of algal extracts and pure cyanotoxins. Additionally, chemical profiling revealed the presence of highly active tryptophan-, humic acid-, and fulvic acid-like fluorescence compounds in the RDE, along with the active constituents of CYN, within a 15-day period, demonstrating the chemical complexity and dynamics of the RDE. Transcriptomics was used to further elucidate the distinct molecular mechanisms of RDE and CYN. They act diversely in terms of cytotoxicity, involving oxidative stress and response, protein content, and energy metabolism, and demonstrate distinct modes of action in neurofunctions. In essence, this study underscores the distinct toxicity mechanisms of RDE and CYN and emphasizes the necessity for context- and objective-specific toxicity assessments, advocating nuanced approaches to evaluate the ecological and health implications of cyanotoxins, thereby contributing to the precision of environmental risk assessments.

Guardians of Liver Health: Unveiling the Resilient Shield of Antioxidant Vitamins (C, E) Against Glyphosate-Induced Havoc in Experimental Rats

Glyphosate, a widely used herbicide, has gained popularity due to its broad-spectrum effects and use in genetically modified, glyphosate-resistant crops. Recent data, however, points to possible adverse effects of glyphosate and herbicides based on glyphosate, such as genotoxic and cytotoxic effects, elevated stress levels, disturbance of the hormones such as estrogen pathway and possible associations with specific cancer types. This has raised concerns about the widespread use of glyphosate and its impact on human health and the environment. The objective of this study was to determine whether antioxidants vitamin C and E could shield experimental rats' livers from the damaging effects of glyphosate. Animals were grouped as Group I-control, 30 days of oral glyphosate-treated rats as Group II, and Rats that received simultaneous glyphosate treatment and oral administration of vitamins C and E were for 30 days as Group III. We used the user's manual to figure out the fasting blood glucose (FBG) levels, the histomorphology of liver tissue using H&amp;E staining, and the liver and kidney function tests using Diatek Greiner kits. The study revealed that prolonged exposure to glyphosate can alter the SREBPI and HNF1 pathways, leading to diabetes. As an herbicide, glyphosate can cause harmful changes in vital organs, leading to diabetes and other disorders.

Unveiling the Role of Exosomes in the Pathophysiology of Sepsis: Insights into Organ Dysfunction and Potential Biomarkers.

Extracellular vesicles (EVs) are tools for intercellular communication, mediating molecular transport processes. Emerging studies have revealed that EVs are significantly involved in immune processes, including sepsis. Sepsis, a dysregulated immune response to infection, triggers systemic inflammation and multi-organ dysfunction, posing a life-threatening condition. Although extensive research has been conducted on animals, the complex inflammatory mechanisms that cause sepsis-induced organ failure in humans are still not fully understood. Recent studies have focused on secreted exosomes, which are small extracellular vesicles from various body cells, and have shed light on their involvement in the pathophysiology of sepsis. During sepsis, exosomes undergo changes in content, concentration, and function, which significantly affect the metabolism of endothelia, cardiovascular functions, and coagulation. Investigating the role of exosome content in the pathogenesis of sepsis shows promise for understanding the molecular basis of human sepsis. This review explores the contributions of activated immune cells and diverse body cells' secreted exosomes to vital organ dysfunction in sepsis, providing insights into potential molecular biomarkers for predicting organ failure in septic shock.

Harnessing eCIRP by PS-OMe miR130: A promising shield against hemorrhage-induced lung injury.

