Aspects of molecular medicine最新文献

The recent Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has posed significant challenges to global healthcare, with a myriad of impacts on the human body, particularly noted in hemostatic abnormalities observed in COVID-19 patients. These abnormalities have been linked to an increased risk of serious thrombotic events like deep vein thrombosis, pulmonary embolism, and stroke. Unlike existing literature, this comprehensive review delves into the long-term implications of these abnormalities, providing invaluable guidance for ongoing patient care as we move into the post-pandemic era. We cover the entire spectrum of hemostatic abnormalities, including elevated levels of aPTT, D-dimer, PT, ferritin, INR, fibrinogen, fibrin, and FDP, all of which create a complex clinical scenario necessitating vigilant monitoring and targeted therapeutic interventions. With a focus on the heightened risk of thrombotic complications, we underscore the importance of timely anticoagulant therapy and other necessary interventions, tailored to the patient's unique clinical presentation. This review stands as a critical resource for clinicians, hematologists, and healthcare providers, equipping them to navigate the complexities of COVID-19 in both acute and long-term settings, ensuring optimal patient outcomes. As we collectively navigate the lasting impact of the pandemic, this targeted and in-depth analysis becomes an indispensable tool in advancing our understanding and management of COVID-19.

Background & aims

Ultra-processed foods (UPF) are formulations of ingredients, resulting from a series of industrial processes. Excess intake of UPF is associated with an increased risk of obesity and chronic disease. The present study investigates the interaction between the consumption of UPF and genetic risk score with body composition, body adiposity index (BAI), and appendicular skeletal muscle mass (ASM) in overweight and obese women.

Method

The study is cross-sectional with 376 overweight and obese women aged 18–65 years. The food consumption was obtained with 147-item food frequency (FFQ), and food items were grouped according to the level of processing as per the NOVA classification. Three single nucleotide polymorphisms (SNPs), including Caveolin_1 (Cav_1), Melanocortin4 receptor (MC4R), and cryptochrome circadian regulator 1 (CRY1), were used to calculate GRS. The individual risk allele for each SNP was calculated using the incremental genetic model. Each SNP was recoded as 0, 1, or 2 based on the number of risk alleles associated with a higher body mass index (BMI). Subsequently, the unweighted GRS was computed by summing the number of risk alleles across the three SNPs. The GRS scale spans from 0 to 6, with each point representing a risk allele.Anthropometric measurements and some blood parameters were measured by standard protocols.

Results

After controlling for confounders such as age, energy intake, and BMI a significant interaction was found for appendicular skeletal muscle mass (β = −1.65, P = 0.04) and appendicular skeletal muscle mass index (β = −0.38, P = 0.07) on the NOVA classification system and GRS.

Conclusions

The findings of this study showed a significant interaction between GRS and the NOVA classification system on some body composition, including appendicular skeletal muscle mass. A higher intake of ultra-processed foods may be associated with lower appendicular skeletal muscle mass in people with high obesity-GRS.

Aim

To compare mRNA [messenger RNA] expression of RELA, NFκB1, TNF-α, IL-6 and MCP-1 in whole blood & serum Total Antioxidant status [TAS] in newly diagnosed lean and obese patients with T2DM.

Methods

Newly diagnosed treatment naïve patients of T2DM were enrolled in this study. The patients were divided into two groups of 30 patients each, lean (BMI< 18.5 kg/m²) and obese (BMI >25 kg/m²) groups. mRNA expression of RELA, NFκB1, TNF-α, IL-6 and MCP-1 was measured by real time PCR. Serum TAS was measured using a commercially available kit.

Results

There was a 2.7-fold increase in mRNA expression of RELA in obese group compared to the lean group. There was a 1.3-fold increase in mRNA expression of NFκB1, a 3.24-fold increase in mRNA expression of TNF-α, a 4.7-fold increase in mRNA expression of IL 6 and a 3.8-fold increase in mRNA expression of MCP-1 in obese group compared to the lean group. Mean fasting serum insulin levels were 16.07 ± 8.39 μIU/mL in the lean group and 27.11 ± 4.91μIU/mL in the obese group (p = 0.001). Mean TAS level was 5.39 ± 2.28 μM Trolox Equivalents in the obese group and 3.85 ± 3.33 μM Trolox Equivalents in the lean group (p = 0.001).

