Effects of EGFR-TKI on epidermal melanin unit integrity: Therapeutic implications for hypopigmented skin disorders.

Epidermal melanin unit integrity is crucial for skin homeostasis and pigmentation. Epidermal growth factor (EGF) receptor (EGFR) is a pivotal player in cell growth, wound healing, and maintaining skin homeostasis. However, its influence on skin pigmentation is relatively unexplored. This study investigates the impact and underlying mechanisms of EGFR inhibitors on skin pigmentation. We evaluated EGF and EGFR expression in various skin cells using quantitative real-time PCR, Western blot, and immunofluorescence. EGF and EGFR were predominantly expressed in epidermal keratinocytes, and treatment with the EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and PD153035 significantly increased stem cell factor (SCF) and endothelin-1 (ET-1) expression in cultured keratinocytes. Enhanced melanocyte migration and proliferation were observed in co-culture, as evidenced by time-lapse live imaging and single-cell tracking assays. Furthermore, topical application of gefitinib to guinea pig dorsal skin induced increased pigmentation and demonstrated efficacy in mitigating rhododendrol-induced leukoderma. Suppression of EGF signaling indirectly enhanced skin pigmentation by upregulating SCF and ET-1 in epidermal keratinocytes. This novel mechanism highlights the pivotal role of EGF signaling in regulating skin pigmentation, and topical EGFR-TKI therapy at an appropriate dose may be a promising approach for depigmentation disorder management.

Rhizoma Paridis saponins attenuate Gram-negative bacteria-induced inflammatory acne by binding to KEAP1 and modulating Nrf2 and MAPK pathways.

Acne vulgaris represents a chronic inflammatory condition, the pathogenesis of which is closely associated with the altered skin microbiome. Recent studies have implicated a profound role of Gram-negative bacteria in acne development, but there is a lack of antiacne agents targeting these bacteria. Polyphyllins are major components of Rhizoma Paridis with great anti-inflammatory potential. In this study, we aimed to evaluate the antiacne effects and the underlying mechanisms of PPH and a PPH-enriched Rhizoma Paridis extract (RPE) in treating the Gram-negative bacteria-induced acne. PPH and RPE treatments significantly suppressed the mRNA and protein expressions of interleukin (IL)-1ß and IL-6 in lipopolysaccharide (LPS)-induced RAW 264.7 and HaCaT cells, along with the intracellular reactive oxygen species (ROS) generation. Furthermore, PPH and RPE inhibited the nuclear translocation of nuclear factor kappa-B (NF-κB) P65 in LPS-induced RAW 264.7 cells. Based on molecular docking, PPH could bind to kelch-like ECH-associated protein 1 (KEAP1) protein. PPH and RPE treatments could activate nuclear factor erythroid 2-related factor 2 (NRF2) and upregulate haem oxygenase-1 (HO-1). Moreover, RPE suppressed the mitogen-activated protein kinase (MAPK) pathway. Therefore, PPH-enriched RPE showed anti-inflammatory and antioxidative effects in vitro, which is promising for alternative antiacne therapeutic.

Global Transcriptome and Co-Expression Network Analyses Revealed Hub Genes Controlling Seed Size/Weight and/or Oil Content in Peanut.

Cultivated peanut (Arachis hypogaea L.) is an important economic and oilseed crop worldwide, providing high-quality edible oil and high protein content. Seed size/weight and oil content are two important determinants of yield and quality in peanut breeding. To identify key regulators controlling these two traits, two peanut cultivars with contrasting phenotypes were compared to each other, one having a larger seed size and higher oil content (Zhonghua16, ZH16 for short), while the second cultivar had smaller-sized seeds and lower oil content (Zhonghua6, ZH6). Whole transcriptome analyses were performed on these two cultivars at four stages of seed development. The results showed that ~40% of the expressed genes were stage-specific in each cultivar during seed development, especially at the early stage of development. In addition, we identified a total of 5356 differentially expressed genes (DEGs) between ZH16 and ZH6 across four development stages. Weighted gene co-expression network analysis (WGCNA) based on DEGs revealed multiple hub genes with potential roles in seed size/weight and/or oil content. These hub genes were mainly involved in transcription factors (TFs), phytohormones, the ubiquitin-proteasome pathway, and fatty acid synthesis. Overall, the candidate genes and co-expression networks detected in this study could be a valuable resource for genetic breeding to improve seed yield and quality traits in peanut.

