Fig 1: Effect of cadmium and/or linagliptin administration on the testicular pro-inflammatory response and HMGB1/TLR4/NF-?B pathway in rats. The co-treatment with linagliptin lowered testicular TNF-a (A) and augmented IL-10 (B) alongside curtailing the testicular HMGB1/TLR4/NF-?B pathway that was stimulated by cadmium metal. The later event was demonstrated by downregulated protein expression of the high mobility group box protein 1 (HMGB1; (C)), toll-like receptor 4 (TLR4; (D)), and nuclear expression of the nuclear factor kappa B (NF-?Bp65; (E)). * p < 0.05, ** p < 0.01, and *** p < 0.001 show statistical significance compared to the group of control rats; # p < 0.05, and ## p < 0.01 show statistical significance compared to the group of cadmium-intoxicated rats. Values are stated as the mean ± standard error of the mean for 6 animals per group. LIN, linagliptin; Cd, cadmium chloride.
Fig 2: An outline of the mechanisms that intercede linagliptin’s amelioration of cadmium-evoked testicular impairment. According to the current findings, the proposed mechanisms are: (A,A') Curbing the inflammatory responses, including HMGB1/TLR4/NF-?B and NLRP3/caspase-1/IL-1ß pathways in the testes of cadmium-intoxicated rats. (B) Stimulation of the autophagy response with activation of AMPK/mTOR pathway in the testes of cadmium-intoxicated rats. (C) Interference with the pro-apoptotic responses, including Bax downregulation, Bcl2 upregulation, and caspase 3 inhibition in the testes of cadmium-intoxicated rats. Of note, the beneficial outcomes of linagliptin are mainly due to DPP-4 inhibition, which has been linked to marked anti-inflammatory/immune-modulatory actions [21,22]. DPP-4 inhibition triggers several downstream targets, including the upregulated protein expression of SDF-1a, which prompts intensified testicular repair and regeneration [21,33]. Moreover, the beheld activation of autophagy may suppress the pro-inflammatory responses/NLRP3 inflammasome activation [12,20] and limit the proapoptotic responses [12,17,19] in the testes of cadmium-intoxicated rats. Activation is represented by solid arrows, whereas inhibition is depicted by blunt arrows. The question marks denote unknown mechanisms.
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