👤 Suriakarthiga Ganesan

Emerging evidence establishes hepatic dysfunction as a critical modulator of breast cancer (BC) progression through metabolic, endocrine, and inflammatory crosstalk, yet the molecular mediators remain incompletely characterized. This review systematically examines the liver-BC axis to identify mechanistic drivers and therapeutic opportunities for patients with comorbid conditions. We conducted an integrated analysis combining a comprehensive literature review with computational biology approaches, including protein-protein interaction network analysis, functional pathway enrichment (KEGG/GO), and multi-omics data mining from GEO, TCGA, and CPTAC databases, supplemented by experimental validations from preclinical models. Our analysis revealed hepatic dysfunction promotes BC progression through five interconnected pathways: insulin resistance-driven IGF1-PI3K/AKT activation, estrogen metabolism imbalance via CYP19A1/ESR1, IL6-STAT3/NLRP3-mediated inflammation, HMOX1/APOE-dependent metabolic rewiring, and FAK-Src/MMP9-regulated ECM remodeling. Key molecular mediators include nuclear receptors (ESR1), cytokines (IL-1β), growth factors (HGF), and receptor tyrosine kinases, with SPP1 and PTPN2 emerging as potential circulating biomarkers linking hepatic dysfunction to aggressive BC phenotypes. The crosstalk between hepatic dysfunction and BC is mediated by a network of proteins and pathways, offering potential targets for therapeutic intervention. Future research should focus on translational validation and personalized strategies for BC patients with comorbid liver conditions. This mechanistic insight may advance early diagnosis and precision treatment paradigms. Show less

Clarifying relationships between amyloid, tau, and cognition is crucial to understanding dementia risk, but has been mainly performed in non-Hispanic White (NHW) participants. It is unknown whether findings are generalizable to other ethnoracial groups. We evaluated relationships between amyloid-β (Aβ) positivity, apolipoprotein E allele (APOE) ε4, tau-positron emission tomography (PET) Black (β = 0.28, p < 0.001) and Hispanic (β = 0.34, p < 0.001) participants had higher medial temporal lobe (MTL) tau than NHW participants; however, findings were attenuated when accounting for choroid plexus off-target binding. Hispanic participants showed higher tau in lateral temporal regions compared to NHW and Black participants; however, reducing meningeal off-target binding through erosion demonstrated similar lateral temporal tau across groups. Factors other than amyloid and tau may impact cognition in Black participants. PI2620 off-target ethnoracial differences should be investigated. Show less

Patients with chronic kidney disease (CKD) are at a significantly increased risk of developing Alzheimer's disease (AD) and cognitive dysfunction compared to the general population. While recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia in CKD, emerging evidence indicates that it also possesses neuroprotective properties. This study aimed to evaluate the therapeutic impact of rHuEPO on platelet expression of amyloid precursor protein (APP) proteolytic fragments, apolipoprotein E (ApoE), glycogen synthase kinase 3β (GSK3β), total Tau, and phosphorylated Tau species (P-Tau181, P-Tau217, and P-Tau231), along with plasma levels of APP cleaving enzymes, P-Tau217, P-Tau231, inflammatory cytokines, and cholinergic markers in CKD patients with cognitive dysfunction. A total of 60 CKD patients were enrolled, including 30 without cognitive dysfunction and 30 with cognitive dysfunction, as determined by neuropsychological assessment. Platelet protein expression levels of total Tau, P-Tau181, P-Tau217, P-Tau231, and ApoE were analyzed using Western blotting. Gene expression levels of APP-cleaving enzymes, ApoE, GSK3β, and MAPT in platelets were assessed by RT-PCR. Plasma concentrations of APP-cleaving enzymes, inflammatory cytokines, cholinergic markers, P Tau217, and P-Tau231 were quantified. Results were compared with healthy controls, normocytic normochromic anemia, and AD. CKD patients with cognitive dysfunction showed significant alterations in the expression of platelet proteins (total Tau, P-Tau181, P Tau217, P-Tau231, and ApoE) and related genes (APP cleaving enzymes, ApoE, GSK3β, and MAPT), resembling the molecular profile observed in AD. Additionally, plasma levels of APP cleaving enzymes, inflammatory cytokines, cholinergic markers, and phosphorylated Tau species (P-Tau217 and P-Tau231) were significantly altered in these patients. Notably, after 6 months of rHuEPO therapy, these biomarkers showed marked improvement in CKD patients with cognitive dysfunction. These findings suggest that rHuEPO may offer therapeutic benefits beyond anemia correction, potentially serving as a supportive treatment for cognitive dysfunction in CKD by modulating AD-related peripheral biomarkers. Show less