Whole-process nursing management for laparo-gastroscopic esophagectomy.

Background: Advances in surgical, anesthesia, and nursing techniques have allowed the development of laparo-gastroscopic esophagectomy (LGE) as a minimally invasive treatment of esophageal cancer. This study summarizes the experience of patient whole-process nursing management for patients who received LGE. Methods: The implementation of LGE at Zhongshan Hospital, Fudan University, was initiated in June 2020. The procedure is indicated for patients with thoracic conditions that can compromise the outcomes of traditional surgical procedures, and is performed coordinately by thoracic surgeons and endoscopists. A whole-process nursing protocol covering peri-operative patient management was proposed based on the LGE procedure. The operative outcomes were analyzed in this study. Results: The data of 10 consecutive patients who received LGE and the whole-process nursing protocol were analyzed, and all patients were compliant with the nursing protocol. Intra-operatively, there were no complications or conversions to other surgical methods. Post-operatively, pulmonary complications occurred in 2 cases [1 patient experienced aspiration, underwent preventive tracheotomy, and was discharged on postoperative day (POD) 10; 1 patient developed a left pleural effusion requiring puncture and drainage, and was discharged on POD 7]. The 30-day mortality was not recorded from the primary LGE cohort. Conclusions: The whole-process nursing protocol showed safety and feasibility for patients who underwent LGE. In the future, more specialized and whole-process nursing management will be carried out for patients undergoing such operations.

A Lower Irradiation Dose of 308 nm Monochromatic Excimer Light Might Be Sufficient for Vitiligo Treatment: A Novel Insight Gained from In Vitro and In Vivo Analyses.

A 308 nm monochromatic excimer light (MEL) is widely used to treat patients with vitiligo. However, dose optimization still needs to be clarified. This study aimed to obtain objective evidence regarding various doses of MEL irradiation, induced cell level changes in vitro, and skin level alterations in vivo. Cultured human keratinocytes were irradiated with MEL using various doses. After irradiation at low doses, stem cell factor, endothelin-1, and glycoprotein nonmetastatic melanoma protein B, factors that activate and protect melanocytes, were found to be significantly elevated in keratinocytes. After irradiation using medium and high doses, inflammatory cytokines were induced. The amount of ATP released and the level of inflammasome activation, which are known to be related to interleukin-1ß activation, were also increased. The back skin of guinea pigs and mice were irradiated with MEL at varying doses. After irradiation, an increase of epidermal melanin and epidermal melanocytes was confirmed, using the minimal erythemal dose or less. In rhododendrol-induced leukoderma guinea pigs, a much lower dose of MEL irradiation was effective, when compared with the effective dose for control guinea pigs. Our results suggest that a lower irradiation dose of MEL might be sufficient and more suitable for repigmentation in vitiligo treatment.

GPNMB Extracellular Fragment Protects Melanocytes from Oxidative Stress by Inhibiting AKT Phosphorylation Independent of CD44.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that plays an important role in cancer metastasis and osteoblast differentiation. In the skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in melanosome formation. In our previous study, GPNMB was also found to be expressed in skin epidermal keratinocytes. In addition, decreased GPNMB expression was observed in the epidermis of lesional skin of patients with vitiligo. However, the exact role of keratinocyte-derived GPNMB and its effect on vitiligo is still unknown. In this study, we demonstrated that GPNMB expression was also decreased in rhododendrol-induced leukoderma, as seen in vitiligo. The extracellular soluble form of GPNMB (sGPNMB) was found to protect melanocytes from cytotoxicity and the impairment of melanogenesis induced by oxidative stress. Furthermore, the effect of rGPNMB was not altered by the knockdown of CD44, which is a well-known receptor of GPNMB, but accompanied by the suppressed phosphorylation of AKT but not ERK, p38, or JNK. In addition, we found that oxidative stress decreased both transcriptional GPNMB expression and sGPNMB protein expression in human keratinocytes. Our results suggest that GPNMB might provide novel insights into the mechanisms related to the pathogenesis of vitiligo and leukoderma.

Herb Sanqi-Derived Compound K Alleviates Oxidative Stress in Cultured Human Melanocytes and Improves Oxidative-Stress-Related Leukoderma in Guinea Pigs.