Hemorrhagic shock (HS) poses a life-threatening condition with the lungs being one of the most susceptible organs to its deleterious effects. Extracellular cold-inducible RNA binding protein (eCIRP) has emerged as a pivotal mediator of inflammation, and its release has been observed as a case of HS-induced tissue injury. Previous studies unveiled a promising engineered microRNA, designated PS-OMe miR130, which inhibits eCIRP, thereby safeguarding vital organs. In this study, we hypothesized that PS-OMe miR130 serves as a protective shield against HS-induced lung injury by curtailing the overzealous inflammatory immune response. Hemorrhagic shock was induced in male C57BL6 mice by withdrawing blood via a femoral artery cannula to a mean arterial pressure of 30 mm Hg for 90 min. The mice were resuscitated with twice the shed blood volume with Ringer's Lactate solution. They were then treated intravenously with either PBS (vehicle) or 62.5 nmol PS-OMe miR130. At 4 h later, blood and lungs were harvested. Following PS-OMe miR130 treatment in HS mice, a substantial decrease was observed in serum injury markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and blood urea nitrogen (BUN). Serum IL-6 exhibited a similar reduction. In lung tissues, PS-OMe miR130 led to a significant decrease in the mRNA expressions of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), chemokines (KC and MIP-2), and an endothelial injury marker, E-selectin. PS-OMe miR130 also produced substantial inhibition of lung MPO activity and resulted in a marked reduction in lung injury as evidenced by histological evaluation. This was further confirmed by the observation that PS-OMe miR130 significantly reduced the presence of Ly6G-positive neutrophils and TUNEL-positive apoptotic cells. PS-OMe miR130 emerges as a potent safeguard against HS-induced lung injury by effectively inhibiting proinflammation and injuries, offering a promising therapeutic strategy in such critical clinical condition.

Histopathological alterations in the vital organs of Indian major carp Labeo rohita exposed to monosodium glutamate (MSG)

BackgroundMonosodium glutamate (MSG E621) is one of the most popular flavouring agents of modern times and is widely used in many commercially packed food and even in house hold cooking. Previous studies revealed that excessive intake of MSG in diet causes obesity, metabolic defects, nephrotoxicity, neurotoxicity and hepatotoxicity in rats, but no reports are available in the literature about the ecotoxicological assessment of MSG by using fishes as a bioindicators. Since fishes are important consumer in aquatic food chain and directly linked with human health status, the present study was aimed to investigate the impact of MSG in freshwater fish Labeo rohita by using histological biomarkers.ResultsNinety-six h-LC50 of MSG to Labeo rohita was determined (1.5 g/L), and fish exposed to sub-lethal concentration of MSG (1/10th of 96 h-LC50 concentration of MSG (150 mg/L)) showed distinguished behavioural changes like erratic movement, loss of appetite and excessive mucous secretion all over the body as an adaptive syndrome to avoid the direct exposure to MSG in the medium. Histopathological analysis clearly depicts severe damages in the vital organs of fish. In gills, epithelial necrosis, hypertrophy, hyperplasia, primary and secondary gill lamellae degeneration, oedema, fusion of adjacent secondary lamellae and rupture of gill epithelium were observed. The intensity of tissue damage was increased as the exposure period was extended. The liver displayed vein congestion, vacuole formation, degeneration in parenchymal cells and bile stagnation, whereas MSG-treated kidney tissue showed high interstitial inflammation. Among the vital organs gill and liver displayed the highest histopathological alterations.ConclusionsThe present study clearly demonstrated that MSG is toxic to fish and able to cause significant damages in the vital organs as the exposure period was extended. Since the studies on the toxicity of MSG to fish are rare, the present investigation may contribute to the scarce literature on sub-lethal toxicity of MSG to freshwater fishes.

Role and uptake of metal-based nanoconstructs as targeted therapeutic carriers for rheumatoid arthritis.

Rheumatoid Arthritis (RA) is a chronic autoimmune systemic inflammatory disease that affects the joints and other vital organs and diminishes the quality of life. The current developments and innovative treatment options have significantly slowed disease progression and improved their quality of life. Medicaments can be delivered to the inflamed synovium via nanoparticle systems, minimizing systemic and undesirable side effects. Numerous nanoparticles such as polymeric, liposomal, and metallic nanoparticles reported are impending as a good carrier with therapeutic properties. Other issues to be considered along are nontoxicity, nanosize, charge, optical property, and ease of high surface functionalization that make them suitable carriers for drug delivery. Metallic nanoparticles (MNPs) (such as silver, gold, zinc, iron, titanium oxide, and selenium) not only act as good carrier with desired optical property, and high surface modification ability but also have their own therapeutical potential such as anti-oxidant, anti-inflammatory, and anti-arthritic properties, making them one of the most promising options for RA treatment. Regardless, cellular uptake of MNPs is one of the most significant criterions for targeting the medication. This paper discusses the numerous interactions of nanoparticles with cells, as well as cellular uptake of NPs. This review provides the mechanistic overview on MNPs involved in RA therapies and regulation anti-arthritis response such as ability to reduce oxidative stress, suppressing the release of proinflammatory cytokines and expression of LPS induced COX-2, and modulation of MAPK and PI3K pathways in Kuppfer cells and hepatic stellate cells. Despite of that MNPs have also ability to regulates enzymes like glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) and act as an anti-inflammatory agent.