The hematopoietic stem cell (HSC) continues their functional integrity and return to quiescence quickly even after inflammatory and other proliferative stress. The mechanism which is responsible for this highly regulatory process is not understood clearly. Previous results have shown that CD53 is noticeably upregulated in HSCs in response to a variety of stimuli. Gene expression profile using RNASeq data of HSCs from the bone marrow and spleen of CD53 knock out and their wild-type littermate had been deposited by Greenberg and co-authors, in GEO database, "GSE219050". They reported that knockout of CD53 promotes continued cell cycle. To identify key genes and specific processes are affected in absence of CD53, we applied weighted gene co-expression analysis. The results show that cyan module is correlated and dark red and light cyan are anti-correlated with CD53 loss. CDK1 is identified as more connected gene or hub gene in cyan module and it is upregulated in the absence of CD53. Likewise, hub genes from dark-red module are EP300, EGF, MCL1, LPL and IGF1R. The gene enrichment analysis depicts, two biological processes, MAPK cascade and Delta Notch signalling were suppressed. Similarly, the biological processes involved in light-cyan module are chromatin organisation and hub genes are Ehmt2, Ezh2, Kdm1a, Rbbp4, Esr1 and Mysm1. It uncovers the roles of Show less

Persea americana fruit (PAF) is a favorable nutraceutical resource that comprises diverse unsaturated fatty acids (UFAs). UFAs are significant dietary supplementation, as they relieve metabolic disorders, including obesity (OB). In another aspect, this study was focused on the anti-OB efficacy of the non-fatty acids (NFAs) in PAF through network pharmacology (NP). Natural product activity & species source (NPASS), SwissADME, similarity ensemble approach (SEA), Swiss target prediction (STP), DisGeNET, and online Mendelian inheritance in man (OMIM) were utilized to gather significant molecules and its targets. The crucial targets were adopted to construct certain networks: protein-protein interaction (PPI), PAF-signaling pathways-targets-compounds (PSTC) networks, a bubble chart, molecular docking assay (MDA), and density function theory (DFT). Finally, the toxicities of the key compounds were validated by ADMETlab 2.0 platform. All 41 compounds in PAF conformed to Lipinski's rule, and the key 31 targets were identified between OB and PAF. On the bubble chart, PPAR signaling pathway had the highest rich factor, suggesting that the pathway might be an agonism for anti-OB. Conversely, estrogen signaling pathway had the lowest rich factor, indicating that the mechanism might be antagonism against OB. Likewise, the PSTC network represented that AKT1 had the greatest degree value. The MDA results showed that AKT1-gamma-tocopherol, PPARA-fucosterol, PPARD-stigmasterol, (PPARG)-fucosterol, (NR1H3)-campesterol, and ILK-alpha-tocopherol formed the most stable conformers. The DFT represented that the five molecules might be promising agents via multicomponent targeting. Overall, this study suggests that the NFAs in PAF might play important roles against OB. Show less

In conventional, the biologically treated tannery wastewaters are rich in dissolved organics and the application of reverse osmosis (RO) to biologically treated tannery wastewater was challenged with fouling and failure of RO membrane due to existence of lingering dissolved organic compounds. In present investigation the bacterial cell immobilized packed bed reactor (CIPBR) was operated to remove the dissolved organic compounds in biologically treated post-tanning wastewater to avoid membrane fouling in RO. The efficient microbial syndicate to eliminate dissolved organics in post-tanning wastewater was isolated and immobilized on to the carbon silica matrix (CSM) in the range of 2.98 ± 0.2 × 10 Show less

The gene for receptor tyrosine kinase ErbB2 is amplified in breast and ovarian tumours. The linear pathway by which signals are transduced through ErbB2 are well known. However, second generation questions that address spatial aspects of signaling remain. To address this, we have undertaken a mass spectrometry approach to identify phosphoproteins specific for ErbB2 using the inhibitors Lapatinib and CP724714 in ovarian cancer cells. The ErbB2 specific proteins identified in SKOV-3 cells were Myristoylated alanine-rich C-kinase substrate, Protein capicua homolog, Protein peptidyl isomerase G, Protein PRRC2C, Chromobox homolog1 and PRP4 homolog. We have evaluated three phosphoproteins PKM2, Aldose reductase and MARCKS in SKOV-3 cells. We observed that PKM2 was phosphorylated by EGF but was not inhibited by Lapatinib and CP724714. The activity of aldose reductase in reducing NADPH as a substrate was significantly higher in EGF stimulated cells which was inhibited by Lapatinib and CP724714 but not by Geftinib (EGFR inhibitor). MARCKS was phosphorylated on stimulation of SKOV-3 cells with EGF that was inhibited by Lapatinib and CP724714 which was dependent on the kinase activity of ErbB2. These results have identified phosphoproteins that are specific to ErbB2 which have not been previously reported and sets the basis for future experiments. Show less

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC-oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8-76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5' fusion partner ZC3H4. We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC-oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care. Show less