Sanqi, a traditional Chinese herb, is widely used for cardiovascular diseases, and its neuroprotective effects against oxidative stress were recently discovered. The purpose of this study was to investigate whether Sanqi-derived compound K (Sanqi-CK), an active metabolite of Sanqi, could protect melanocytes from oxidative stress. Cultured human primary skin epidermal melanocytes (HEMn-MPs) were treated with hydrogen peroxide (H2O2) in the presence or absence of Sanqi-CK. Sanqi-CK exhibited protective effects against H2O2-induced cell death by reducing oxidative stress. In addition, treatment with Sanqi-CK reversed the decreased glutathione reductase activity and decreased ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) seen in H2O2-treated melanocytes. Furthermore, topical application of Sanqi-CK alleviated leukoderma in guinea pigs, a disorder characterized by melanocyte cell death resulting from rhododendrol-induced oxidative stress. Taken together, these data suggest that Sanqi-CK protects melanocytes against oxidative stress, and its protective effects are associated with modulating the redox balance between GSH and GSSG and activating glutathione reductase. Thus, Sanqi-CK may be a good candidate for preventing melanocyte loss in oxidative-stress-associated pigmentary disorders.

Ginsenoside Rb1 exerts antidepressant-like effects via suppression inflammation and activation of AKT pathway.

Depression-like behaviors caused by chronic stress are related to inflammation and microglia activation. Antidepressant therapy may contribute to inhibiting inflammation responses and microglia activation. Ginsenoside Rb1 (GRb1) is known to display antidepressant-like effect on chronic unpredictable mild stress-induced depressive rats. However, the antidepressant-like effects of GRb1 on chronic restraint stress (CRS) mice and the potential anti-inflammatory mechanisms are unclear. Here, we focused on the molecular mechanisms related to inhibition of inflammation response and the protection on microglia. Our results showed that GRb1 had an antidepressant effects via relieving the depression-like behaviors in CRS model. Furthermore, GRb1 increased the protein expressions of brain-derived neurotrophic factor and phospho- protein kinase B/ protein kinase B (p-AKT/AKT), and decreased the protein expressions of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α) and ionized calcium binding adapter molecule 1 in hippocampus, reduced the levels IL-1ß and TNF-α in serum. Finally, GRb1 lowered the protein expressions of IL-1ß and TNF-α in BV-2 microglia induced by lipopolysaccharides. Taken together, the results indicate that GRb1 prevents CRS-induced depression-like behaviors in mice, which may be related to anti-inflammatory effects in hippocampus, serum and microglia and activation of AKT pathway.

Environmental factors and microbial communities jointly regulate biological dephosphorization process in pond-ditch circulation systems (PDCSs) for rural wastewater treatment.

Pond-ditch circulation systems (PDCSs) were proved to be an appropriate operation selection in rural wastewater remediation. However, the biological dephosphorization process has not been investigated and quantified in PDCSs. In this study, PDCSs exhibited higher total phosphorus (TP) removal efficiencies (77.8%-97.4%). The activities of polyphosphate kinase (PPK) and exopolyphosphatase (PPX) tightly associated with phosphorus biological removal ranged from 0.356 to 11.844 µmol hydroxamic acid min-1 mg-1 protein, and 0.008 to 0.446 µmol p-nitrophenol min-1 mg-1 protein, respectively. Both PPK and PPX in PDCSs increased with time, peaked at day 30, and then declined, and were negatively correlated with sediment total phosphorus (STP), sediment inorganic phosphorus (SIP), P bound to Al/Fe/Mn oxides and hydroxides (NaOH-P), P associated with Ca (HCl-P), and organic matter (OM) (p < 0.05). Results of high-throughput sequencing suggested that Bacillus (0.46%-19.77%) and Clostridium (0.40%-21.0%) genus might be the predominant groups in phosphorus aerobic biological absorption; while Geobacter (0.15%-4.74%) and Arthrobacter (0.03%-4.01%) genus dominated in anaerobic biological process. The RDA results showed that compared to the ditch, temperature (W-temp), TP, dissolved oxygen (DO), NaOH-P, and OM had stronger effects on microbial community structures in two ponds at day 30 than those at days 14 and 60. Path analysis further indicated that STP could impact PPK and PPX activities in PDCSs both directly and indirectly via altering the relative abundances of bacteria taxa. We found that the indirect effects of W-temp, DO, and OM on PPK and PPX activities mediated through modulating the relative abundances of bacteria taxa and STP. Our findings provide evidences that biological dephosphorization process in PDCSs are jointly modulated by environmental factors and microbial communities. The less-studied W-temp, DO, STP, and OM modulating the relative abundances of bacteria taxa was an existing but previously underestimated indirect pathway influencing on biological dephosphorization process in PDCSs.

