Preparation of glycopeptide-modified pH-sensitive liposomes for promoting antigen cross-presentation and induction of antigen-specific cellular immunity.

Cross-presentation, exogenous antigen presentation onto major histocompatibility complex class I molecules on antigen presenting cells, is crucially important for inducing antigen-specific cellular immune responses for cancer immunotherapy and for the treatment of infectious diseases. One strategy to induce cross-presentation is cytosolic delivery of an exogenous antigen using fusogenic or endosomolytic molecule-introduced nanocarriers. Earlier, we reported liposomes modified with pH-responsive polymers to achieve cytosolic delivery of an antigen. Polyglycidol-based or polysaccharide-based pH-responsive polymers can provide liposomes with delivery performance of antigenic proteins into cytosol via membrane fusion with endosomes responding to acidic pH, leading to induction of cross-presentation. Mannose residue was introduced to pH-responsive polysaccharides to increase uptake selectivity to antigen presenting cells and to improve cross-presentation efficiency. However, direct introduction of mannose residue into pH-responsive polysaccharides suppressed cytoplasmic delivery performance of liposomes. To avoid such interference, for this study, mannose-containing glycans were incorporated separately into pH-responsive polysaccharide-modified liposomes. Soybean agglutinin-derived glycopeptide was used as a ligand for lectins on antigen presenting cells. Incorporation of glycopeptide significantly increased the cellular uptake of liposomes by dendritic cell lines and increased cross-presentation efficiency. Liposomes incorporated both glycopeptide and pH-responsive polysaccharides exhibited strong adjuvant effects in vitro and induced the increase of dendritic cells, M1 macrophages, and effector T cells in the spleen. Subcutaneous administration of these liposomes induced antigen-specific cellular immunity, resulting in strong therapeutic effects in tumor-bearing mice. These results suggest that separate incorporation of glycopeptides and pH-responsive polysaccharides into antigen-loaded liposomes is an effective strategy to produce liposome-based nanovaccines to achieve antigen cross-presentation and induction of cellular immunity towards cancer immunotherapy.

Synthetic Biology Facilitates Semisynthetic Development of Type V Glycopeptide Antibiotics Targeting Vancomycin-Resistant Enterococcus.

The continued efficacy of glycopeptide antibiotics (GPAs) against Gram-positive bacteria is challenged by the emergence and spread of GPA-resistant pathogens, particularly vancomycin-resistant enterococci (VRE). The growing frequency of GPA resistance propels the need for innovative development of more effective antibiotics. Unlike canonical GPAs like vancomycin, Type V GPAs adopt a distinct mode of action by binding peptidoglycan and blocking the activity of autolysins essential for cell division, rendering them a promising class of antibiotics for further development. In this study, the Type V GPA, rimomycin A, was modified to generate 32 new analogues. Compound 17, derived from rimomycin A through N-terminal acylation and C-terminal amidation, exhibited improved anti-VRE activity and solubility. In a VRE-A neutropenic thigh infection mouse model, compound 17 significantly lowered the bacterial load by 3-4 orders of magnitude. This study sets the stage to develop next-generation GPAs in response to growing VRE infections.

Lycium barbarum (Wolfberry) glycopeptide prevents stress-induced anxiety disorders by regulating oxidative stress and ferroptosis in the medial prefrontal cortex.

BACKGROUND: Lycium barbarum (Wolfberry) extract has been shown to be effective in neuroprotection against aging or neural injury. Knowledge of its potential roles and biological mechanisms in relieving mental disorders, however, remains limited. PURPOSE: To investigate the potency of Lycium barbarum glycopeptide (LbGp) in alleviating anxiety disorders and the related biological mechanisms. METHODS: LbGp was administrated to mice subjected to 14 days of chronic restrain stress (CRS) via the intragastric route. The anxiolytic effect was evaluated by a battery of behavioral assays. The morphology of neurons and glial cells was evaluated, and cortical neuronal calcium transients were recorded in vivo. The molecular mechanism of LbGp was also investigated. RESULTS: LbGp effectively relieved anxiety-like and depressive behaviors under CRS. Mechanistic studies further showed that LbGp treatment relieved oxidative stress and lipid peroxidation in the medial prefrontal cortex (mPFC). In particular, the ferroptosis pathway was inhibited by LbGp, revealing a previously unrecognized mechanism of the anxiolytic role of wolfberry extract. CONCLUSION: In summary, our results supported the future development of LbGp to prevent or ameliorate stress-induced anxiety disorders. Our work provides a promising strategy for early intervention for pateitents with mental disorders by applying natural plant extracts.

