Neuroprotection by acrolein sequestration through exogenously applied scavengers and endogenous enzymatic enabling strategies in mouse EAE model.

We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology. In this study, we found that the acrolein scavenger hydralazine (HZ), when applied from the day of induction, can suppress acrolein and alleviate motor and sensory deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. Furthermore, we also demonstrated that HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making potential anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a connection between acrolein and inflammation. We also found that in addition to HZ, phenelzine (PZ), a structurally distinct acrolein scavenger, can mitigate motor deficits in EAE when applied from the day of induction. This suggests that the likely chief factor of neuroprotection offered by these two structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization. Finally, up-and-down regulation of the function of aldehyde dehydrogenase 2 (ALDH2) in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a potential key role of ALDH2 in influencing acrolein levels, oxidative stress, inflammation, and behavior in EAE. These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.

Phenelzine protects against acetaminophen induced apoptosis in HepG2 cells.

Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized for treatment. The purpose of this study was to evaluate the effect and mechanisms of phenelzine, an FDA-approved antidepressant, on APAP-induced toxicity in HepG2 cells. The human liver hepatocellular cell line HepG2 was used to investigate APAP-induced cytotoxicity. The protective effects of phenelzine were determined by examining the cell viability, combination index calculation, Caspase 3/7 activation, Cytochrome c release, H2O2 levels, NO levels, GSH activity, PERK protein levels, and pathway enrichment analysis. Elevated H2O2 production and decreased glutathione (GSH) levels were indicators of APAP-induced oxidative stress. The combination index of 2.04 indicated that phenelzine had an antagonistic effect on APAP-induced toxicity. When compared to APAP alone, phenelzine treatment considerably reduced caspase 3/7 activation, cytochrome c release, and H2O2 generation. However, phenelzine had minimal effect on NO and GSH levels and did not alleviate ER stress. Pathway enrichment analysis revealed a potential connection between APAP toxicity and phenelzine metabolism. These findings suggested that phenelzine's protective effect against APAP-induced cytotoxicity could be attributed to the drug's capacity to reduce APAP-mediated apoptotic signaling.

Identification of core genes, critical signaling pathways, and potential drugs for countering BPA-induced hippocampal neurotoxicity in male mice.

Although the neurotoxicity of the common chemical bisphenol A (BPA) to the mouse hippocampus has been often reported, the mechanism underlying BPA-induced depression-like behavior in mice remains unclear. We evaluated BPA's role in inducing depressive-like behavior by exposing male mice to different BPA concentrations (0, 0.01, 0.1, and 1 µg/mL) and using the forced swimming test (FST) and tail suspension test (TST). We aimed to identify critical gene and anti-BPA-neurotoxicity compounds using RNA sequencing combined with bioinformatics analysis. Our results showed that 1 µg/mL BPA exposure increased mouse immobility during the FST and TST. Based on BPA-induced hippocampal transcriptome changes, we identified NADH: ubiquinone oxidoreductase subunit AB1 (Ndufab1) as a critical and potential therapeutic target gene, and Ndufab1 mRNA and protein levels were downregulated in the BPA-exposed groups. Furthermore, molecular docking identified phenelzine as a compound that could counteract BPA-related neurotoxicity. Conclusively, our analyses confirmed that BPA triggers depressive behavior in male mice by downregulating Ndufab1 expression and suggested that phenelzine might reduce BPA-induced neurotoxicity.

Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine.

The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the antidepressant. In the years and decades that followed, MAOIs have been used in the treatment of several pathologies including Parkinson's disease, Alzheimer's disease, and various cancers and as anti-inflammatory agents. Despite once enjoying widespread use, MAOIs have dwindled in popularity due to side effects, food-drug interactions, and the introduction of other antidepressant drug classes such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The recently published prescriber's guide for the use of MAOIs in treating depression has kindled a resurgence of their use in the clinical space. It is therefore timely to review key aspects of the four "classic" MAOIs: high-dose selegiline, isocarboxazid, phenelzine, and tranylcypromine. This review discusses their chemical synthesis, metabolism, pharmacology, adverse effects, and the history and importance of these drugs within the broader field of chemical neuroscience.

Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception.

Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil®). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.

Monoamine Oxidase Inhibitors for Trichotillomania: A Case Series.

PURPOSE/BACKGROUND: Despite several decades of research, there are no US Food and Drug Administration-approved medications for trichotillomania or medications generally approved in other geographical jurisdictions. Monoamine oxidase inhibitors show efficacy in the treatment of depression and some possible promise for obsessive compulsive disorder. METHODS/PROCEDURES: We present new data from a case series collected in a specialty clinical practice over a 4-year period. FINDINGS/RESULTS: In 5 treatment-resistant patients whose trichotillomania had not improved with at least 1 course of cognitive behavior therapy and trials of n -acetyl cysteine, an antipsychotic, and a serotonin selective reuptake inhibitor, 2 had marked clinical improvement (>40% improvement) on phenelzine, 1 improved on tranylcypromine, and 2 showed no improvement (<10%) on phenelzine. In 2 of the 3 patients who experienced improvement, there was co-occurring depression. IMPLICATIONS/CONCLUSIONS: Monoamine oxidase inhibitors in trichotillomania may deserve large-scale randomized controlled trials, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.

