Novel TMPRSS6 variants and their impact on iron-refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study.

Iron-refractory iron deficiency anaemia (IRIDA) is a rare autosomal recessive disorder, distinguished by hypochromic microcytic anaemia, low transferrin levels and inappropriately elevated hepcidin (HEPC) levels. It is caused by mutations in TMPRSS6 gene. Systematic screening of 500 pregnant women with iron deficiency anaemia having moderate to severe microcytosis with no other causes of anaemia were enrolled to rule out oral iron refractoriness. It identified a final cohort of 10 (2.15% prevalence) individuals with IRIDA phenotype. Haematological and biochemical analysis revealed significant differences between iron responders and iron non-responders, with iron non-responders showing lower haemoglobin, red blood cell count, serum iron and serum ferritin levels, along with elevated HEPC (9.47 ± 2.75 ng/mL, p = 0.0009) and erythropoietin (4.58 ± 4.07 µ/mL, p = 0.0196) levels. Genetic sequencing of the TMPRSS6 gene in this final cohort identified 10 novel variants, including seven missense and three frame-shift mutations, with four missense variants showing high functional impact defining the IRIDA phenotype. Structural analysis revealed significant damage caused by two variants (p.L83R and p.S235R). This study provides valuable insights into IRIDA among pregnant women in the Indian subcontinent, unveiling its underlying causes of unresponsiveness, genetic mechanisms and prevalence. Furthermore, research collaboration is essential to validate these findings and develop effective treatments.

The role of TMPRSS6 gene polymorphism in iron resistance iron deficiency anaemia (IRIDA): a systematic review.

Iron resistance iron deficiency anaemia is a rare autosomal recessive disorder characterized by hypochromic microcytic anaemia, low transferrin saturation and inappropriately high hepcidin levels. The aetiology of this condition is rooted in genetic variations within the transmembrane serine protease 6 (TMPRSS6) genes, responsible for encoding matriptase-2, a pivotal negative regulator of hepcidin. We conducted a systematic search across four electronic databases, yielding 538 articles in total out of which 25 were finally included and were preceded further, aiming to prognosticate prevalent single nucleotide polymorphisms (SNPs) and detrimental genetic alterations. This review aims to elucidate the effects of various SNPs and pathogenic mutations on both haematological and biochemical parameters, as well as their potential interethnic correlation. Employing bioinformatics tools, we subjected over 100 SNPs to scrutiny, discerning their potential functional ramifications. We found rs1373272804, rs1430692214 and rs855791 variants to be most frequent and were having a significant impact on haematological and biochemical profile. We found that individuals of European ancestry were more prone to have these variants compared to other ethnic groups. In conclusion, this review not only sheds light on the association of TMPRSS6 polymorphism in iron resistance iron deficiency anaemia (IRIDA), but also highlights the critical need for further investigations involving larger sample size and more diverse ethnic groups around the globe. These future studies will be vital for gaining a stronger and more reliable understanding of how these genetic differences are linked to the development of IRIDA.

Wnt Signaling Modulators Exhibit Neuroprotective Effects via Combating Astrogliosis and Balancing Synaptic Density at Early and Late Stage Temporal Lobe Epilepsy.

Temporal Lobe Epilepsy (TLE) is a severe neurological condition characterized by recurrent seizures that often do not respond well to available anti-seizure medications. TLE has been associated with epileptogenesis, a process that starts during the latent period following a neurologic insult and is followed by chronic phase. Recent research has linked canonical Wnt signaling to the pathophysiology of epileptogenesis and TLE. Our previous study demonstrated differential regulation of canonical Wnt signaling during early and late stage post status epilepticus (SE) induction. Building on these findings, our current study utilized Wnt modulators: GSK-3ß inhibitor 6-bromoindirubin-3'-oxime (6-Bio) and disheveled inhibitor niclosamide and investigated their impact on canonical Wnt signaling during the early (30 days) and later stages (60 days) following SE induction. We assessed several parameters, including seizure frequency, astrogliosis, synaptic density, and neuronal counts in hippocampal tissue. We used immunohistochemistry and Nissl staining to evaluate gliosis, synaptic density, and neuronal counts in micro-dissected hippocampi. Western blotting was used to examine the expression of proteins involved in canonical Wnt/ß-catenin signaling, and real-time PCR was conducted to analyze their relative mRNA expression. Wnt modulators, 6-Bio and Niclosamide were found to reduce seizure frequency and various other parameters including behavioral parameters, hippocampal morphology, astrogliosis and synaptic density at different stages of TLE.