GPNMB is expressed in human epidermal keratinocytes but disappears in the vitiligo lesional skin.

GPNMB is involved in multiple cellular functions including cell adhesion, stress protection and stem cell maintenance. In skin, melanocyte-GPNMB is suggested to mediate pigmentation through melanosome formation, but details of keratinocyte-GPNMB have yet to be well understood. We confirmed the expression of GPNMB in normal human epidermal keratinocytes (NHEKs) by reducing the expression using siRNA. A higher calcium concentration of over 1.25 mM decreased the GPNMB expression. Histological staining showed that GPNMB was expressed in the basal layer of normal skins but completely absent in vitiligo skins. The normal expression of GPNMB in nevus depigmentosus skin suggested that lack of GPNMB is characteristic of vitiligo lesional skins. IFN-γ and IL-17A, two cytokines with possible causal roles in vitiligo development, inhibited GPNMB expression in vitro. Approximately 4-8% of the total GPNMB expressed on NHEKs were released possibly by ADAM 10 as a soluble form, but the process of release was not affected by the cytokines. The suppressive effect of IFN-γ on GPNMB was partially via IFN-γ/JAK2/STAT1 signaling axis. Decreased GPNMB expression in keratinocytes may affect melanocyte maintenance or survival against oxidative stress although further studies are needed. These findings indicate a new target for vitiligo treatment, focusing on the novel role of IFN-γ and IL-17 in downregulating keratinocyte-GPNMB.

Local Epidermal Endocrine Estrogen Protects Human Melanocytes against Oxidative Stress, a Novel Insight into Vitiligo Pathology.

As the outermost barrier of the body, skin is a major target of oxidative stress. In the brain, estrogen has been reported synthesized locally and protects neurons from oxidative stress. Here, we explored whether estrogen is also locally synthesized in the skin to protect from oxidative stress and whether aberrant local estrogen synthesis is involved in skin disorders. Enzymes and estrogen receptor expression in skin cells were examined first by quantitative real-time PCR and Western blot analyses. Interestingly, the estrogen synthesis enzyme was mainly localized in epidermal keratinocytes and estrogen receptors were mainly expressed in melanocytes among 13 kinds of cultured human skin cells. The most abundant estrogen synthesis enzyme expressed in the epidermis was 17ß-hydroxysteroid dehydrogenase 1 (HSD17ß1) localized in keratinocytes, and the most dominant estrogen receptor expressed in the epidermis was G protein-coupled estrogen receptor 1 (GPER1) in melanocytes. To investigate whether keratinocyte-derived estradiol could protect melanocytes from oxidative stress, cultured human primary epidermal melanocytes (HEMn-MPs) were treated with H2O2 in the presence or absence of 17ß estradiol or co-cultured with HSD17ß1 siRNA-transfected keratinocytes. Keratinocyte-derived estradiol exhibited protective effects against H2O2-induced cell death. Further, reduced expression of HSD17ß1 in the epidermis of skin from vitiligo patients was observed compared to the skin from healthy donors or in the normal portions of the skin in vitiligo patients. Our results suggest a possible new target for interventions that may be used in combination with current therapies for patients with vitiligo.

Integrating Multifaceted Information to Predict Mycobacterium tuberculosis-Human Protein-Protein Interactions.

Tuberculosis (TB) is one of the biggest infectious disease killers caused by Mycobacterium tuberculosis (MTB). Studying the protein-protein interactions (PPIs) between MTB and human can deepen our understanding of the pathogenesis of TB and offer new clues to the treatment against MTB infection, but the experimentally validated interactions are especially scarce in this regard. Herein we proposed an integrated framework that combined template-, domain-domain interaction-, and machine learning-based methods to predict MTB-human PPIs. As a result, we established a network composed of 13 758 PPIs including 451 MTB proteins and 3167 human proteins ( http://liulab.hzau.edu.cn/MTB/ ). Compared to known human targets of various pathogens, our predicted human targets show a similar tendency in terms of the network topological properties and enrichment in important functional genes. Additionally, these human targets largely have longer sequence lengths, more protein domains, more disordered residues, lower evolutionary rates, and older protein ages. Functional analysis demonstrates that these proteins show strong preferences toward the phosphorylation, kinase activity, and signaling transduction processes and the disease and immune related pathways. Dissecting the cross-talk among top-ranked pathways suggests that the cancer pathway may serve as a bridge in MTB infection. Triplet analysis illustrates that the paired targets interacting with the same partner are adjacent to each other in the intraspecies network and tend to share similar expression patterns. Finally, we identified 36 potential anti-MTB human targets by integrating known drug target information and molecular properties of proteins.

Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30).

BACKGROUND Regorafenib (RGF) is the drug of choice for treating hepatic carcinoma (HCC), but the drug has drawbacks due to resistance and associated adverse effects. Thus, it becomes crucial to understand the causal 'map' of the resistance conferred by RGF, so that its clinical potency can be amplified, resulting in enhanced efficacy with reduced adverse effects. Metformin (MTF) has been reported to target NLK (Nemo-like kinase) to inhibit non-small lung cancer cells. Based on the literature, the present investigation was carried out to reveal the effect of RGF and MTF, with an expectation that MTF can synergize therapeutic potential as well reduce chances of resistance. MATERIAL AND METHODS Protein expression of hypoxia inducible factors (HIF)-2α, 30 kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK were assessed by Western blot analysis. RGF and MTF were exposed to MHCC97H cell and proliferation was quantified by assay of cell viability. Gene silencing and chromatin immunoprecipitation assay were done to reveal the relationship between TIP30 and HIF-2α. The impact of RGF and MTF together on postoperative recurrence and lung metastasis of hepatocellular carcinoma was investigated using tumor engrafted mice after administration of MTF and RGF once daily for 35 days. Immunohistochemistry was used to reveal CD31, Ki67, and TUNEL. RESULTS The results suggested MTF-RGF combination lowered expression of HIF-2α gene silencing and suggested increased TIP30 after reduction of HIF-2α. The chromatin immunoprecipitation study indicated that under hypoxia, HIF-2α could bind with TIP30 promoter. Cell number quantification (CCK8), viable cell count, and apoptosis data (using Annexin V-FITC) indicated co-administration of RGF and MTF reduced cell proliferation, encouraging cell apoptosis, and reduced epithelial-mesenchymal transition course. Thus, in orthotopic mice, the RGF-MTF combination exhibited substantial reduction of HCC in lung metastasis and postoperative relapse. CONCLUSIONS MTF can enhance the potential of RGF and inhibit the recurrence and metastasis of HCC after postoperative liver section by regulating the levels of TIP30 and HIF-2α.

Uncoupling of ER/Mitochondrial Oxidative Stress in mTORC1 Hyperactivation-Associated Skin Hypopigmentation.

Accumulating evidence has described the involvement of mTORC1 signaling in pigmentation regulation; however, the precise mechanism is not fully understood. Here, we generated mice with conditional deletion of the mTORC1 suppressor Tsc2 in melanocytes. It resulted in constitutive hyperactivation of mTORC1 and reduced skin pigmentation. Mechanistically, neither the number of melanocytes nor the expression of melanogenesis-related enzymes was decreased; however, endoplasmic reticulum and mitochondrial oxidative stress and lower melanization in melanosomes were observed. By contrast, abrogation of mTORC1 by rapamycin completely reversed the reduced pigmentation, and alleviation of endoplasmic reticulum stress by SMER28 or 4-phenylbutyrate (PBA) or alleviation of mitochondrial oxidative stress by administration of adenosine triphosphate partially reversed the reduced pigmentation in these mice. In addition, we showed that these mechanisms were involved in reduced pigmentation of TSC2 small interfering RNA-transfected cultured human primary melanocytes and skin lesions of patients with the TSC gene mutation.