Collagen Glycopeptides from Transglutaminase-Induced Glycosylation Exhibit a Significant Salt Taste-Enhancing Effect.

This study aimed to prepare collagen glycopeptides by transglutaminase-induced glycosylation and to explore their salt taste-enhancing effects and mechanism. Collagen glycopeptides were obtained by Flavourzyme-catalyzed hydrolysis, followed by transglutaminase-induced glycosylation. The salt taste-enhancing effects of collagen glycopeptides were evaluated by sensory evaluation and an electronic tongue. LC-MS/MS and molecular docking technologies were employed to investigate the underlying mechanism responsible for the salt taste-enhancing effect. The optimal conditions were 5 h for enzymatic hydrolysis, 3 h for enzymatic glycosylation, and 1.0% (E/S, w/w) for transglutaminase. The grafting degree of collagen glycopeptides was 26.9 mg/g, and the salt taste-enhancing rate was 59.0%. LC-MS/MS analysis revealed that Gln was the glycosylation modification site. Molecular docking confirmed that collagen glycopeptides can bind to salt taste receptors epithelial sodium channel protein and transient receptor potential vanilloid 1 through hydrogen bonds and hydrophobic interaction. Overall, collagen glycopeptides have a significant salt taste-enhancing effect, which contributes to the application of collagen glycopeptides for salt reduction without compromising taste in the food industry.

Reprogramming Hypoxic Tumor-Associated Macrophages by Nanoglycoclusters for Boosted Cancer Immunotherapy.

The tumor-associated macrophages (TAMs) in intratumoral hypoxic regions are key drivers of immune escape. Reprogramming the hypoxic TAMs to antitumor phenotype holds great therapeutic benefits but remains challenging for current drugs. Here, an in situ activated nanoglycocluster is reported to realize effective tumor penetration and potent repolarization of hypoxic TAMs. Triggered by the hypoxia-upregulated matrix metalloproteinase-2 (MMP-2), the nanoglycocluster is self-assembled from the administered mannose-containing precursor glycopeptides and presents densely-arrayed mannoses to multivalently engage with mannose receptors on M2-like TAMs for efficient phenotype switch. By virtue of the high diffusivity of precursor glycopeptides due to their low molecular mass and weak affinity with TAMs in perivascular regions, the nanoglycoclusters are capable of substantially accumulating in hypoxic areas to strongly interact with local TAMs. This enables the efficient repolarization of overall TAMs with a higher rate than the small-molecule drug R848 and CD40 antibody, and beneficial therapeutic effects in mouse tumor models especially when combining with PD-1 antibody. This on-demand activated immunoagent is endowed with tumor-penetrating properties and inspires the design of diverse intelligent nanomedicines for hypoxia-related cancer immunotherapy.

Single Modification at the N-Terminus of Norvancomycin to Combat Drug-Resistant Gram-Positive Bacteria.

In the arsenal of glycopeptide antibiotics, norvancomycin, which differs from vancomycin by a single methyl group, has received much less attention. Facing the risks of serious antibiotic resistance and even the collapse of last-line defenses, we designed and synthesized 40 novel norvancomycin derivatives to combat the threat. 32 compounds are single N-terminally modified derivatives generated through simple and efficient methods. Diversity at the N-terminus was greatly enriched, mainly by lipophilic attachment and strategies for the introduction of lipo-sulfonium moieties for extensive structure-activity relationship analysis. The first incorporation of a sulfonium moiety into the norvancomycin structure gave rise to compounds that exhibited 4- to 2048-fold higher activity against vancomycin-resistant bacteria VISA and VRE. This N-terminal modification for norvancomycin provides an alternatively useful and promising strategy to restore the antibacterial activity of glycopeptide antibiotics against resistant bacteria, highlighting the same importance of the N-terminal site as well as the vancosamine position, which is worth further study and development.