Lipid Toxicity in the Cardiovascular–Kidney–Metabolic Syndrome (CKMS)

Recent studies of Cardiovascular–Kidney–Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.

Echocardiography Based Cardiac Ischemic Detection Using Red-CNN Classifier

One of the most vital and hardest-working organs of the human body is the Heart. Nevertheless, a condition termed Cardiac Ischemia or CAD is engendered by the inadequate supply of blood along with oxygen to the heart muscle. So, with the aid of a Regularisation Dropout-centered Convolutional Neural Network (ReD-CNN) classifier, an efficient CAD detection system is proposed. At first, the input videos and the data are amassed from the Echonet Dynamic dataset. Next, frame conversion is undergone by the input video. For further processing, keyframes are extracted and preprocessed after frame conversion. Afterward, by means of a Contraction Expansion-Residual Network (CE-ResNet), the heart chambers are segmented, and then the features are extracted. Simultaneously, utilizing the Feynman Kan Formalism-based Tissue Doppler Imaging (FKF-TDI) approach, wall motion is estimated. Meanwhile, the features are extracted from the data and grouped via Average Distance-centric Fuzzy C Means (AD-FCM). After that, mapping of the features extracted from the frames and the grouped features occurs and the resultant data is divided into training, testing, along with validation stages. Then, utilizing the Cosine Similarity-centered Circulatory System Based Optimization (2(CS)BO) methodology, the Feature Selection (FS) is done. Therefore, to compute the Ischemic index, the features that are selected and the estimated wall motions are wielded. Lastly, for effective classification, the Ischemic index and the selected features are fed into the ReD-CNN classifier. Finally, to ascertain the superiority of this technique, the proposed system’s performance is contrasted with the prevailing methodologies.

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.

Nutritional Values of Partially Replacing the Commercial Soybean Meal by Raw, Full-Fat Soybean in Diets of Layers

The aim of this study was to investigating the effects of partially replacing the commercial soybean meal (SBM) by locally produced raw, full-fat soybean (RFFSB) in diets of layers. After cleaning, the tested ingredient (RFFSB) was hammered to pass through a 0.2-mm sieve. Then, four experimental diets were formulated by replacing the SBM by RFFSB at 0, 15, 30 or 45% (equivalents to 0, 30, 60 or 90 g/kg of diet, respectively). Before the commencement of this feeding trial, birds were uniformly managed and fed as per their requirements (i.e., starter, grower and pullet diets). This feeding trial was started when birds’ age was 24 weeks. Every treatment was replicated 4 times and 17 laying birds per replicate. The results revealed that replacing the commercial SBM by raw soybean (up to 45%) in the layer diets had no negative effects on the final live BWT and also on the vital organ developments, such as pancreas, duodenum, intestines and gizzard. Hen-day egg production, hen-housed egg production and egg quality measuring parameters were not significant affected by that of partially replacing the commercially SBM by the raw soybean. It is concluded that without compromising the productivity and health, a hammered RFFSB can replace (up to 45%) the commercial SBM in diets of the laying hens.

CRISPR/Cas9-mediated knockout of a male accessory glands-specific gene takeout1 decreases the fecundity of Zeugodacus cucurbitae female.

The melon fly, Zeugodacus cucurbitae (Coquillett), is an invasive Tephritidae pest with robust fertility. The male accessory glands (MAGs) form a vital organ that ensures insect reproductive efficiency. Most of the secreted proteins by MAGs exhibit a male bias expression. Takeout, one of these proteins, is abundantly presented in the MAGs of many insects. In this study, we identified 32 takeout genes in Z. cucurbitae. The phylogenetic analysis and multiple sequence alignment results showed that Zctakeout1 is the most related homolog to the MAGs-specific takeout in Tephritidae. The real-time quantitative PCR results showed that Zctakeout1 was exclusively expressed in the male adult stage, and its expression level gradually increased with the increase in age and then remained stable at the sexually matured stage. The distribution among tissues demonstrated the specific expression of Zctakeout1 in the MAGs, and fluorescence immunohistochemical results confirmed the presence of Zctakeout1 in close proximity to binuclear cells of the mesoderm epidermal MAGs. In continuation, CRISPR/Cas9 genome editing was employed, resulting in successfully generating a homozygous strain with an +8 bp insertion. The mating experiments with the Zctakeout1-/- males resulted in significant reductions in both the mating rate and egg production of females. These findings prove that the MAGs-specific Zctakeout1 is essential in regulating fecundity in female Z. cucurbitae fruit flies. Our data suggests its utilization in future essential insect-specific gene-directed sterility insect technique (SIT) by the genetic manipulation to keep these important Tephritidae populations under control. This article is protected by copyright. All rights reserved.