Conclusion

Inflammation and OS is higher in obese patients of T2DM compared to lean patients of T2DM. This could be the result of excess adipokines production or resistance to the anti-inflammatory effects of insulin with multiple explanations. Our study suggests a difference in the pathogenic mechanism in lean patients when compared with obese T2DM patients.

Objective

Malaria, the plasmodium parasite, which causes and affects nearly half of the world's population, is the biggest human health issue. Malaria results in an annual death toll ranging from 1.2 to 2.7 million worldwide. Consequently, there is a pressing need for novel active ingredients with targeted effects to curb the worldwide spread of malaria.

Methods

This research is to explore innovative pharmacological molecules and employ bioinformatics methods (in silico) for the development of effective anti-malarial drugs. As part of the newest research into antimalarial chemicals, our study found seven drug combinations from different databases that showed drug-like properties and strong antimalarial activity in silico.

Results

The hexokinase-1 protein (PDB: 1CZA) was docked with dioncophyllin-A, hugorosenone, marmesine, oxyprotostemonin, pachyrrhizin, plumbagin, and stemocurtisin. Among the pachyrrhizin compounds, the one with the highest docking score (−9.9 kcal/mol) was directed towards the 1CZA protein. Through superimposing the target and template structures, the active centres of the hexokinase I protein were identified, revealing structurally identical folds and undoubtedly conserved active sites. The SWISS-ADME tool was used to check how well the drug candidates were absorbed, distributed, broken down, and flushed out of the body (ADME).

Conclusions

In summary, our research identifies pachyrrhizin as a as a potential anti-malarial drug combination with strong in silico activity. We've elucidated their interaction with the hexokinase-1 protein and assessed their favourable pharmacokinetic properties. These findings represent a significant step toward developing effective treatments for malaria, emphasizing the importance of further experimental validation and clinical studies.

Objective

Sightly low serum free T4 levels are associated with longer life expectancy. However, hypothyroidism is associated with increased risk of inflammation and vascular complications. Therefore, relation of thyroid hormones (THs) with life expectancy seems to be complex. This study was carried out in an effort to understand the contribution of THs in inflammation and aging.

Methodology

15 cases of treatment naïve primary hypothyroidism and 15 age and sex matched euthyroid controls were recruited. mRNA expression of Telomerase (hTERT), leucocyte telomere length (LTL) and Lipoprotein associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation and risk predictor of cardiovascular events were measured by qPCR in whole blood.

Result

Expression of hTERT was found to be 6.95 times higher in the cases as compared to the controls. mRNA expression of Lp-PLA(2) was also 3.3 times higher in cases. LTL in euthyroid was approximately 81% of the length in hypothyroid patients.

Conclusion

A higher expression of hTERT indicates that hypothyroidism confers better cell survival in peripheral leucocytes inspite of the presence of vascular inflammation. However causal relationship cannot be ascertained with these results.

We report a subcutaneous mastocytoma in a mid-aged Italian greyhound dog with a small 41 bp genomic deletion of the c-kit gene leading to skipping of the authentic 3′-splice junction of intron 10. The shift to an alternative splice junction in exon 11 leads to a mis-spliced in-frame mRNA transcript with a 27 bp deletion of exon 11 coding for 9 amino acids in the juxtamembrane negative regulatory domain of c-kit tyrosine kinase. In the tumor, c-kit was activated as revealed by more pronounced c-kit-regulated signaling by the PI3K/Akt and G-coupled receptor pathways. The same 9 amino acids deletion was reported in several human gastrointestinal stromal tumors (GIST) pointing to a remarkable similarity of c-kit activation by small deletions and aberrant splicing in humans and dogs, independent of exact sequence context, tumor type and location. Interestingly, the alternative splice junction in exon 11 has been conserved in Primates but less in other Orders with increased body temperature such as ruminants. We hypothesize that elevated body temperature has acted as evolutionary pressure to eliminate the alternative splice site at this hotspot. At a molecular level, hyperthermia may increase the frequency of small deletions in the c-kit gene by facilitating base slipping or hindering repair. An RT-qPCR assay was developed to detect c-kit alternative splicing in tumors and cell lines exposed to hyperthermia. The molecular mechanisms of tumorigenesis are discussed.