Newest perspectives of glycopeptide antibiotics: biosynthetic cascades, novel derivatives, and new appealing antimicrobial applications.

Glycopeptide antibiotics (GPAs) are a family of non-ribosomal peptide natural products with polypeptide skeleton characteristics, which are considered the last resort for treating severe infections caused by multidrug-resistant Gram-positive pathogens. Over the past few years, an increasing prevalence of Gram-positive resistant strain "superbugs" has emerged. Therefore, more efforts are needed to study and modify the GPAs to overcome the challenge of superbugs. In this mini-review, we provide an overview of the complex biosynthetic gene clusters (BGCs), the ingenious crosslinking and tailoring modifications, the new GPA derivatives, the discoveries of new natural GPAs, and the new applications of GPAs in antivirus and anti-Gram-negative bacteria. With the development and interdisciplinary integration of synthetic biology, next-generation sequencing (NGS), and artificial intelligence (AI), more GPAs with new chemical structures and action mechanisms will constantly be emerging.

A Dynamic Membrane-Active Glycopeptide for Enhanced Protection of Human Red Blood Cells against Freeze-Stress.

Intracellular delivery of freezing-tolerant trehalose is crucial for cryopreservation of red blood cells (RBCs) and previous strategies based on membrane-disruptive activity usually generate severe hemolysis. Herein, a dynamic membrane-active glycopeptide is developed by grafting with 25% maltotriose and 50% p-benzyl alcohol for the first time to effectively facilitate entry of membrane-impermeable trehalose in human RBCs with low hemolysis. Results of the mechanism acting on cell membranes suggest that reversible adsorption of such benzyl alcohol-grafted glycopeptide on cell surfaces upon weak perturbation with phospholipids and dynamic transition toward membrane stabilization are essential for keeping cellular biofunctions. Furthermore, the functionalized glycopeptide is indicative of typical α-helical/ß-sheet structure-driven regulations of ice crystals during freeze-thaw, thereby strongly promoting efficient cryopreservation. Such all-in-one glycopeptide enables achieving both high cell recovery post-thaw >85% and exceptional cryosurvival >95% in direct freezing protocols. The rationally designed benzyl alcohol-modified glycopeptide permits the development of a competent platform with high generality for protection of blood cells against freeze-stress.

Synthesis of an amphiphilic vancomycin aglycone derivative inspired by polymyxins: overcoming glycopeptide resistance in Gram-positive and Gram-negative bacteria in synergy with teicoplanin in vitro.

Gram-negative bacteria possess intrinsic resistance to glycopeptide antibiotics so these important antibacterial medications are only suitable for the treatment of Gram-positive bacterial infections. At the same time, polymyxins are peptide antibiotics, structurally related to glycopeptides, with remarkable activity against Gram-negative bacteria. With the aim of breaking the intrinsic resistance of Gram-negative bacteria against glycopeptides, a polycationic vancomycin aglycone derivative carrying an n-decanoyl side chain and five aminoethyl groups, which resembles the structure of polymyxins, was prepared. Although the compound by itself was not active against the Gram-negative bacteria tested, it synergized with teicoplanin against Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii, and it was able to potentiate vancomycin against these Gram-negative strains. Moreover, it proved to be active against vancomycin- and teicoplanin-resistant Gram-positive bacteria.

Postexposure Prophylaxis and Treatment of Bacillus anthracis Infections: A Systematic Review and Meta-analyses of Animal Models, 1947-2019.

BACKGROUND: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. METHODS: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. RESULTS: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, ß-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. CONCLUSIONS: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.

Advances in clinical antibiotic testing.

Although the measurement of aminoglycosides and glycopeptides in blood has been well established, it has become evident that therapeutic drug monitoring (TDM) should be extended to other antibiotics such as beta-lactams, daptomycin and linezolid. The use of a TDM guided approach allows reliable assessment of target concentration thus mitigating the risk for toxicity and preventing antibiotic resistance. This is especially relevant for the critically ill in intensive care. Herein we provide an overview on the different antibacterial antibiotics and their target pharmacokinetic/pharmacodynamic indexes in general as well as the importance for TDM of antibacterial antibiotics specifically. Analytical methods applicable to this approach in clinical laboratories are explored and highlighted.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions.

