Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8⁺ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8⁺ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8⁺ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

Albizzia julibrissin is empirically used as an antidepressant in clinical practice. Preclinical studies have indicated that its total extracts or bioactive constituents exerted antidepressant-like responses in animal models, providing the molecular basis to reveal its underlying mechanism of action. While attempts have been made to understand the antidepressant effect of A. julibrissin, many fundamental questions regarding its mechanism of action remain to be addressed at the molecular and systems levels. In this review, we conclusively discussed the mechanism of action of A. julibrissin and A. julibrissin formulae by reviewing recent preclinical and clinical studies conducted by using depressive animal models and depressive patients. Several representative bioactive constituents and formulae were highlighted as examples, and their mechanisms of action were discussed. In addition, some representative A. julibrissin formulae that have been shown to be compatible with conventional antidepressants in clinical practice were also reviewed. Furthermore, we discussed the future research directions to reveal the underlying mechanism of A. julibrissin at the molecular and systems levels in depression treatment. The integrated study using both the molecular and systematic approaches is required not only for improving our understanding of its molecular basis and mechanisms of action, but also for providing a way to discover novel agents or approaches for the effective and systematic treatment of depression.

Significance: The NSS (neurotransmitter sodium symporter) or SLC6 family comprises a group of plasma membrane transport proteins that includes transporters for amino acid and amine neurotransmitters. Transporters in this family use transmembrane ion gradients as driving forces for intracellular accumulation of their substrates. Although all NSS transporters use Na ⁺ ions for transport, a large subset also requires Cl ⁻ ions. Na ⁺ is known to act at two sites on these proteins to stabilize an outward-open conformation and to interact with substrate to facilitate transition to an inward-open conformation, but the role of Cl ⁻ has not previously been established. We show here how Cl ⁻ acts independently from substrate to facilitate the conversion of an NSS transporter for glycine from outward- to inward-open states.

The neuroimmune and neuroendocrine systems are two critical biological systems in the pathogenesis of depression. Clinical and preclinical studies have demonstrated that the activation of the neuroinflammatory response of the immune system and hyperactivity of the hypothalamus–pituitary–adrenal (HPA) axis of the neuroendocrine system commonly coexist in patients with depression and that these two systems bidirectionally regulate one another through neural, immunological, and humoral intersystem interactions. The neuroendocrine-immune network poses difficulties associated with the development of antidepressant agents directed toward these biological systems for the effective treatment of depression. On the other hand, multidrug and multitarget Chinese Herbal Medicine (CHM) has great potential to assist in the development of novel medications for the systematic pharmacotherapy of depression. In this narrative essay, we conclusively analyze the mechanisms of action of CHM antidepressant constituents and formulas, specifically through the modulation of the neuroendocrine-immune network, by reviewing recent preclinical studies conducted using depressive animal models. Some CHM herbal constituents and formulas are highlighted as examples, and their mechanisms of action at both the molecular and systems levels are discussed. Furthermore, we discuss the crosstalk of these two biological systems and the systems pharmacology approach for understanding the system-wide mechanism of action of CHM on the neuroendocrine-immune network in depression treatment. The holistic, multidrug, and multitarget nature of CHM represents an excellent example of systems medicine in the effective treatment of depression.

Albizia julibrissin Durazz. is one of the most common herbs used for depression and anxiety treatment, but its molecular basis and mechanism of action as an antidepressant or anxiolytic drug are not understood. In this study, we separated and identified two lignan glycosides that inhibit serotonin transporter (SERT) noncompetitively by decreasing V_max with little change in K_m for its fluorescence substrate. In addition, treatment with lignan glycosides did not alter total and cell surface expression levels of the transporter protein. The two compounds decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of SERT. These results are consistent with molecular docking for the association of the lignan glycosides to the allosteric site in SERT. The present work supports the proposal that these compounds act on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs.

Lycium barbarum extracts have been shown to be effective in male reproductive protection and male infertility. However, its role in enhancing testicular function, such as testosterone synthesis, and the potential mechanism remain to be understood. To elucidate the effects of Lycium barbarum glycopeptide (LbGp) on testosterone synthesis, we isolated primary Leydig cells (LCs) from testes and performed RNA sequencing (RNA seq) on LCs treated with LbGp. In this study, we demonstrated that LbGp promoted testosterone synthesis in LCs both in vivo and in vitro. We also demonstrated that LbGp elevated adenosine 5′-triphosphate (ATP) synthesis and cell proliferation by enhancing glucose metabolism. Mechanistically, LbGp upregulated testosterone synthesis by suppressing TGF-β pathway and enhancing the expression of steroidogenic genes: Cyp11a1, Hsd3b1, Hsd17b3, Star, and Sf-1. These findings indicate that LbGp plays an important role in enhancing testicular function and promoting testosterone synthesis.