Neuroprotective effect of PPAR gamma agonist in rat model of autism spectrum disorder: Role of Wnt/ß-catenin pathway.

BACKGROUND: The clinical manifestation of autism spectrum disorder (ASD) is linked to the disruption of fundamental neurodevelopmental pathways. Emerging evidences claim to have an upregulation of canonical Wnt/ß-catenin pathway while downregulation of PPARγ pathway in ASD. This study aims to investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in rat model of ASD. The study further explores the possible role of PPARγ and Wnt/ß-catenin pathway and their interaction in ASD by using their modulators. MATERIAL AND METHODS: Pregnant female Wistar rats received 600 mg/kg of valproic acid (VPA) to induce autistic symptoms in pups. Pioglitazone (10 mg/kg) was used to evaluate neurobehaviors, relative mRNA expression of inflammatory (IL-1ß, IL-6, IL-10, TNF-α), apoptotic markers (Bcl-2, Bax, & Caspase-3) and histopathology (H&E, Nissl stain, Immunohistochemistry). Effect of pioglitazone was evaluated on Wnt pathway and 4 µg/kg dose of 6-BIO (Wnt modulator) was used to study the PPARγ pathway. RESULTS: ASD model was established in pups as indicated by core autistic symptoms, increased neuroinflammation, apoptosis and histopathological neurodegeneration in cerebellum, hippocampus and amygdala. Pioglitazone significantly attenuated these alterations in VPA-exposed rats. The expression study results indicated an increase in key transcription factor, ß-catenin in VPA-rats suggesting an upregulation of canonical Wnt pathway in them. Pioglitazone significantly downregulated the Wnt signaling by suppressing the expression of Wnt signaling-associated proteins. The inhibiting effect of Wnt pathway on PPARγ activity was indicated by downregulation of PPARγ-associated protein in VPA-exposed rats and those administered with 6-BIO. CONCLUSION: In the present study, upregulation of canonical Wnt/ß-catenin pathway was demonstrated in ASD rat model. Pioglitazone administration significantly ameliorated these symptoms potentially through its neuroprotective effect and its ability to downregulate the Wnt/ß-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.

Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review.

Colorectal cancer (CRC) affects 1 in 23 males and 1 in 25 females, making it the third most common cancer. With roughly 608000 deaths worldwide, CRC accounts for 8% of all cancer-related deaths, making it the second most common cause of death due to cancer. Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy, chemotherapy, immunotherapy, and their combinational regimen for non-resectable CRC. Despite these tactics, nearly half of patients develop incurable recurring CRC. Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways, including drug inactivation, drug influx and efflux modifications, and ATP-binding cassette transporter overexpression. These constraints necessitate the development of new target-specific therapeutic strategies. Emerging therapeutic approaches, such as targeted immune boosting therapies, non-coding RNA-based therapies, probiotics, natural products, oncolytic viral therapies, and biomarker-driven therapies, have shown promising results in preclinical and clinical studies. We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.

Modernising autism spectrum disorder model engineering and treatment via CRISPR-Cas9: A gene reprogramming approach.

A neurological abnormality called autism spectrum disorder (ASD) affects how a person perceives and interacts with others, leading to social interaction and communication issues. Limited and recurring behavioural patterns are another feature of the illness. Multiple mutations throughout development are the source of the neurodevelopmental disorder autism. However, a well-established model and perfect treatment for this spectrum disease has not been discovered. The rising era of the clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) system can streamline the complexity underlying the pathogenesis of ASD. The CRISPR-Cas9 system is a powerful genetic engineering tool used to edit the genome at the targeted site in a precise manner. The major hurdle in studying ASD is the lack of appropriate animal models presenting the complex symptoms of ASD. Therefore, CRISPR-Cas9 is being used worldwide to mimic the ASD-like pathology in various systems like in vitro cell lines, in vitro 3D organoid models and in vivo animal models. Apart from being used in establishing ASD models, CRISPR-Cas9 can also be used to treat the complexities of ASD. The aim of this review was to summarize and critically analyse the CRISPR-Cas9-mediated discoveries in the field of ASD.

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. METHODS: Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1ß, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum. KEY FINDINGS: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1ß, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage. CONCLUSIONS: Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.