The Prescriber's Guide to the MAOI Diet-Thinking Through Tyramine Troubles.

This review article features comprehensive discussions on the dietary restrictions issued to patients taking a classic monoamine oxidase inhibitor (phenelzine, tranylcypromine, isocarboxazid), or high-dose (oral or transdermal) selegiline. It equips doctors with the knowledge to explain to their patients which dietary precautions are necessary, and why that is so: MAOIs alter the capacity to metabolize certain monoamines, like tyramine, which causes dose-related blood pressure elevations. Modern food production and hygiene standards have resulted in large reductions of tyramine concentrations in most foodstuffs and beverages, including many cheeses. Thus, the risk of consequential blood pressure increases is considerably reduced-but some caution remains warranted. The effects of other relevant biogenic amines (histamine, dopamine), and of the amino acids L-dopa and L-tryptophan are also discussed. The tables of tyramine data usually presented in MAOI diet guides are by nature unhelpful and imprecise, because tyramine levels vary widely within foods of the same category. For this reason, it is vital that doctors understand the general principles outlined in this guide; that way, they can tailor their instructions and advice to the individual, to his/her lifestyle and situation. This is important because the pressor response is characterized by significant interpatient variability. When all factors are weighed and balanced, the conclusion is that the MAOI diet is not all that difficult. Minimizing the intake of the small number of risky foods is all that is required. Many patients may hardly need to change their diet at all.

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine.

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite ß-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.

Time to Reconsider Monoamine Oxidase Inhibitors for Obsessive Compulsive Disorder?: A Case Series Using Phenelzine.

PURPOSE/BACKGROUND: Despite the availability of a range of efficacious evidence-based treatments for obsessive-compulsive disorder (OCD), not all patients experience sufficient benefit or are able to tolerate them in practice. Monoamine oxidase inhibitors (MAOIs) show efficacy in the treatment of depression and certain anxiety disorders (such as social anxiety disorder). METHODS/PROCEDURES: We survey the evidence base from case reports, and clinical trials, regarding use of MAOIs in OCD. We then present new data from a case series collected in routine clinical practice in a specialist clinical service. FINDINGS/RESULTS: In 9 treatment-resistant patients whose OCD had not improved with at least 2 standard treatment trials, 3 had marked clinical improvement (>35% improvement on YBOCS) on phenelzine, 3 had some improvement (15-34.9%), and 3 showed minimal or no improvement (<15%). In the 3 patients who experienced minimal/no improvement, 2 had discontinued early because of lack of tolerability, and the other patient discontinued after 4 weeks because of perceived lack of symptom benefit. IMPLICATIONS/CONCLUSIONS: We suggest that (1) MAOIs in treatment-resistant OCD require appropriate research scrutiny in large-scale randomized controlled trials; and (2) MAOIs merit consideration as a treatment option in individual cases of OCD, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.

Hemoglobin induces oxidative stress and mitochondrial dysfunction in oligodendrocyte progenitor cells.

Oligodendrocyte progenitor cells (OPCs) in the infant brain give rise to mature oligodendrocytes that myelinate CNS axons. OPCs are particularly vulnerable to oxidative stress that occurs in many forms of brain injury. One common cause of infant brain injury is neonatal intraventricular hemorrhage (IVH), which releases blood into the CSF and brain parenchyma of preterm infants. Although blood contains the powerful oxidant hemoglobin, the direct effects of hemoglobin on OPCs have not been studied. We utilized a cell culture system to test if hemoglobin induced free radical production and mitochondrial dysfunction in OPCs. We also tested if phenelzine (PLZ), an FDA-approved antioxidant drug, could protect OPCs from hemoglobin-induced oxidative stress. OPCs were isolated from Sprague Dawley rat pups and exposed to hemoglobin with and without PLZ. Outcomes assessed included intracellular reactive oxygen species levels using 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent dye, oxygen consumption using the XFe96 Seahorse assay, and proliferation measured by BrdU incorporation assay. Hemoglobin induced oxidative stress and impaired mitochondrial function in OPCs. PLZ treatment reduced hemoglobin-induced oxidative stress and improved OPC mitochondrial bioenergetics. The effects of hemoglobin and PLZ on OPC proliferation were not statistically significant, but showed trends towards hemoglobin reducing OPC proliferation and PLZ increasing OPC proliferation (P=0.06 for both effects). Collectively, our results indicate that hemoglobin induces mitochondrial dysfunction in OPCs and that antioxidant therapy reduces these effects. Therefore, antioxidant therapy may hold promise for white matter diseases in which hemoglobin plays a role, such as neonatal IVH.

Phase 2 trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer.

PURPOSE: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer. MATERIALS AND METHODS: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline. RESULTS: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). There was one episode of grade 4 hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment. CONCLUSIONS: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate-sensitive prostate cancer. Most treatment-related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer.

Phenelzine and Morphine Drug-Drug Interaction? A Literature Review.

