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<p>Male infertility accounts for nearly half of all infertility cases globally, often resulting from oxidative stress and hormonal dysregulation. Conventional treatments offer limited efficacy, prompting interest in multi-target botanical therapies. This study evaluates a standardized polyherbal formulation (PHP), comprising <i>Mucuna pruriens</i>, <i>Anacyclus pyrethrum</i>, <i>Asparagus racemosus</i>, and <i>Tribulus terrestris</i>, for its protective effects against carbon tetrachloride (CCl<sub>4</sub>)-induced reproductive toxicity. In vitro, assays confirmed the antioxidant capacity of PHP, with dose-dependent radical scavenging in DPPH and FRAP assays and inhibition of GC-1/GC-2 spermatogonia cell proliferation. In vivo, PHP administration (100, 300, 500&#xa0;mg/kg) in carbon tetrachloride (CCl<sub>4</sub>)-exposed rats significantly reduced oxidative stress, including a 52% reduction in thiobarbituric acid reactive substances (TBARS), 47% reduction in hydrogen perocide (H<sub>2</sub>O<sub>2</sub>), and normalization of enzymatic antioxidants glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD); <i>P</i> &lt; 0.01 vs. CCl<sub>4</sub>. Hepatic injury biomarkedly improved, with alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin levels reduced by 40–55% compared to CCl<sub>4</sub> group (<i>P</i> &lt; 0.01). PHP also restored reproductive hormones testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and Prolactin levels elevated by 1.8 to 2.2-fold relative to intoxicated controls (<i>p</i> &lt; 0.05). Gene expression analysis revealed significant recovery, with sex-hormone-binding globulin (SHBG), protein kinase B (AKT1), and androgen receptor (AR) transcripts upregulated 2.0–2.5-fold in PHP-treated animals (<i>p</i> &lt; 0.05 vs. CCl<sub>4</sub>), approaching control values. Histopathological analysis confirmed structural restoration of testicular architecture, with reduced seminiferous tubule degeneration and active spermatogenesis. In silico docking identified luteolin and acacetin as key phytochemicals. Luteolin exhibits strong binding to the androgen receptor (AR: -9.6&#xa0;kcal/mol), AKT1 (-9.9&#xa0;kcal/mol), and SHBG (-9.5&#xa0;kcal/mol). It complied with Lipinski's rule of five and displayed favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Collectively, these findings suggest that PHP exerts multi-target protective effects against CCl<sub>4</sub>-induced male infertility by mitigating oxidative stress, restoring hormonal balance, and modulating key reproductive signaling pathways. Further mechanistic and clinical investigations are warranted to validate its therapeutic potential.</p> Graphical Abstract <p></p>

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Polyherbal Therapeutics Mitigate CCl4-Induced Testicular Toxicity through Modulation of SHBG, AKT1, and AR Pathways: An Integrated In Vitro, In Vivo, and In Silico Approach

  • 期刊论文

  • 发表日期：

    2025年11月13日

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  • Shoukat Hussain,
  • Alia Javed,
  • Dur EMaknoon Razia,
  • Naosheen Ashiq,
  • Muhammad Javid Iqbal,
  • Muhammad Jahangeer,
  • Uzma Shaheen,
  • Muhammad Yameen,
  • Asif Shahzad

摘要

Male infertility accounts for nearly half of all infertility cases globally, often resulting from oxidative stress and hormonal dysregulation. Conventional treatments offer limited efficacy, prompting interest in multi-target botanical therapies. This study evaluates a standardized polyherbal formulation (PHP), comprising Mucuna pruriens, Anacyclus pyrethrum, Asparagus racemosus, and Tribulus terrestris, for its protective effects against carbon tetrachloride (CCl4)-induced reproductive toxicity. In vitro, assays confirmed the antioxidant capacity of PHP, with dose-dependent radical scavenging in DPPH and FRAP assays and inhibition of GC-1/GC-2 spermatogonia cell proliferation. In vivo, PHP administration (100, 300, 500 mg/kg) in carbon tetrachloride (CCl4)-exposed rats significantly reduced oxidative stress, including a 52% reduction in thiobarbituric acid reactive substances (TBARS), 47% reduction in hydrogen perocide (H2O2), and normalization of enzymatic antioxidants glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD); P < 0.01 vs. CCl4. Hepatic injury biomarkedly improved, with alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin levels reduced by 40–55% compared to CCl4 group (P < 0.01). PHP also restored reproductive hormones testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and Prolactin levels elevated by 1.8 to 2.2-fold relative to intoxicated controls (p < 0.05). Gene expression analysis revealed significant recovery, with sex-hormone-binding globulin (SHBG), protein kinase B (AKT1), and androgen receptor (AR) transcripts upregulated 2.0–2.5-fold in PHP-treated animals (p < 0.05 vs. CCl4), approaching control values. Histopathological analysis confirmed structural restoration of testicular architecture, with reduced seminiferous tubule degeneration and active spermatogenesis. In silico docking identified luteolin and acacetin as key phytochemicals. Luteolin exhibits strong binding to the androgen receptor (AR: -9.6 kcal/mol), AKT1 (-9.9 kcal/mol), and SHBG (-9.5 kcal/mol). It complied with Lipinski's rule of five and displayed favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Collectively, these findings suggest that PHP exerts multi-target protective effects against CCl4-induced male infertility by mitigating oxidative stress, restoring hormonal balance, and modulating key reproductive signaling pathways. Further mechanistic and clinical investigations are warranted to validate its therapeutic potential.

Graphical Abstract