Type 2 diabetes (T2D) is a chronic and prevalent multisystemic disease that significantly increases morbidity and mortality. Dysfunction of the thyroid hormone system is common in patients with T2D, increasing their risk of both hyperthyroidism and hypothyroidism. Several components of the thyroid system are candidate risk genes for T2D. The thyrotropin-releasing hormone receptor (TRHR) gene encoding for TRHR is of particular interest since it is expressed by the dorsomedial hypothalamus neurons, which are known to regulate food intake. In humans, a variant in the TRHR gene has been previously reported in T2D patients in a population-based case-control study but not in familial T2D. We recruited 212 multigenerational families with T2D originated from the Italian peninsula with multiple cases of T2D and tested, via Pseudomarker 9 single nucleotide polymorphisms (SNPs) in the TRHR gene for linkage and linkage disequilibrium (i.e., linkage plus association) to/with T2D. We identified 2 novel risk variants (rs3110045 and rs28499085) significantly linked to and associated with the risk of T2D in the Italian families across several inheritance models. Our study is the first to confirm the previously reported association of TRHR gene with T2D and extends the risk to familial inheritance. However, functional and replication studies are still needed to confirm these results.

The Transient Receptor Potential Canonical 6 (TRPC6) channel was implicated in the pathogenesis of pulmonary airway inflammation, chronic obstructive pulmonary disease, pulmonary edema, and pulmonary fibrosis. It was also proposed that Ca²⁺ influx through TRPC6 may contribute to triggering pulmonary inflammatory responses. The ChEMBL database lists 44 drugs that are clinically used to treat asthma, a type of obstructive airway inflammation (OAI). Since the mode of action and targets are not fully elucidated for many of these 44 drugs, we used computational approaches to determine the drugs’ potential to interact with the inhibitor binding site on the TRPC6 protein. We also screened a library of natural compounds to retrieve the phytochemicals with a potential to interact with TRPC6. The binding affinities of two well-known TRPC6 inhibitors, BTDM and 2-aminoethoxydiphenyl borate (2-APB), were compared with those of the screened compounds. We found that despite stable in silico binding and a well-defined three-dimensional molecular interaction pattern with the TRPC6 protein of the two top-scoring compounds, montelukast and solanesol, the molecules from the approved-drug and natural-compound libraries respectively, failed to show any significant efficacy in the in vitro assays.

Diabetes and chronic liver and kidney disease are common long-term conditions worldwide. Taraxacum officinale (TOE) has many medicinal properties, due to it phytochemicals constitutions. This study investigate activities of TOE in Streptozotocin diabetes-Induced Hepatorenal toxicity. Sixty rats were randomized into groups A, B, C, D, E, and F of ten rats each (n = 10). Group normal control, group B treated with TOE, group C diabetic (DM) negative control, group D DM rats treated with TOE, group E DM rats treated with metformin (MF)], group F treated with TOE follow by STZ-diabetic). Serum lipid profile, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), Gamma-glutamyl transferase (GGT), total proteins (TP), albumin (ALB), Urea, and creatinine, electrolyte, oxidative and antioxidant enzymes, caspase 3, inflammatory cytokines, tricarboxylic acid (TCA) cycle enzymes and mitochondrial membrane potential (ΔΨm), liver and kidney histology were investigated.

Treatment with TOE ameliorated all the electrolyte disruptions in DM rats. Treatment with TOE and TOE + MF recovered caspase 3, inflammatory makers, oxidative and antioxidant enzymes in DM rats. Moreover, an increase in lipid profile, hepatic and renal functional markers, ALT, AST, ALP, GGT, TP, ALB, Urea, TCA and renal mitochondrial respiratory-chain complexes (I-IV) and ΔΨm and a decrease in creatinine clearance was recovered in DM rats by TOE and TOE + MF treatment. TOE and TOE + MF protected against hepatic and renal histological damage in DM group.

Hepatorenal toxicity was effectively ameliorated by the TOE administration. TOE might be considered as a potential protective agent against hepatorenal toxicity.