Harnessing highly conserved peptides derived from the receptor binding domain (RBD) of spike (S) protein to construct peptide-based inhibitors is one of the most effective strategies to fight against the ever-mutating coronavirus SARS-CoV-2. But how the O-glycosylation affects their inhibition abilities has not been intensively explored. Herein, an intrinsic O-glycosylated peptide P320-334 derived from RBD was screened and homogeneous O-linked glycopeptides containing Tn (GalNAcα1-O-Ser/Thr), T (Galß1-3GalNAcα1-O-Ser/Thr), sialyl-Tn (sTn, Siaα2-6GalNAcα1-O-Ser/Thr), and sialyl-T (sT, Siaα2-3Galß1-3GalNAcα1-O-Ser/Thr) structures were first synthesized via chemoenzymatic strategies. Compared with the unglycosylated peptide, the binding of sT-P320-334 to hACE2 was enhanced to 133% and the inhibition capacity against RBD-hACE2 binding of sTn- and sT-P320-334 was significantly increased up to 150-410%. Thus, our results suggest the sialic acid residue on the terminal of short O-glycan structures might strengthen the inhibition capacities of these peptide-based inhibitors, which might provide novel optimization directions for the inhibitor design.

Beyond vancomycin: recent advances in the modification, reengineering, production and discovery of improved glycopeptide antibiotics to tackle multidrug-resistant bacteria.

Glycopeptide antibiotics (GPAs), which include vancomycin and teicoplanin, are important last-resort antibiotics used to treat multidrug-resistant Gram-positive bacterial infections. Whilst second-generation GPAs - generated through chemical modification of natural GPAs - have proven successful, the emergence of GPA resistance has underlined the need to develop new members of this compound class. Significant recent advances have been made in GPA research, including gaining an in-depth understanding of their biosynthesis, improving titre in production strains, developing new derivatives via novel chemical modifications and identifying a new mode of action for structurally diverse type-V GPAs. Taken together, these advances demonstrate significant untapped potential for the further development of GPAs to tackle the growing threat of multidrug-resistant bacteria.

ECM-mimetic immunomodulatory hydrogel for methicillin-resistant Staphylococcus aureus-infected chronic skin wound healing.

The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment-responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness diabetic and scalding skin by orchestrating a pro-regenerative response indicated by abundant M2-type macrophages, attenuated inflammation, and promoted angiogenesis. Collectively, ECM-mimetic and immunomodulatory glycopeptide hydrogel is a promising multifunctional dressing to reshape the damaged tissue environment without additional drugs, exogenous cytokines, or cells, providing an effective strategy for the repair and regeneration of chronic cutaneous wounds.

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014-2022.

The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine's capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.

The effect of glucose dynamics on plasma copeptin levels upon glucagon, arginine, and macimorelin stimulation in healthy adults : Data from: Glucacop, Macicop, and CARGO study.

PURPOSE: Non-osmotic stimulation tests using glucagon, arginine, or macimorelin were recently evaluated for their ability to assess posterior pituitary function. Glucagon and arginine, but not macimorelin, stimulated copeptin secretion (a surrogate marker of vasopressin) and, therefore, provide novel tests to assess the posterior pituitary. The exact underlying mechanism behind their stimulatory effect remains elusive. METHODS: This analysis combined data from three diagnostic studies conducted at the University Hospital Basel, Switzerland. In total, 80 healthy adults underwent the glucagon (n = 22), arginine (n = 30), or macimorelin (n = 28) stimulation tests. The primary objective was to investigate glucose course upon glucagon, arginine, and macimorelin stimulation tests and its effect on plasma copeptin release. RESULTS: Upon glucagon stimulation, the median [IQR] glucose level at baseline was 5.0 [4.6, 5.2] mmol/l, peaked at 8.1 [7.2, 9.4] mmol/l after 30 min and decreased to a minimum of 3.8 [3.5, 4.5] mmol/l after 120 min. The median copeptin increase upon glucagon stimulation was 7.7 [2.6, 28.0] pmol/l. Upon arginine, the glucose level at baseline was 4.9 [4.8, 5.5] mmol/l, peaked at 6.0 [5.2, 6.4] mmol/l after 30 min and decreased to a minimum of 4.3 [3.8, 4.8] mmol/l after 60 min. The median copeptin increase upon arginine stimulation was 4.5 [2.9, 7.5] pmol/l. Upon macimorelin, glucose levels showed no notable dynamics over the 120 min, and no major change in copeptin was observed. In the pooled dataset, a decrease in glucose levels was significantly correlated with copeptin increase (ρ = 0.53, p < 0.01). CONCLUSION: A similar course in plasma glucose was observed in the copeptin-stimulating test, i.e., after glucagon and arginine, while macimorelin had no effect on glucose and copeptin levels. We hypothesize that a drop in glucose levels observed upon glucagon and arginine might stimulate copeptin.