Dysregulation of autophagy in melanocytes contributes to hypopigmented macules in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) gene mutations lead to constitutive activation of the mammalian target of rapamycin (mTOR) pathway, resulting in a broad range of symptoms. Hypopigmented macules are the earliest sign. Although we have already confirmed that topical rapamycin treatment (an mTOR inhibitor) protects patients with TSC against macular hypopigmentation, the pathogenesis of such lesions remains poorly understood. OBJECTIVE: Recently emerging evidence supports a role for autophagy in skin pigmentation. Herein, we investigated the impact of autophagic dysregulation on TSC-associated hypopigmentation. METHODS: Skin samples from 10 patients with TSC, each bearing characteristic hypopigmented macules, and 6 healthy donors were subjected to immunohistochemical and electron microscopic analyses. In addition, TSC2-knockdown (KD) was investigated in human epidermal melanocytes by melanin content examination, real-time PCR, western blotting analyses, and intracellular immunofluorescence staining. RESULTS: Activation of the mTOR signaling pathway decreased melanocytic pigmentation in hypopigmented macules of patients with TSC and in TSC2-KD melanocytes. In addition, LC3 expression (a marker of autophagy) and autophagosome counts increased, whereas, intracellular accumulation of autophagic degradative substrates (p62 and ubiquitinated proteins) was evident in TSC2-KD melanocytes. Furthermore, depigmentation in TSC2-KD melanocytes was accelerated by inhibiting autophagy (ATG7-KD or bafilomycin A1-pretreatment) and was completely reversed by induction of autophagy via mTOR-dependent (rapamycin) or mTOR-independent (SMER28) exposure. Finally, dysregulation of autophagy, marked by increased LC3 expression and accumulation of ubiquitinated proteins, was also observed in melanocytes of TSC-related hypopigmented macules. CONCLUSION: Our data demonstrate that melanocytes of patients with TSC display autophagic dysregulation, which thereby reduced pigmentation, serving as the basis for the hypomelanotic macules characteristic of TSC.

Serum cystatin C is associated with large cerebral artery stenosis in acute ischemic stroke.

Large cerebral artery stenosis is a major cause of acute ischemic stroke (AIS); however, the correlation between serum cystatin C (CysC) and the stenosis of large cerebral arteries in patients with AIS has not been established. We performed a retrospective review of acute ischemic stroke patients, who were examined by cerebral digital subtraction angiography(DSA). Participants (252 cases) included 131 patients without stenosis and 121 patients with large cerebral artery stenosis. Serum CysC levels in patients with large cerebral artery stenosis were much higher than that of control subjects (p<0.001). However, serum CysC levels were not related to the location of stenosis. Further, logistic regression analyses showed that increased serum CysC was an independent risk factor of large cerebral artery stenosis in patients with acute ischemic stroke. Total participants were subdivided into quintiles based on serum CysC levels. Compared with the first quintile, the odds ratios of risk for large cerebral artery stenosis in the fourth and the fifth quintile were 1.26 (p<0.05) and 4.71(p<0.05) respectively, after the adjustment for age, sex, and smoking, hypertension, type 2 diabetes mellitus(DM), dyslipidemia, creatinine(Cr), urea, uric acid, and C reactive protein(CRP). Therefore, a significant positive correlation was observed between elevated serum CysC levels and large cerebral artery stenosis in patients with acute ischemic stroke. In summary, our findings provide new insights into the correlation between increased serum CysC and large cerebral artery stenosis in patients with acute ischemic stroke.

Low-Level Laser Irradiation Improves Depression-Like Behaviors in Mice.

Major depressive disorder (MDD) is one of the leading forms of psychiatric disorders, characterized by aversion to mobility, neurotransmitter deficiency, and energy metabolic decline. Low-level laser therapy (LLLT) has been investigated in a variety of neurodegenerative disorders associated with mitochondrial dysfunction and functional impairments. The goal of this study was to examine the effect of LLLT on depression-like behaviors and to explore the potential mechanism by detecting mitochondrial function following LLLT. Depression models in space restriction mice and Abelson helper integration site-1 (Ahi1) knockout (KO) mice were employed in this work. Our results revealed that LLLT effectively improved depression-like behaviors, in the two depression mice models, by decreasing immobility duration in behavioral despair tests. In addition, ATP biosynthesis and the level of mitochondrial complex IV expression and activity were significantly elevated in prefrontal cortex (PFC) following LLLT. Intriguingly, LLLT has no effects on ATP content and mitochondrial complex I-IV levels in other tested brain regions, hippocampus and hypothalamus. As a whole, these findings shed light on a novel strategy of transcranial LLLT on depression improvement by ameliorating neurotransmitter abnormalities and promoting mitochondrial function in PFC. The present work provides concrete groundwork for further investigation of LLLT for depression treatment.