Frequent Presentation of Counterfeit Gunshot Wounds in a Tertiary Care Hospital in North India: A Case Series

Introduction: Self-inflicted wounds, or wounds produced by another acting in accord with him, are wounds inflicted by a person on his own body. The purpose of fabricating injuries is to file a false claim of assault against an opponent, to alter the appearance of a minor injury in order to attract more attention and a harsher punishment for the alleged accused. Someone may also pretend these as defence wounds, so as to conceal homicide.Result: In a short period of 1 year, i.e. from August 2020 to July 2021 in a single unit of Department of General Surgery, 8 cases of Counterfeit Gunshot Wounds are there which depicts that the foul play is at large scale and these gunshot wounds are not present over the vital organs of the body.Conclusion: The combined efforts of all investigating authorities and doctors can help to avoid injury fabrication, which will not only decrease wasteful litigation in the courts, but will also help to avoid harassment of innocent individuals.

Histomorphological Spectrum of Lung Lesions in Medico- legal Autopsy in a Tertiary Care Centre

Background: Organ specific pathological changes seen during autopsy give a clear idea of the cause of death. Lungs are one of the most important vital organs in the human body. They are almost always involved in terminal events of cardiovascular diseases.Autopsy is important not only to know the state of lungs but also to study the morphology of various diseases.Various studies have demonstrated that,20-30% of sudden deaths are due to underlying pulmonary pathology. Aims and objectives: The significance of this study is to highlight the spectrum of histomorphological features of lung lesions in medico-legal autopsies irrespective of cause of death. Material and Methods:This was a retrospectivestudy Medico legal autopsies over a period of 5 years carried out in the Department of Pathology in coordination with the Department of Forensic Medicine, Gulbarga Institute of Medical Sciences. Standard protocols are used for gross and histopathology processing. Results: After thorough histopathological examination, of total 100 cases, various lesions were identified in 93 cases, in 7 cases tissue was autolyzed. Majority cases seen in the age group of 20-40yrs with male predominance. The most common cause of death was Road Traffic Accident (RTA) and majority victims were males. The commonly observed pathological features congestion and oedema(44.4%), Pneumonia(26.8%),CVC(22.2%) tuberculosis(9.6%) and ARDS(6.6%). Conclusion: The present study observed and documented histomorphological spectrum of lung lesions in medico-legal autopsies and highlighted various pathological conditions which are either direct or indirect cause of death. This study emphasizes that spectrum of histopathological changes in lungs of autopsy cases irrespective of cause of death and highlights some incidental interesting findings in lungs.  

Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation

Kidney transplantation stands as the ultimate recourse for restoring vital organ functions, particularly in cases of end-stage kidney disease where alternative treatments, such as dialysis, prove less effective. With over 102,000 kidney transplants conducted globally in 2022, the demand for organ transplantation is ever-increasing, fueled by a rising incidence of end-stage renal disease attributed to causes like diabetes and hypertension.&lt;br /&gt; Despite significant advancements in kidney transplantation, immunosuppressive therapy remains crucial to preventing graft rejection. Tacrolimus (TAC), a calcineurin inhibitor, plays a pivotal role in this regard. Discovered in 1984, TAC inhibits T-lymphocyte activation, preventing acute rejection by disrupting the transcription of crucial genes involved in early T-cell activation. However, the use of TAC is not without challenges. The drug exhibits serious side effects, a narrow therapeutic index, and unpredictable pharmacokinetics. Therapeutic drug monitoring (TDM) becomes imperative in daily practice to maintain TAC blood concentrations within the therapeutic range. This literature review delves into the genetic aspects influencing TAC metabolism, focusing on key polymorphisms in CYP3A5, CYP3A4, and ABCB1 genes. Genetic variations in CYP3A5, a major enzyme in TAC metabolism, impact enzyme activity, necessitating personalized dosing strategies. CYP3A4 polymorphisms, especially CYP3A4*22, demonstrate associations with altered TAC clearance and dose requirements. The ABCB1 gene, encoding P-glycoprotein, another player in TAC pharmacokinetics, also exhibits polymorphisms influencing drug absorption and distribution. The ABCB1 3435C&amp;gt;T variant, in particular, shows potential implications on Tacrolimus bioavailability. Understanding these genetic variations aids in the development of personalized dosing regimens. Studies suggest that tailoring TAC doses based on CYP3A5 genotypes significantly improves the proportion of patients achieving therapeutic concentrations. Additionally, incorporating genetic information, particularly CYP3A4*22, into dosing strategies enhances the precision of TAC therapy, reducing the risk of adverse effects.

Radiation exposure in therapeutic endoscopic retrograde cholangiopancreatography with two types of fluoroscopy systems

AbstractFluoroscopy is necessary for endoscopic retrograde cholangiopancreatography (ERCP). Occupational radiation exposure of staff (endoscopists, nurses, or assistants) is inevitable. Fluoroscopes with a tube over‐couch (OC) rather than under‐couch (UC) may have more radiation reflection dosage on the staff's upper body theoretically, where the most vital organs are. In the study, we assessed the radiation exposure on staff by two different types of fluoroscopes in real‐world practice. Using a radiation dosimeter to measure the radiation dosage on endoscopists and assistants in each ERCP procedure under two different fluoroscopic systems (UC vs. OC). Forty‐one ERCP procedures were enrolled. Dosimeters were used NanoDots for the measurement of personal radiation exposure. Those dosimeters were attached to the left forearm and chest of the endoscopist and only the chest of two assistants, the wall of the ERCP room, and the controlling room in every procedure. Nine‐teen ERCPs were performed under the OC unit, and the other 22 ERCPs were UC method. Fluoroscopic time and output of radiation dose showed no significant difference between the two groups. Radiation exposure in endoscopist were 0.0911[0.1041–0.3974] mGy (OC) versus 0.0276 [0.0080–0.2924] mGy (UC), p &lt; .01 for the forearm; and 0.0318 [0.0070–0.2628] mGy (OC) versus 0.0182 [0.0088–0.1628] mGy (UC), p = .04 for the endoscopist's body. There was no difference in radiation exposure from assistants in both groups. For all the ERCP procedures, the measurement of radiation exposure from high to low is endoscopist's hand, endoscopist's body, assistant 1, assistant 2, and ERCP room (p &lt; .01). Radiation detection from ERCP room is slightly higher but close to controlling room (p = .06). For the safety of occupational radiation protection, tube of fluoroscope UC is better than OC for the endoscopists more than assistants. Besides, the assistant 1 took higher radiation exposure than assistant 2 for each ERCP procedure.

Significance of radiation therapy in the myxoid round-cell liposarcoma treatment regimen.

Because myxoid liposarcomas are more radiosensitive than other soft tissue sarcomas, there have been several reports of 50Gy preoperative radiation therapy combined with surgery, but the wound complication rate is reportedly high. We have performed preoperative irradiation at a reduced dose of 40Gy and definitive radiation therapy for unresectable cases. This study aimed to report the tumor reduction rate and oncological results with a reduced dose of preoperative irradiation and the outcome of definitive irradiation for unresectable cases. Forty-one patients with myxoid liposarcoma treated in our institution between 2002 and 2021 were included. We examined the tumor volume shrinkage rate with preoperative radiation, compared complications and oncological outcomes between preoperative radiation and surgery-only cases, and investigated the prognosis and tumor shrinkage of definitive radiation cases. The total dose irradiated was 40Gy except in two cases. The mean tumor volume reduction rate was 52.0%. A decreased dose of preoperative radiation did not worsen clinical outcomes with fewer complications. The total dose of definitive radiation was approximately 60Gy. The mean tumor volume reduction rate was 55.0%. The tumor shrinkage maintenance rate was 100% in a median follow-up period of 50.5months. Preoperative radiation therapy for myxoid liposarcoma near vital organs is a good approach because even with a reduced dose of 40Gy, significant tumor reduction and excellent results were achieved. Definitive radiation therapy is the recommended treatment for older patients with serious comorbidities or inoperable patients.