Biomimetic glycopeptide hydrogel coated PCL/nHA scaffold for enhanced cranial bone regeneration via macrophage M2 polarization-induced osteo-immunomodulation.

The reconstruction of large cranial bone defects by bioactive materials without exogenous cells or growth factors remains a substantial clinical challenge. Here, synthetic fibrous glycopeptide hydrogel (GRgel) self-assembled by ß-sheet RADA16-grafted glucomannan was designed to mimic the glycoprotein composition and the fibrillar architecture of natural extracellular matrix (ECM), which was non-covalently composited with 3D-printed polycaprolactone/nano hydroxyapatite (PCL/nHA) scaffold for cranial bone regeneration. The glycopeptide hydrogel significantly promoted the proliferation, osteogenic differentiation of bone mesenchymal stem cells (BMSCs), which was further augmented by GRgel-induced macrophage M2-phonotype polarization and the effective M2 macrophage-BMSC crosstalk. The repair of critical-size skull bone defect in rat indicated a superior efficacy of PCL/nHA@GRgel implant on bone regeneration and osseointegration, with an average bone area of 83.3% throughout the defect location at 12 weeks post treatment. Furthermore, the osteo-immunomodulatory GRgel induced a reparative microenvironment similar with that in normal cranium, as characterized by an increased percentage of anti-inflammatory M2 macrophages and osteoblasts, and high-level vascularization. Collectively, the composite scaffold developed here with macrophage polarization-mediated osteo-immunomodulation may represent a promising implant for expediting in situ bone regeneration by providing biochemical and osteoinductive cues at the injured tissue.

New Perspectives on Antimicrobial Agents: Long-Acting Lipoglycopeptides.

The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.

Effects of Lycium barbarum glycopeptide on renal and testicular injury induced by di(2-ethylhexyl) phthalate.

Di(2-ethylhexyl) phthalate (DEHP) is a common environmental pollutant with renal and reproductive toxicity. Lycium barbarum glycopeptide (LbGp) is the main active component of Lycium barbarum, which can protect the kidney and promote reproduction. Autophagy and apoptosis are the regulatory mechanisms of cell adaptation to external stress. This study investigated whether DEHP and LbGp affect kidney and testis by regulating autophagy and apoptosis. DEHP induced apoptosis in human embryonic kidney-293 (HEK-293) cells and human kidney-2 (HK-2) cells, as well as glomerular enlargement, enhanced renal autophagy and inflammation, decreased testicular germ cells, and enhanced testicular autophagy. LbGp reduced apoptosis in HEK-293 cells and HK-2 cells, reduced glomerular enlargement and renal inflammation, enhanced renal autophagy, increased testicular germ cells, and alleviated testicular autophagy. These results suggested that DEHP induced inflammation to cause kidney injury, mildly enhanced renal autophagy, and also induced excessive autophagy, leading to testicular injury. LbGp reduced inflammation and appropriately enhanced autophagy to alleviate renal injury and also reduced excessive autophagy to alleviate testicular injury. Silent information regulator 1 (SIRT1)/forkhead box O3a (FoxO3a)-mediated autophagy and p38 mitogen-activated protein kinase (p38 MAPK)-mediated inflammation played important roles.