Cardiotoxicity is the most serious side effect of anthracyclines (doxorubicin, daunorubicin or epirubicin). The incidence of anthracycline induced late cardiac toxicity (AIC) that is overt clinically is 3-5% in the Indian population. Polymorphism in intron 32 (deletion of 25bp) of MYBPC3 has been shown to be present exclusively in Asians and more so in South India (3-8%). The frequency of the polymorphism is significantly higher (13%) in patients with cardiomyopathy in India. Fifteen patients were identified to have cardiac dysfunction following treatment for malignant lymphoma with doxorubicin containing regimens. Peripheral blood DNA from control, amplified by polymerase chain reaction yielded a 467bp fragment while in the presence of the 25bp deletion only a 442bp fragment was detected. To confirm the presence or absence of the polymorphism, amplified DNA was restricted using Bgl1 in all samples. Bgl1 restricted amplified DNA only if the 25bp deletion was absent. A 467 base pair band was observed in all the 15 samples, which suggested the absence of polymorphism in MYBPC3. In a sample of DNA from a patient with a deletion in exon 33 (confirmed by sequencing) a 442bp fragment was detected. Amplified DNA from this patient was not restricted with Bgl1. Wild type MYBPC3 when amplified gave a distinct restriction banding pattern consisting of two bands of 401bp and 66bp. Amplified DNA from all peripheral blood samples restricted with Bgl1 suggesting the absence of the polymorphism. In this preliminary report, MYBPC3 does not seem to play a role in anthracycline induced cardiotoxicity. Show less

Phagocytosis of filamentous bacteria occurs through tubular phagocytic cups (tPCs) and takes many minutes to engulf these filaments into phagosomes. Contravening the canonical phagocytic pathway, tPCs mature by fusing with endosomes. Using this model, we observed the sequential recruitment of early and late endolysosomal markers to the elongating tPCs. Surprisingly, the regulatory early endosomal lipid phosphatidylinositol-3-phosphate (PtdIns(3)P) persists on tPCs as long as their luminal pH remains neutral. Interestingly, by manipulating cellular pH, we determined that PtdIns(3)P behaves similarly in canonical phagosomes as well as endosomes. We found that this is the product of a pH-based mechanism that induces the dissociation of the Vps34 class III phosphatidylinositol-3-kinase from these organelles as they acidify. The detachment of Vps34 stops the production of PtdIns(3)P, allowing for the turnover of this lipid by PIKfyve. Given that PtdIns(3)P-dependent signaling is important for multiple cellular pathways, this mechanism for pH-dependent regulation of Vps34 could be at the center of many PtdIns(3)P-dependent cellular processes. Show less

Mutations in sarcomeric genes are the leading cause for cardiomyopathies. However, not many genetic studies have been carried out on Indian cardiomyopathy patients. We performed sequence analyses of a thin filament sarcomeric gene, α-tropomyosin (TPM1), in 101 hypertrophic cardiomyopathy (HCM) patients and 147 dilated cardiomyopathy (DCM) patients against 207 ethnically matched healthy controls, revealing 13 single nucleotide polymorphisms (SNPs). Of these, one mutant, S215L, was identified in two unrelated HCM cases-patient #1, aged 44, and patient #2, aged 65-and was cosegregating with disease in these families as an autosomal dominant trait. In contrast, S215L was completely absent in 147 DCM and 207 controls. Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2. Therefore, these two patients and the family members positive for S215L were further screened for variations in MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC. Interestingly, two novel thick filaments, D896N (homozygous) and I524K (heterozygous) mutations, in the MYH7 gene were identified exclusively in patient #1 and his family members. Thus, we strongly suggest that the coexistence of these digenic mutations is rare, but leads to severe hypertrophy in a South Indian familial hypertrophic cardiomyopathy (FHCM). Show less

Type 2 diabetes mellitus (T2DM) is a major cause of coronary artery disease (CAD) and is responsible for a great deal of morbidity and mortality in Asian Indians. Several gene polymorphisms have been associated with CAD and T2DM in different ethnic groups. This study will give an insight about the association of two selected candidate gene polymorphisms; paraoxonase1 (PON1) Q192R and apolipoprotein A5 (APOA5) -1131T>C were assessed in a cohort of South Indian patients having CAD with and without T2DM. Polymerase chain reaction-based genotyping of PON1 Q192R (rs662) and APOA5-1131T>C (rs662799) polymorphism was carried out in 520 individuals, including 250 CAD patients (160 with T2DM and 90 without T2DM), 150 T2DM patients with no identified CAD, and 120 normal healthy sex- and age-matched individuals as controls. The PON1 192RR genotype and R allele frequency were elevated in both CAD and T2DM patients when compared with controls; however, only CAD patients with T2DM showed a statistical significance (p=0.023; OR=1.49; 95% CI: 1.04-2.12) when compared with controls. The APOA5-1131CC genotype and C allele also showed a significant association between the CAD+T2DM patients when compared with CAD without T2DM and healthy controls (p=0.012; OR=1.71; 95% CI: 1.0-2.67). An additive interaction between the PON1 RR and APOA5 TC genotypes was identified between the T2DM and CAD patients (p=0.028 and 0.0382, respectively). PON1 and APOA5 polymorphisms may serve as biomarkers in the South Indian population to identify T2DM patients who are at risk of developing CAD. Show less