Oxidative stress, inflammation, and steatosis elucidate the complex dynamics of HgCl2 induced liver damage in Channa punctata

Water bodies are highly pollution-prone areas in which mercury (Hg) is considered as a major menace to aquatic organisms. However, the information about the toxicity of mercuric chloride (HgCl2) in a vital organ such as the liver of fish is still inadequate. This study aimed to assess the impact of mercuric chloride (HgCl2) exposure on the liver of Channa punctata fish over 15, 30, and 45 days, at two different concentrations (0.039 mg/L and 0.078 mg/L). Mercury is known to be a significant threat to aquatic life, and yet, information regarding its effects on fish liver remains limited. The results of this study demonstrate that exposure to HgCl2 significantly increases oxidative stress markers, such as lipid peroxidation (LPO) and protein carbonyls (PC), as well as the levels of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in the fish. Additionally, the transcriptional and protein analysis of specific genes and molecules associated with necroptosis and inflammation, such as ABCG2, TNF α, Caspase 3, RIPK 3, IL-1β, Caspase-1, IL-18, and RIPK1, confirm the occurrence of necroptosis and inflammation in the liver. Histopathological and ultrastructural examinations of the liver tissue further reveal a significant presence of liver steatosis. Interestingly, the upregulation of PPARα suggests that the fish's body is actively responding to counteract the effects of liver steatosis. This study provides a comprehensive analysis of oxidative stress, biochemical changes, gene expression, protein profiles, and histological findings in the liver tissue of fish exposed to mercury pollution in freshwater environments.

“GC-MS profiling, sub-acute toxicity study and total phenolic and flavonoid content analysis of methanolic leaf extract of Schima wallichii (D.C.) Korth-a traditional antidiabetic medicinal plant”

Ethnopharmacological relevanceSchima wallichii (D.C.) Korth is traditionally used in Manipur, India for treatment of diabetes and hypertension. However, there is no data reported regarding safety profile of this medicinal plant upon repeated per oral administration over a period of time. Aim of the studyIn the current study phytochemical profile, toxicological profile and total phenolic and flavonoid compound content of Schima wallichii leaves extract were evaluated. Materials and methodsGas chromatography coupled to mass spectrometry was performed for chemical profiling by using Gas Chromatography-Mass Spectrometry/Mass Spectrometry (GC-MS/MS), Shimadzu, TQ8040 system. A 28 days sub-acute toxicity study was carried out using albino Wistar rats by administering 3 different doses (200, 400 and 800 mg/kg body weight per oral) of methanol leaves extract. Changes in body weights were recorded weekly. Serum biochemical parameters were estimated as well as blood-cell count was done to check the effect of extract on haematopoietic system. Histopathology of vital organs viz. kidney, heart, brain, liver was performed to find any pathological indications. Since, liver is main the site for xenobiotic metabolism, estimation of the level of glutathione, catalase and lipid peroxidation were done. Further, total phenolic and flavonoid compound content estimation was performed for the leaves extract. ResultsGC-MS revealed 14 major compounds with area percentage >1% of which quinic acid, n-Hexadecanoic acid, 9,12,15-Octadecatrienoic acid, (Z,Z,Z)-, Octatriacontyl trifluoroacetate, are three major compounds. No mortality was observed after the treatment with extract. Blood-cell count and biochemical parameters didn't show significant deviation as compared to control group. Histopathology study of vital organs viz. (liver, kidney, heart and brain) showed normal cellular construction comparing to control group. There was no sign of membrane lipid peroxidation, depletion of catalase level and glutathione level in liver. The result demonstrates that NOAEL (no-observed-adverse-effect levels) in the sub-acute toxicity was above 800 mg/kg. The leaves extract showed significant total phenol and flavonoid content. ConclusionThe present study revealed that Schima wallichii possessed important bioactive compounds with therapeutic values. The plant was safe for consumption after repeated high doses administration in rats and possesses significant amount of total phenol and flavonoid content.