The objectives of this manuscript are to describe a case report of a patient whose phenelzine maintenance therapy was discontinued due to concern for a phenelzine-morphine drug interaction, to review the available literature regarding the potential for this drug-drug interaction, and provide recommendations for this clinical scenario. A PubMed/MEDLINE literature search was conducted and all publications determined to be relevant to this case report were included. Literature describing in vitro data, case reports/human studies, and review articles concerning the interaction between morphine and monoamine oxidase inhibitors (MAOIs) were included. A total of 14 publications pertinent to the potential phenelzine-morphine interaction were included in this review including 5 in vitro studies, 4 human studies, and 6 review articles detailing the drug interaction profile between opioids and antidepressants. Of these publications, only a single case report of a potential drug interaction between morphine and phenelzine was identified. The literature suggesting a drug interaction between morphine and phenelzine is limited. The combination of phenelzine and morphine, with close monitoring for signs and symptoms of serotonin syndrome, is reasonable for patients with appropriate indications for both agents.

Unravelling the antimicrobial action of antidepressants on gut commensal microbes.

Over the past decade, there has been increasing evidence highlighting the implication of the gut microbiota in a variety of brain disorders such as depression, anxiety, and schizophrenia. Studies have shown that depression affects the stability of gut microbiota, but the impact of antidepressant treatments on microbiota structure and metabolism remains underexplored. In this study, we investigated the in vitro antimicrobial activity of antidepressants from different therapeutic classes against representative strains of human gut microbiota. Six different antidepressants: phenelzine, venlafaxine, desipramine, bupropion, aripiprazole and (S)-citalopram have been tested for their antimicrobial activity against 12 commensal bacterial strains using agar well diffusion, microbroth dilution method, and colony counting. The data revealed an important antimicrobial activity (bacteriostatic or bactericidal) of different antidepressants against the tested strains, with desipramine and aripiprazole being the most inhibitory. Strains affiliating to most dominant phyla of human microbiota such as Akkermansia muciniphila, Bifidobacterium animalis and Bacteroides fragilis were significantly altered, with minimum inhibitory concentrations (MICs) ranged from 75 to 800 µg/mL. A significant reduction in bacterial viability was observed, reaching 5 logs cycle reductions with tested MICs ranged from 400 to 600 µg/mL. Our findings demonstrate that gut microbiota could be altered in response to antidepressant drugs.

The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer.

The antiandrogen enzalutamide (Enz) has improved survival in castration resistant prostate cancer (CRPC) patients. However, most patients eventually develop Enz resistance that may involve inducing the androgen receptor (AR) splicing variant 7 (ARv7). Here we report that high expression of monoamine oxidase-A (MAO-A) is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, resensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC.

Protective effects of phenelzine administration on synaptic and non-synaptic cortical mitochondrial function and lipid peroxidation-mediated oxidative damage following TBI in young adult male rats.

Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations, with synaptic mitochondria being more vulnerable to injury-dependent consequences. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following TBI using phenelzine (PZ), an aldehyde scavenger, would preferentially protect synaptic mitochondria against LP-mediated damage in a dose- and time-dependent manner. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ (3-30 mg/kg) was administered subcutaneously (subQ) at different times post-injury. We found PZ treatment preserves both synaptic and non-synaptic mitochondrial bioenergetics at 24 h and that this protection is partially maintained out to 72 h post-injury using various dosing regimens. The results from these studies indicate that the therapeutic window for the first dose of PZ is likely within the first hour after injury, and the window for administration of the second dose seems to fall between 12 and 24 h. Administration of PZ was able to significantly improve mitochondrial respiration compared to vehicle-treated animals across various states of respiration for both the non-synaptic and synaptic mitochondria. The synaptic mitochondria appear to respond more robustly to PZ treatment than the non-synaptic, and further experimentation will need to be done to further understand these effects in the context of TBI.

Prediction of Severity of Drug-Drug Interactions Caused by Enzyme Inhibition and Activation.

Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by alterations of the plasma concentrations of one drug due to another drug inhibiting and/or inducing the metabolism or transporter-mediated disposition of the victim drug. Accurate assessment of clinically relevant DDIs for novel drug candidates represents one of the significant tasks of contemporary drug research and development and is important for practicing physicians. This work is a development of our previous investigations and aimed to create a model for the severity of DDIs prediction. PASS program and PoSMNA descriptors were implemented for prediction of all five classes of DDIs severity according to OpeRational ClassificAtion (ORCA) system: contraindicated (class 1), provisionally contraindicated (class 2), conditional (class 3), minimal risk (class 4), no interaction (class 5). Prediction can be carried out both for known drugs and for new, not yet synthesized substances using only their structural formulas. Created model provides an assessment of DDIs severity by prediction of different ORCA classes from the first most dangerous class to the fifth class when DDIs do not take place in the human organism. The average accuracy of DDIs class prediction is about 0.75.

Oral Phenelzine Treatment Mitigates Metabolic Disturbances in Mice Fed a High-Fat Diet.

Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT: Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.

Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer.

Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 (CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both in vitro and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.