Discovering the Triad between Nav1.5, Breast Cancer, and the Immune System: A Fundamental Review and Future Perspectives.

Nav1.5 is one of the nine voltage-gated sodium channel-alpha subunit (VGSC-α) family members. The Nav1.5 channel typically carries an inward sodium ion current that depolarises the membrane potential during the upstroke of the cardiac action potential. The neonatal isoform of Nav1.5, nNav1.5, is produced via VGSC-α alternative splicing. nNav1.5 is known to potentiate breast cancer metastasis. Despite their well-known biological functions, the immunological perspectives of these channels are poorly explored. The current review has attempted to summarise the triad between Nav1.5 (nNav1.5), breast cancer, and the immune system. To date, there is no such review available that encompasses these three components as most reviews focus on the molecular and pharmacological prospects of Nav1.5. This review is divided into three major subsections: (1) the review highlights the roles of Nav1.5 and nNav1.5 in potentiating the progression of breast cancer, (2) focuses on the general connection between breast cancer and the immune system, and finally (3) the review emphasises the involvements of Nav1.5 and nNav1.5 in the functionality of the immune system and the immunogenicity. Compared to the other subsections, section three is pretty unexploited; it would be interesting to study this subsection as it completes the triad.

Subacute Toxicity Evaluation of Methanolic Extract of Syzygium polyanthum in Rats.

Syzygium polyanthum (Wight) Walp. var. polyanthum (serai kayu) leaves is a popular herb and widely used in traditional medicine. Despite the ethnomedicinal benefits, very limited studies have researched on the toxicity of this plant. The aim of the present study was to investigate the potential effects of methanolic extract of Syzygium polyanthum (MESP) leaves via 28-day repeated oral dosing in Sprague Dawley rats. MESP leaves was administered at doses of 0 (control), 400, 1000 or 2000 mg/kg to an equal number of male and female rats (n = 10/group). Results obtained indicated that MESP did not affect the general conditions (body weight, feed intake and oestrous cycle) and apparent behavioural changes of the rats. Biochemical parameters revealed a slight significant variation in the aspartate aminotransferase (AST) level between the male rats treated with the lowest and highest doses of MESP, but these findings were both statistically insignificant when compared to the control group. The liver of the males (dose 1000 and 2000 mg/kg/day) also exhibited histoarchitectural defects on the hepatocytes and cytoplasm when compared to those of the control group. In contrast, female rats did not encounter any significant findings in all parameters tested. In conclusion, this study suggests that the MESP leaves might exhibit sex-based variation effects and thus, the use of this extract particularly at higher doses should be thoroughly considered.

Daun Syzygium polyanthum (Wight) Walp. var. polyanthum (serai kayu) ialah herba popular dan banyak digunakan dalam perubatan tradisional. Walaupun terdapat manfaat etnoperubatan, kajian ke atas ketoksikan tumbuhan ini sangat terhad. Tujuan kajian ini adalah untuk mengkaji kemungkinan kesan ekstrak metanol daun Syzygium polyanthum (MESP) melalui dos oral berulang 28 hari ke atas tikus Sprague Dawley. MESP diberikan pada dos 0 (kawalan), 400, 1000 atau 2000 mg/kg kepada tikus jantan dan betina yang sama bilangan (n = 10/kumpulan). Hasil yang diperolehi menunjukkan bahawa MESP tidak mempengaruhi keadaan fizikal (berat badan, pengambilan makanan dan kitaran estrus) dan perubahan jelas ke atas tingkah laku tikus. Parameter biokimia menunjukkan sedikit perbezaan yang signifikan dalam aras aspartate aminotransferase (AST) di antara tikus jantan yang dirawat dengan dos MESP terendah dengan dos tertinggi, tetapi keputusan ini tidak signifikan secara statistik bila dibandingkan dengan kumpulan kawalan. Hepar tikus jantan (dos 1000 dan 2000 mg/kg/hari) juga menunjukkan kecacatan histoarkitek pada hepatosit dan sitoplasma bila dibandingkan dengan kumpulan kawalan. Sebaliknya, tikus betina tidak menunjukkan keputusan yang signifikan dalam semua parameter yang diuji. Kesimpulannya, kajian ini mencadangkan bahawa MESP mungkin menunjukkan perbezaan kesan berdasarkan jantina dan oleh itu, penggunaan ekstrak ini terutama pada dos tinggi harus dipertimbangkan sewajarnya.

Breast cancer therapy affects the expression of antineonatal Nav1.5 antibodies in the serum of patients with breast cancer.

Neonatal Nav1.5 (nNav1.5) is the alternative splice variant of Nav1.5 and it has been widely associated with the progression of breast cancer. The immunological context of nNav1.5 with respect to breast cancer metastases remains unexplored. The presence of antibodies against nNav1.5 may highlight the immunogenicity of nNav1.5. Hence, the aim of the present study was to detect the presence of antineonatal Nav1.5 antibodies (antinNav1.5-Ab) in the serum of patients with breast cancer and to elucidate the effects of breast cancer therapy on its expression. A total of 32 healthy female volunteers and 64 patients with breast cancer were randomly recruited into the present study as the control and breast cancer group, respectively. Patients with breast cancer were divided equally based on their pre- and ongoing-treatment status. Serum samples were tested with in-house indirect enzyme-linked immunosorbent assay (ELISA) to detect antinNav1.5-Ab, CD25 (T regulatory cell marker) using an ELISA kit and Luminex assay to detect the expression of metastasis-associated cytokines, such as vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-10, IL-8, chemokine (C-C motif) ligand 2 and tumor necrosis factor-alpha (TNF-α) The mean difference in the expression of antinNav1.5-Ab among the three groups (control, pretreatment and ongoing-treatment) was significant (P=0.0005) and the pretreatment breast cancer group exhibited the highest expression. The concentration of CD25 was highest in the pretreatment breast cancer group compared with the control and ongoing-treatment groups. There was a significant positive correlation between antinNav1.5-Ab and IL-6 in the pretreatment group (r=0.7260; P=0.0210) and a significant negative correlation between antinNav1.5-Ab and VEGF in the ongoing-treatment group (r=-0.842; P-value=0.0040). The high expression of antinNav1.5-Ab in the pretreatment group was in accordance with the uninterrupted presence of metastasis and highlighted the immunogenicity of nNav1.5 whereas the low expression of antinNav1.5-Ab in the ongoing-treatment group reflected the efficacy of breast cancer therapy in eliminating metastases. The augmented manifestation of T regulatory cells in the pretreatment group highlighted the functional role of nNav1.5 in promoting metastasis. The parallel expression of antinNav1.5-Ab with the imbalanced expression of cytokines promoting metastasis (IL-8, IL-6 and TNF-α) and cytokines that prevent metastasis (IL-10) indicated the role of nNav1.5 in breast cancer growth. The expression of antinNav1.5-Ab in accordance to the metastatic microenvironment indicates the immunogenicity of the protein and highlights the influence of breast cancer therapy on its expression level.